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Almansour S, Alsalamah A, Almutlaq M, Sheikh A, Hamdan HZ, Al-Nafeesah A, AlEed A, Adam I, Al-Wutayd O. Association of vitamin D deficiency and insufficiency with uncontrolled type 1 diabetes Mellitus among Saudi pediatric patients; a hospital-based retrospective study. Front Pediatr 2025; 12:1479815. [PMID: 39845452 PMCID: PMC11753226 DOI: 10.3389/fped.2024.1479815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 12/18/2024] [Indexed: 01/24/2025] Open
Abstract
Background The association between 25-hydroxy-vitamin D [25(OH)D] levels and glycemic control in pediatric patients with type 1 diabetes mellitus (T1DM) is unclear. In this study, we aimed to investigate the association between 25(OH)D levels and glycemic control in Saudi pediatric patients' with T1DM in a region that is sunny year-round. Materials and methods A retrospective study was conducted in the Pediatric Department of King Saud Hospital in Unaizah, Saudi Arabia. A total of 218 children with T1DM were enrolled in the study and grouped according to their glycated hemoglobin (HbA1C) levels into the controlled T1DM (HbA1C ≤ 7.5%) and the uncontrolled T1DM (HbA1C > 7.5%). Their 25(OH)D levels and thyroid function were measured using standard methods. Results Of the 218 children in this study, 182 (83.5%) had uncontrolled T1DM, while only 36 (16.5%) had controlled T1DM. The median (interquartile range) of 25(OH)D levels was significantly lower in the uncontrolled T1DM group compared with the controlled group [45.4 (31.2-59.7) nmol/L vs. 56.1 (37.5-77.6) nmol/L; p = 0.007], respectively. Vitamin D deficiency (<50.0 nmol/L) and insufficiency (50-74 nmol/L) were detected in 55.0% and 31.1% of all the enrolled children, respectively. Vitamin D deficiency was detected in 86.6% of the uncontrolled T1DM patients and in 16.5% of the controlled T1DM patients (p = 0.012). The multivariable analysis showed that both vitamin D deficiency [adjusted odds ratio (aOR) = 2.92, p = 0.048] and insufficiency [aOR = 3.17, p = 0.042] were risk factors for uncontrolled diabetes. Conclusion Vitamin D deficiency was highly prevalent in the studied group. Both vitamin D deficiency and insufficiency are associated with uncontrolled T1DM. Further study is needed.
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Affiliation(s)
- Salman Almansour
- Department of Pediatrics, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | | | | | - Ahmed Sheikh
- Diabetic Center, King Saud Hospital, Unaizah, Saudi Arabia
| | - Hamdan Z. Hamdan
- Department of Pathology, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Abdullah Al-Nafeesah
- Department of Pediatrics, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Ashwaq AlEed
- Department of Pediatrics, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Ishag Adam
- Department of Obstetrics and Gynecology, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Osama Al-Wutayd
- Department of Family and Community Medicine, College of Medicine, Qassim University, Buraydah, Saudi Arabia
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Li J, Zhang M, Zhang S, Wang R, Cai Y, Chen X, Dong Y, Wang P, Shu J, Lv L, Cai C. CTSG polymorphisms in Chinese children with type 1 diabetes mellitus. J Trop Pediatr 2024; 70:fmae017. [PMID: 39122654 DOI: 10.1093/tropej/fmae017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/12/2024]
Abstract
Cathepsin G (CTSG) plays an important role in the regulation of immune processes. Accumulated studies show that CTSG is involved in the onset and development of type 1 diabetes mellitus (T1DM). As the genetic background of T1DM varies widely among populations, we aimed to study the relationship between genetic polymorphisms in CTSG and T1DM susceptibility in Chinese populations. A total of 141 patients with T1DM and 200 healthy controls were enrolled in the study. Serum CTSG expression was detected using enzyme-linked immunosorbent assay (ELISA). Genotyping of two selected single nucleotide polymorphisms (SNPs) (rs2236742 and rs2070697) of CTSG was performed using PCR and Sanger sequencing. CTSG expression in patients with T1DM was significantly higher than in the control group. Alleles C and T of CTSG SNP rs2236742 were increased in T1DM. No significant associations were found for the SNP rs2070697. Our results indicate that the CTSG rs2236742 allele (C/T) is associated with T1DM in Chinese children and may serve as a new biomarker for predicting T1DM susceptibility.
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Affiliation(s)
- Jiaci Li
- Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
- Tianjin Pediatric Research Institute, Tianjin, 300074, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, 300074, China
| | - Mingying Zhang
- Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
- Department of Endocrinology, Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
| | - Shuyue Zhang
- Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
- Graduate College of Tianjin Medical University, Tianjin, 300070, China
| | - Rui Wang
- Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
- Graduate College of Tianjin Medical University, Tianjin, 300070, China
| | - Yingzi Cai
- Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
- Medical College of Tianjin University, Tianjin, 300072, China
| | - Xiaofang Chen
- Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
- Graduate College of Tianjin Medical University, Tianjin, 300070, China
| | - Yan Dong
- Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
- Graduate College of Tianjin Medical University, Tianjin, 300070, China
| | - Ping Wang
- Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
- Tianjin Pediatric Research Institute, Tianjin, 300074, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, 300074, China
| | - Jianbo Shu
- Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
- Tianjin Pediatric Research Institute, Tianjin, 300074, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, 300074, China
| | - Ling Lv
- Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
- Department of Endocrinology, Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
| | - Chunquan Cai
- Tianjin Children's Hospital (Children's Hospital, Tianjin University), Tianjin, 300074, China
- Tianjin Pediatric Research Institute, Tianjin, 300074, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, 300074, China
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Kawahara T, Okada Y, Tanaka Y. Vitamin D efficacy in type 1 and type 2 diabetes. J Bone Miner Metab 2024; 42:438-446. [PMID: 38664254 DOI: 10.1007/s00774-024-01509-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 03/19/2024] [Indexed: 09/21/2024]
Abstract
It is well known that vitamin D has a profound effect on calcium and bone metabolism, but its influence on other organs (extraskeletal effect) has been proposed. Consistently, vitamin D deficiency is associated with an increased incidence of various diseases, including type 1 and type 2 diabetes, as reported by many observational studies. However, there has been no consensus on whether vitamin D deficiency is a causative factor in the incidence of diabetes mellitus. There have been no randomized controlled trials (RCTs) aimed at preventing the onset of type 1 diabetes with vitamin D intake. In addition, the results of RCTs evaluating the preventive effect of vitamin D supplementation on type 2 diabetes development have been inconsistent. The recent observational studies, randomized controlled trials, and meta-analyses are confirming that vitamin D or active vitamin D administration is effective in preventing the incident of type 1 and type 2 diabetes.
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Affiliation(s)
- Tetsuya Kawahara
- Devision of Endocrinoloy and Diabetes, Department of Internal Medicine, Shin Komonji Hospital, 2-5 Dairishinmachi, Moji-ku, Kitakyushu, Fukuoka, 800-0057, Japan.
| | - Yosuke Okada
- First Department of Internal Medicine, University of Occupational and Health, Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan
| | - Yoshiya Tanaka
- First Department of Internal Medicine, University of Occupational and Health, Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan
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Thirunavukkarasu R, Chitra A, Asirvatham A, Jayalakshmi M. Association of Vitamin D Deficiency and Vitamin D Receptor Gene Polymorphisms with Type 1 Diabetes Risk: A South Indian Familial Study. J Clin Res Pediatr Endocrinol 2024; 16:21-30. [PMID: 37559366 PMCID: PMC10938518 DOI: 10.4274/jcrpe.galenos.2023.2022-12-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 07/26/2023] [Indexed: 03/12/2024] Open
Abstract
Objective Vitamin D is a potent immune modulator and is associated with autoimmune diseases, including type 1 diabetes (T1D). The vitamin D levels and its receptor gene polymorphisms together in T1D are not yet investigated in the South Indian population. The present study focused on exploring the significance of vitamin D levels and vitamin D receptor (VDR) gene polymorphisms with the risk of developing T1D in the South Indian population. Methods Patients with T1D and unaffected first-degree relatives (FDRs) were included in this study. Genotyping of VDR polymorphisms at four different loci (FokI- F/f, BsmI- B/b, TaqI- T/t, and ApaI- A/a) was assessed through the amplification refractive mutation system-polymerase chain reaction method. Serum vitamin D levels were measured in 98 T1D patients and 75 age- and sex-matched siblings. Results A total of 120 patients with T1D and 214 FDRs were included. Vitamin D deficiency (VDD) was observed in a higher proportion of T1D patients than in controls (52% vs. 32%; p<0.03). The frequency of the FokI-FF genotype was significantly higher [odds ratio (OR)=1.66; p<0.03] in T1D patients conferring a susceptible association with the disease. Nevertheless, the increased frequency of heterozygous Ff genotype (OR=0.57; p<0.02) among controls may confer a protective association with T1D. Furthermore, the transmission disequilibrium test revealed over-transmission of ApaI-A (T: U=15/5; p<0.006) and BsmI-B alleles (T: U=17/5; p<0.01) and under-transmission of BsmI-b/ApaI-a/TaqI-T haplotype (T: U=5.4/14.4; p=0.04) from parents to T1D patients. Conclusion The present study concludes that VDD is the major contributing risk factor to T1D development in the South Indian population. Furthermore, the FokI-FF genotype, BsmI-B, and ApaI-A alleles were positively associated with T1D. In contrast, the FokI-Ff genotype and BsmI-b/ApaI-a/TaqI-T haplotype were negatively associated with T1D.
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Affiliation(s)
| | - Ayyappan Chitra
- Government Rajaji Hospital, Institute of Child Health and Research Centre, Madurai, India
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Tsang HW, Tung KTS, Wong RS, Wong SY, Tung JYL, Chua GT, Ho MHK, Pang CP, Wong WHS, Chan GCF, Wong ICK, Ip P. Association of vitamin D-binding protein polymorphisms and serum 25(OH)D concentration varies among Chinese healthy infants of different VDR-FokI genotypes: A multi-centre cross-sectional study. NUTR BULL 2024; 49:63-72. [PMID: 38146611 DOI: 10.1111/nbu.12656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 11/03/2023] [Accepted: 12/05/2023] [Indexed: 12/27/2023]
Abstract
Hypovitaminosis D during infancy is associated with the development of chronic diseases and poor health later in life. While the effect of environmental factors on vitamin D concentration has been extensively explored, this study aimed to explore the effect of genetic factors on vitamin D concentration among Chinese infants. We conducted a multi-centre cross-sectional study in Hong Kong from July 2019 to May 2021. A candidate genetic approach was adopted to study four selected genetic variants of the vitamin D-binding protein (DBP) and vitamin D receptor (VDR) (rs4588, rs7041, rs2282679 and rs2228570) to examine their associations with measured serum 25(OH)D concentration. A total of 378 Chinese infants aged 2-12 months were recruited in this study. Peripheral blood samples were collected from the infants to measure serum 25(OH)D concentration and extract DNA. Results showed that rs7041T and rs2282679C were significantly associated with lower serum 25(OH)D concentration. Further analysis of the DBP variants revealed that the GC1F allele was significantly associated with lower 25(OH)D concentration and identified as the risk DBP isoform in infants. While our results revealed that there is no direct association between VDR-FokI genotype and serum 25(OH)D concentration, a VDR-FokI genotype-specific pattern was observed in the association between DBP isoforms and serum 25(OH)D concentration. Specifically, significant associations were observed in the DBP genotypes GC1F/F, GC1F/2 and GC1S/2 among VDR-FokI TT/TC carriers, but not in VDR-FokI CC carriers. Our findings lay down the basis for the potential of genetic screening to identify high risk of hypovitaminosis D in Chinese infants.
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Affiliation(s)
- Hing Wai Tsang
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Keith T S Tung
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Rosa S Wong
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Siew Yan Wong
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Joanna Y L Tung
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Department of Paediatrics, Hong Kong Children's Hospital, Hospital Authority, Hong Kong SAR, China
| | - Gilbert T Chua
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Marco H K Ho
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Chi Pui Pang
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Wilfred H S Wong
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Godfrey C F Chan
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ian C K Wong
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Patrick Ip
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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Liu J, Qin L, Zheng J, Tong L, Lu W, Lu C, Sun J, Fan B, Wang F. Research Progress on the Relationship between Vitamins and Diabetes: Systematic Review. Int J Mol Sci 2023; 24:16371. [PMID: 38003557 PMCID: PMC10671335 DOI: 10.3390/ijms242216371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/27/2023] [Accepted: 11/12/2023] [Indexed: 11/26/2023] Open
Abstract
Diabetes is a serious chronic metabolic disease that causes complications over time, bringing serious public health challenges that affect different countries across the world. The current clinical drugs for diabetes may lead to adverse effects such as hypoglycemia and liver and abdominal distension and pain, which prompt people to explore new treatments for diabetes without side effects. The research objective of this review article is to systematically review studies on vitamins and diabetes and to explain their possible mechanism of action, as well as to assess the role of vitamins as drugs for the prevention and treatment of diabetes. To achieve our objective, we searched scientific databases in PubMed Central, Medline databases and Web of Science for articles, using "vitamin" and "diabetes" as key words. The results of numerous scientific investigations revealed that vitamin levels were decreased in humans and animals with diabetes, and vitamins show promise for the prevention and/or control of diabetes through anti-inflammation, antioxidation and the regulation of lipid metabolism. However, a few studies showed that vitamins had no positive effect on the development of diabetes. Currently, studies on vitamins in the treatment of diabetes are still very limited, and there are no clinical data to clarify the dose-effect relationship between vitamins and diabetes; therefore, vitamins are not recommended as routine drugs for the treatment of diabetes. However, we still emphasize the great potential of vitamins in the prevention and treatment of diabetes, and higher quality studies are needed in the future to reveal the role of vitamins in the development of diabetes.
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Affiliation(s)
| | | | | | | | | | | | | | - Bei Fan
- Key Laboratory of Agro-Products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Fengzhong Wang
- Key Laboratory of Agro-Products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China
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Eleftheriou A, Ong KK, Hughes IA, Petry CJ. Leptin and IGF-1 in Infancy Are Associated With Variants in DHCR7 and CYP2R1 That Relate With Type 1 Diabetes and 25OHD. J Clin Endocrinol Metab 2023; 108:e1394-e1402. [PMID: 37170809 PMCID: PMC10584008 DOI: 10.1210/clinem/dgad263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 05/04/2023] [Accepted: 05/08/2023] [Indexed: 05/13/2023]
Abstract
CONTEXT Vitamin D has been variably implicated in risk of developing type 1 diabetes based on cohorts of at-risk individuals. Emergent type 1 diabetes in childhood is putatively preceded by altered growth. OBJECTIVE We explored whether polymorphisms in vitamin D metabolism genes modify risk of type 1 diabetes via effects on growth in a prospective, population-based cohort of infants. METHODS The Cambridge Baby Growth Study enrolled newborns from Cambridgeshire, UK, for follow-up in infancy. In 612 infants, we genotyped single nucleotide polymorphisms in vitamin D metabolism genes that relate with type 1 diabetes: rs10741657 and rs12794714 in CYP2R1, rs12785878 in DHCR7, and rs10877012 in CYP27B1. Multivariate linear regression analyses tested associations between genotypes and anthropometric indices (weight, length, and skinfold thickness) or growth-related hormones (C-peptide, IGF-1, and leptin) in infancy. RESULTS Birth weight showed borderline associations with the diabetes risk-increasing alleles in CYP2R1, rs10741657 (β = -.11, P = .02) and rs12794714 (β = -.09, P = .04). The risk-increasing allele rs12794714 was also associated with higher IGF-1 levels at age 24 months (β = .30, P = .01). At age 3 months, the risk-increasing allele rs12785878 in DHCR7, known to negatively associate with 25-hydroxyvitamin D levels, showed a positive association with leptin levels (β = .23, P = .009), which was pronounced in girls (P = .004) vs boys (P = .7). CONCLUSION The vitamin D metabolism genes DHCR7 and CYP2R1 might influence infancy leptin and IGF-1 levels respectively. These findings open the possibility for a developmental role of vitamin D that is mediated by growth-related hormones with implications for the onset of type 1 diabetes autoimmunity.
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Affiliation(s)
| | - Ken K Ong
- Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK
- MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
- Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Ieuan A Hughes
- Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Clive J Petry
- Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK
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Daryabor G, Gholijani N, Kahmini FR. A review of the critical role of vitamin D axis on the immune system. Exp Mol Pathol 2023; 132-133:104866. [PMID: 37572961 DOI: 10.1016/j.yexmp.2023.104866] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 08/05/2023] [Accepted: 08/08/2023] [Indexed: 08/14/2023]
Abstract
In recent years, the physiological and molecular functions of vitamin D (Vit-D) have been deeply investigated. At first, Vit-D was considered a regulator of mineral and skeletal homeostasis. However, due to the extensive-expression pattern of Vit-D receptor (VDR) in almost every non-skeletal cell, Vit-D is considered mainly a multifunctional agent with broad effects on various tissues, notably the immune system. The expression of VDR in immune cells such as dendritic cells, monocyte/macrophage, neutrophils, B cells and T cells has been well demonstrated. Besides, such immune cells are capable of metabolizing the active form of Vit-D which means that it can module the immune system in both paracrine and autocrine manners. Vit-D binding protein (DBP), that regulates the levels and homeostasis of Vit-D, is another key molecule capable of modulating the immune system. Recent studies indicate that dysregulation of Vit-D axis, variations in the DBP and VDR genes, and Vit-D levels might be risk factors for the development of autoimmune disease. Here, the current evidence regarding the role of Vit-D axis on the immune system, as well as its role in the development of autoimmune disease will be clarified. Further insight will be given to those studies that investigated the association between single nucleotide polymorphisms of DBP and VDR genes with autoimmune disease susceptibility.
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Affiliation(s)
- Gholamreza Daryabor
- Autoimmune Diseases Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nasser Gholijani
- Autoimmune Diseases Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Rezaei Kahmini
- Autoimmune Diseases Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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Ghaseminejad-Raeini A, Ghaderi A, Sharafi A, Nematollahi-Sani B, Moossavi M, Derakhshani A, Sarab GA. Immunomodulatory actions of vitamin D in various immune-related disorders: a comprehensive review. Front Immunol 2023; 14:950465. [PMID: 37520529 PMCID: PMC10379649 DOI: 10.3389/fimmu.2023.950465] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 06/27/2023] [Indexed: 08/01/2023] Open
Abstract
For many years, vitamin D has been acknowledged for its role in maintaining calcium and phosphate balance. However, in recent years, research has assessed its immunomodulatory role and come up with conflicting conclusions. Because the vitamin D receptor is expressed in a variety of immune cell types, study into the precise role of this molecule in diseases, notably autoimmune disorders, has been made possible. The physiologically activated version of vitamin D also promotes a tolerogenic immunological condition in addition to modulating innate and acquired immune cell responses. According to a number of recent studies, this important micronutrient plays a complex role in numerous biochemical pathways in the immune system and disorders that are associated with them. Research in this field is still relatively new, and some studies claim that patients with severe autoimmune illnesses frequently have vitamin D deficiencies or insufficiencies. This review seeks to clarify the most recent research on vitamin D's immune system-related roles, including the pathophysiology of major disorders.
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Affiliation(s)
| | - Ali Ghaderi
- Students Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirmohammad Sharafi
- Students Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Maryam Moossavi
- Nanobiology and Nanomedicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Afshin Derakhshani
- Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Gholamreza Anani Sarab
- Cellular and Molecular Research Committee, Birjand University of Medical Sciences, Birjand, Iran
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Abouzid M, Karaźniewicz-Łada M, Abdelazeem B, Brašić JR. Research Trends of Vitamin D Metabolism Gene Polymorphisms Based on a Bibliometric Investigation. Genes (Basel) 2023; 14:215. [PMID: 36672957 PMCID: PMC9859253 DOI: 10.3390/genes14010215] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/05/2023] [Accepted: 01/11/2023] [Indexed: 01/19/2023] Open
Abstract
Vitamin D requires activation to show its pharmacological effect. While most studies investigate the association between vitamin D and disease, only a few focus on the impact of vitamin D metabolism gene polymorphisms (vitDMGPs). This bibliometric study aims to provide an overview of current publications on vitDMGPs (CYP27B1, CYP24A1, CYP2R1, CYP27A1, CYP2R1, DHCR7/NADSYN1), compare them across countries, affiliations, and journals, and inspect keywords, co-citations, and citation bursts to identify trends in this research field. CiteSpace© (version 6.1.R3, Chaomei Chen), Bibliometrix© (R version 4.1.3 library, K-Synth Srl, University of Naples Federico II, Naples, Italy), VOSviewer© (version 1.6.1, Nees Jan van Eck and Ludo Waltman, Leiden University, Leiden, Netherlands) and Microsoft® Excel 365 (Microsoft, Redmond, Washington, USA) classified and summarized Web of Science articles from 1998 to November 2022. We analyzed 2496 articles and built a timeline of co-citations and a bibliometric keywords co-occurrence map. The annual growth rate of vitDMGPs publications was 18.68%, and their relative research interest and published papers were increasing. The United States of America leads vitDMGPs research. The University of California System attained the highest quality of vitDMGPs research, followed by the American National Institutes of Health and Harvard University. The three productive journals on vitDMGPs papers are J. Steroid. Biochem. Mol. Biol., PLOS ONE, and J. Clin. Endocrinol. Metab. We highlighted that the vitDMGPs domain is relatively new, and many novel research opportunities are available, especially those related to studying single nucleotide polymorphisms or markers in a specific gene in the vitamin D metabolism cycle and their association with disease. Genome-wide association studies, genetic variants of vitDMGPs, and vitamin D and its role in cancer risk were the most popular studies. CYP24A1 and CYB27A1 were the most-studied genes in vitDMGPs. Insulin was the longest-trending studied hormone associated with vitDMGPs. Trending topics in this field relate to bile acid metabolism, transcriptome and gene expression, biomarkers, single nucleotide polymorphism, and fibroblast growth factor 23. We also expect an increase in original research papers investigating the association between vitDMGPs and coronavirus disease 2019, hypercalcemia, Smith-Lemli-Opitz syndrome, 27-hydroxycholesterol, and mendelian randomization. These findings will provide the foundations for innovations in the diagnosis and treatment of a vast spectrum of conditions.
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Affiliation(s)
- Mohamed Abouzid
- Department of Physical Pharmacy and Pharmacokinetics, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3 St., 60-806 Poznan, Poland
- Doctoral School, Poznan University of Medical Sciences, 60-812 Poznan, Poland
| | - Marta Karaźniewicz-Łada
- Department of Physical Pharmacy and Pharmacokinetics, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3 St., 60-806 Poznan, Poland
| | - Basel Abdelazeem
- Department of Internal Medicine, McLaren Health Care, Flint, MI 48532, USA
- Department of Internal Medicine, Michigan State University, East Lansing, MI 48823, USA
| | - James Robert Brašić
- Section of High Resolution Brain Positron Emission Tomography Imaging, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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11
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Vitamin D Repletion and AA/EPA Intake in Children with Type 1 Diabetes: Influences on Metabolic Status. Nutrients 2022; 14:nu14214603. [PMID: 36364863 PMCID: PMC9655859 DOI: 10.3390/nu14214603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/21/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022] Open
Abstract
Our study aimed to show a relationship between metabolic control, vitamin D status (25OHD), and arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio in children with type 1 diabetes (T1D). The secondary aim was to evaluate dietary intake and the presence of ketoacidosis (DKA) at the onset of T1D. Methods: A cohort of 40 children with T1D was recruited, mean age 9.7 years (7.1; 13), with onset of T1D in the last 5 years: some at onset (n: 20, group A) and others after 18.0 ± 5 months (n: 20; group B). Twenty healthy children were compared as control subjects (CS). Dietary intakes were assessed through a diary food frequency questionnaire. Moreover, dried blood spots were used to test AA/EPA ratio by gas chromatography. Results: T1D children had a lower percentage of sugar intake (p < 0.02) than CS. Furthermore, group B introduced a greater amount of AA with the diet (g/day; p < 0.05) than CS (p < 0.01) and group A (p < 0.01). Children with an AA/EPA ratio ≤ 22.5 (1st quartile) required a lower insulin demand and had higher 25OHD levels than those who were in the higher quartiles (p < 0.05). Subjects with DKA (9/40) had levels of 25OHD (p < 0.05) and C-peptide (p < 0.05) lower than those without DKA. Moreover, analyzing the food questionnaire in group A, subjects with DKA showed a lower intake of proteins, sugars, fiber (g/day; p< 0.05), vitamin D, EPA, and DHA (g/day; p < 0.01) compared to subjects without DKA. Non-linear associations between vitamin D intake (p < 0.0001; r2:0.580) and linear between EPA intake and C-peptide (p < 0.05; r: 0.375) were found in all subjects. Conclusions: The study shows a relationship between vitamin D status, AA/EPA ratio, and metabolic state, probably due to their inflammatory and immune mechanisms. A different bromatological composition of the diet could impact the severity of the onset.
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Cave EM, Bhola S, Crowther NJ, Padoa CJ. The association of vitamin D binding protein levels and genotypes with type 1 diabetes in the black South African population. BMC Endocr Disord 2022; 22:182. [PMID: 35843941 PMCID: PMC9290305 DOI: 10.1186/s12902-022-01097-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 07/04/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Vitamin D deficiency and the vitamin D pathway have previously been associated with type 1 diabetes (T1D). The majority of vitamin D is transported through the blood bound to the vitamin D binding protein (VDBP). Two polymorphisms in the VDBP gene (rs4588 and rs7041) result in different VDBP variants and have been associated with T1D, however the results are not consistent. The association of VDBP levels and its polymorphisms with T1D have not been investigated in the black South African population. Therefore, this study aimed to determine whether rs4588, rs7041 or serum VDBP levels were associated with T1D in this population. METHODS Participants with type 1 diabetes and controls were recruited from the greater Johannesburg area, South Africa. Participants were genotyped for rs4588 and rs7041 using PCR-RFLP and serum VDBP levels were determined by ELISA. RESULTS There was no difference in VDBP allelic or genotypic frequencies between participants with T1D and controls (rs4588 C allele frequency 0.92 vs. 0.94; p = 0.390 and rs7041 T allele frequency 0.95 vs. 0.95; p = 0.890). In univariate analysis, the rs4588 CC genotype was associated with increased serum VDBP levels, however, this association was lost with multivariate analysis. The VDBP genotypes were not associated with any other study variables. In logistic regression analysis, higher VBDP levels were associated with T1D (OR: (95% CI): 6.58 (1.45-29.9); p = 0.015), and within a linear regression analysis, T1D disease status was found to be associated with 0.044 mg/ml higher VDBP levels (p = 0.028). CONCLUSIONS These data suggest that serum VDBP levels are positively associated with the presence of T1D in the African population. Whether VDBP lies in the causal pathway or its elevation is an effect of T1D is uncertain and requires further investigation.
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Affiliation(s)
- Eleanor M Cave
- Department of Chemical Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Sureka Bhola
- Department of Chemical Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Chemical Pathology, National Health Laboratory Service, Johannesburg, South Africa
| | - Nigel J Crowther
- Department of Chemical Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Chemical Pathology, National Health Laboratory Service, Johannesburg, South Africa
| | - Carolyn J Padoa
- Department of Chemical Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
- Department of Chemical Pathology, National Health Laboratory Service, Johannesburg, South Africa.
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13
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Alathari BE, Nyakotey DA, Bawah AM, Lovegrove JA, Annan RA, Ellahi B, Vimaleswaran KS. Interactions between Vitamin D Genetic Risk and Dietary Factors on Metabolic Disease-Related Outcomes in Ghanaian Adults. Nutrients 2022; 14:2763. [PMID: 35807945 PMCID: PMC9269445 DOI: 10.3390/nu14132763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 06/22/2022] [Accepted: 06/27/2022] [Indexed: 11/16/2022] Open
Abstract
The Ghanaian population is experiencing an upsurge in obesity and type 2 diabetes (T2D) due to rapid urbanization. Besides dietary factors, vitamin D-related genetic determinants have also been shown to contribute to the development of obesity and T2D. Hence, we aimed to examine the interactions between dietary factors and vitamin D-related genetic variants on obesity and T2D related outcomes in a Ghanaian population. Three hundred and two healthy Ghanaian adults (25-60 years old) from Oforikrom, Municipality in Kumasi, Ghana were randomly recruited and had genetic tests, dietary consumption analysis, and anthropometric and biochemical measurements of glucose, HbA1c, insulin, cholesterol, and triglycerides taken. A significant interaction was identified between vitamin D-GRS and fiber intake (g/day) on BMI (pinteraction = 0.020) where those who were consuming low fiber (≤16.19 g/d) and carrying more than two risk alleles for vitamin D deficiency (p = 0.01) had a significantly higher BMI. In addition, an interaction between vitamin D-GRS and fat intake (g/day) on HbA1c (total fat, pinteraction = 0.029) was found, where participants who had a lower total fat intake (≤36.5 g/d), despite carrying more than two risk alleles, had significantly lower HbA1c (p = 0.049). In summary, our study has identified novel gene-diet interactions of vitamin D-GRS with dietary fiber and fat intakes on metabolic traits in Ghanaian adults.
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Affiliation(s)
- Buthaina E. Alathari
- Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, Harry Nursten Building, Pepper Lane, University of Reading, Reading RG6 6DZ, UK; (B.E.A.); (J.A.L.)
- Department of Food Science and Nutrition, Faculty of Health Sciences, The Public Authority for Applied Education and Training, P.O. Box 14281, AlFaiha 72853, Kuwait
| | - David A. Nyakotey
- Department of Biochemistry and Biotechnology, College of Science, Kwame Nkrumah University of Science and Technology, Accra Road, Kumasi GH233, Ghana; (D.A.N.); (A.-M.B.); (R.A.A.)
- Liggins Institute, University of Auckland, 85 Park Road, Grafton, Auckland 1023, New Zealand
| | - Abdul-Malik Bawah
- Department of Biochemistry and Biotechnology, College of Science, Kwame Nkrumah University of Science and Technology, Accra Road, Kumasi GH233, Ghana; (D.A.N.); (A.-M.B.); (R.A.A.)
| | - Julie A. Lovegrove
- Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, Harry Nursten Building, Pepper Lane, University of Reading, Reading RG6 6DZ, UK; (B.E.A.); (J.A.L.)
- Institute of Cardiovascular and Metabolic Research, Harry Nursten Building, Pepper Lane, University of Reading, Reading RG6 6DZ, UK
| | - Reginald A. Annan
- Department of Biochemistry and Biotechnology, College of Science, Kwame Nkrumah University of Science and Technology, Accra Road, Kumasi GH233, Ghana; (D.A.N.); (A.-M.B.); (R.A.A.)
| | - Basma Ellahi
- Faculty of Health and Social Care, University of Chester, Riverside Campus, Chester CH1 4BJ, UK;
| | - Karani S. Vimaleswaran
- Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, Harry Nursten Building, Pepper Lane, University of Reading, Reading RG6 6DZ, UK; (B.E.A.); (J.A.L.)
- Institute of Cardiovascular and Metabolic Research, Harry Nursten Building, Pepper Lane, University of Reading, Reading RG6 6DZ, UK
- Institute for Food, Nutrition and Health, University of Reading, Reading RG6 6AH, UK
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14
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Berretta M, Quagliariello V, Bignucolo A, Facchini S, Maurea N, Di Francia R, Fiorica F, Sharifi S, Bressan S, Richter SN, Camozzi V, Rinaldi L, Scaroni C, Montopoli M. The Multiple Effects of Vitamin D against Chronic Diseases: From Reduction of Lipid Peroxidation to Updated Evidence from Clinical Studies. Antioxidants (Basel) 2022; 11:1090. [PMID: 35739987 PMCID: PMC9220017 DOI: 10.3390/antiox11061090] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/27/2022] [Accepted: 05/28/2022] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Vitamin D exerts multiple beneficial effects in humans, including neuronal, immune, and bone homeostasis and the regulation of cardiovascular functions. Recent studies correlate vitamin D with cancer cell growth and survival, but meta-analyses on this topic are often not consistent. METHODS A systematic search of the PubMed database and the Clinical Trial Register was performed to identify all potentially relevant English-language scientific papers containing original research articles on the effects of vitamin D on human health. RESULTS In this review, we analyzed the antioxidant and anti-inflammatory effects of vitamin D against acute and chronic diseases, focusing particularly on cancer, immune-related diseases, cardiomyophaties (including heart failure, cardiac arrhythmias, and atherosclerosis) and infectious diseases. CONCLUSIONS Vitamin D significantly reduces the pro-oxidant systemic and tissue biomarkers involved in the development, progression, and recurrence of chronic cardiometabolic disease and cancer. The overall picture of this review provides the basis for new randomized controlled trials of oral vitamin D supplementation in patients with cancer and infectious, neurodegenerative, and cardiovascular diseases aimed at reducing risk factors for disease recurrence and improving quality of life.
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Affiliation(s)
- Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy
| | - Vincenzo Quagliariello
- Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80121 Naples, Italy; (V.Q.); (N.M.)
| | - Alessia Bignucolo
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano, Italy;
| | - Sergio Facchini
- Oncology Operative Unit, Santa Maria delle Grazie Hospital, 80078 Naples, Italy;
| | - Nicola Maurea
- Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80121 Naples, Italy; (V.Q.); (N.M.)
| | - Raffaele Di Francia
- Gruppo Oncologico Ricercatori Italiani, GORI Onlus, 33170 Pordenone, Italy;
- Italian Association of Pharmacogenomics and Molecular Diagnostics (IAPharmagen), 60126 Ancona, Italy
| | - Francesco Fiorica
- Department of Radiation Oncology and Nuclear Medicine, AULSS 9 Scaligera, 37100 Verona, Italy;
| | - Saman Sharifi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padova, Italy; (S.S.); (S.B.); (M.M.)
| | - Silvia Bressan
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padova, Italy; (S.S.); (S.B.); (M.M.)
- Veneto Institute of Molecular Medicine, 35129 Padova, Italy
| | - Sara N. Richter
- Department of Molecular Medicine, University of Padova, Via A. Gabelli 63, 35121 Padova, Italy; (S.N.R.); (C.S.)
| | - Valentina Camozzi
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy;
| | - Luca Rinaldi
- Department of Advanced Medical and Surgery Sciences, Internal Medicine COVID Center, University of Campania Luigi Vanvitelli, 81100 Naples, Italy;
| | - Carla Scaroni
- Department of Molecular Medicine, University of Padova, Via A. Gabelli 63, 35121 Padova, Italy; (S.N.R.); (C.S.)
| | - Monica Montopoli
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padova, Italy; (S.S.); (S.B.); (M.M.)
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15
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Chan HN, Zhang XJ, Ling XT, Bui CHT, Wang YM, Ip P, Chu WK, Chen LJ, Tham CC, Yam JC, Pang CP. Vitamin D and Ocular Diseases: A Systematic Review. Int J Mol Sci 2022; 23:ijms23084226. [PMID: 35457041 PMCID: PMC9032397 DOI: 10.3390/ijms23084226] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/01/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
The contributory roles of vitamin D in ocular and visual health have long been discussed, with numerous studies pointing to the adverse effects of vitamin D deficiency. In this paper, we provide a systematic review of recent findings on the association between vitamin D and different ocular diseases, including myopia, age-related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), dry eye syndrome (DES), thyroid eye disease (TED), uveitis, retinoblastoma (RB), cataract, and others, from epidemiological, clinical and basic studies, and briefly discuss vitamin D metabolism in the eye. We searched two research databases for articles examining the association between vitamin D deficiency and different ocular diseases. One hundred and sixty-two studies were found. There is evidence on the association between vitamin D and myopia, AMD, DR, and DES. Overall, 17 out of 27 studies reported an association between vitamin D and AMD, while 48 out of 54 studies reported that vitamin D was associated with DR, and 25 out of 27 studies reported an association between vitamin D and DES. However, the available evidence for the association with other ocular diseases, such as glaucoma, TED, and RB, remains limited.
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Affiliation(s)
- Hei-Nga Chan
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; (H.-N.C.); (X.-J.Z.); (X.-T.L.); (C.H.-T.B.); (Y.-M.W.); (W.-K.C.); (L.-J.C.); (C.C.T.)
| | - Xiu-Juan Zhang
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; (H.-N.C.); (X.-J.Z.); (X.-T.L.); (C.H.-T.B.); (Y.-M.W.); (W.-K.C.); (L.-J.C.); (C.C.T.)
| | - Xiang-Tian Ling
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; (H.-N.C.); (X.-J.Z.); (X.-T.L.); (C.H.-T.B.); (Y.-M.W.); (W.-K.C.); (L.-J.C.); (C.C.T.)
| | - Christine Huyen-Trang Bui
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; (H.-N.C.); (X.-J.Z.); (X.-T.L.); (C.H.-T.B.); (Y.-M.W.); (W.-K.C.); (L.-J.C.); (C.C.T.)
| | - Yu-Meng Wang
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; (H.-N.C.); (X.-J.Z.); (X.-T.L.); (C.H.-T.B.); (Y.-M.W.); (W.-K.C.); (L.-J.C.); (C.C.T.)
| | - Patrick Ip
- Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, China;
| | - Wai-Kit Chu
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; (H.-N.C.); (X.-J.Z.); (X.-T.L.); (C.H.-T.B.); (Y.-M.W.); (W.-K.C.); (L.-J.C.); (C.C.T.)
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
| | - Li-Jia Chen
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; (H.-N.C.); (X.-J.Z.); (X.-T.L.); (C.H.-T.B.); (Y.-M.W.); (W.-K.C.); (L.-J.C.); (C.C.T.)
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
- Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China
| | - Clement C. Tham
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; (H.-N.C.); (X.-J.Z.); (X.-T.L.); (C.H.-T.B.); (Y.-M.W.); (W.-K.C.); (L.-J.C.); (C.C.T.)
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
- Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China
- Department of Ophthalmology, Hong Kong Children’s Hospital, Hong Kong, China
- Hong Kong Eye Hospital, Hong Kong, China
| | - Jason C. Yam
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; (H.-N.C.); (X.-J.Z.); (X.-T.L.); (C.H.-T.B.); (Y.-M.W.); (W.-K.C.); (L.-J.C.); (C.C.T.)
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
- Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China
- Department of Ophthalmology, Hong Kong Children’s Hospital, Hong Kong, China
- Hong Kong Eye Hospital, Hong Kong, China
- Correspondence: (J.C.Y.); (C.-P.P.)
| | - Chi-Pui Pang
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; (H.-N.C.); (X.-J.Z.); (X.-T.L.); (C.H.-T.B.); (Y.-M.W.); (W.-K.C.); (L.-J.C.); (C.C.T.)
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
- Correspondence: (J.C.Y.); (C.-P.P.)
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16
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Nanotechnology in Immunotherapy for Type 1 Diabetes: Promising Innovations and Future Advances. Pharmaceutics 2022; 14:pharmaceutics14030644. [PMID: 35336018 PMCID: PMC8955746 DOI: 10.3390/pharmaceutics14030644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 03/05/2022] [Accepted: 03/08/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetes is a chronic condition which affects the glucose metabolism in the body. In lieu of any clinical “cure,” the condition is managed through the administration of pharmacological aids, insulin supplements, diet restrictions, exercise, and the like. The conventional clinical prescriptions are limited by their life-long dependency and diminished potency, which in turn hinder the patient’s recovery. This necessitated an alteration in approach and has instigated several investigations into other strategies. As Type 1 diabetes (T1D) is known to be an autoimmune disorder, targeting the immune system in activation and/or suppression has shown promise in reducing beta cell loss and improving insulin levels in response to hyperglycemia. Another strategy currently being explored is the use of nanoparticles in the delivery of immunomodulators, insulin, or engineered vaccines to endogenous immune cells. Nanoparticle-assisted targeting of immune cells holds substantial potential for enhanced patient care within T1D clinical settings. Herein, we summarize the knowledge of etiology, clinical scenarios, and the current state of nanoparticle-based immunotherapeutic approaches for Type 1 diabetes. We also discuss the feasibility of translating this approach to clinical practice.
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17
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Sunlight, dietary habits, genetic polymorphisms and vitamin D deficiency in urban and rural infants of Bangladesh. Sci Rep 2022; 12:3623. [PMID: 35256680 PMCID: PMC8901932 DOI: 10.1038/s41598-022-07661-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 02/16/2022] [Indexed: 12/26/2022] Open
Abstract
We conducted an observational study to assess the prevalence and risk factors of vitamin D deficiency in 12–24 months old children living in urban and rural Bangladesh. Serum 25-hydroxyvitamin D (free 25(OH)D) level, socio-demographic status, anthropometric status, dietary intake, exposure to sunlight and single nucleotide polymorphisms in vitamin-D pathway genes were measured in 208 children. Vitamin D deficiency (free 25(OH)D < 50 nmol/l) was reported in 47% of the children. Multivariable logistic regression model identified duration to sunlight exposure (regression coefficient, β = − 0.01; 95% CI 0.00, − 0.02; p-value < 0.05), UV index (β = − 0.36; 95% CI 0.00, − 0.02; p-value < 0.05) and breast-feeding (β = − 1.15; 95% CI − 0.43, − 1.86; p-value < 0.05) to be negatively associated with vitamin D deficiency. We measured the role of single nucleotide polymorphisms in pathway genes (GC-rs7041 T > G, rs4588 C > A, CYP2R1-rs206793 A > G, CYP27B1-rs10877012 A > C and DHCR7-rs12785878 G > T) and found statistically significant differences in serum vitamin D levels between various genotypes. SNPs for CYP27B1 (CA & CC genotype) had statistically significant positive association (β = 1.61; 95% CI 2.79, 0.42; p-value < 0.05) and TT genotype of GC-rs7041 had negative association (β = − 1.33; 95% CI − 0.02, − 2.64; p-value < 0.05) with vitamin-D deficiency in the surveyed children.
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18
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He LP, Song YX, Zhu T, Gu W, Liu CW. Progress in the Relationship between Vitamin D Deficiency and the Incidence of Type 1 Diabetes Mellitus in Children. J Diabetes Res 2022; 2022:5953562. [PMID: 36090587 PMCID: PMC9463035 DOI: 10.1155/2022/5953562] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/03/2022] [Accepted: 08/12/2022] [Indexed: 11/24/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disease, due to a large number of islet β cells damaged, resulting in an absolute lack of insulin, ultimately relying on insulin therapy. Vitamin D is a fat-soluble sterol derivative that not only participates in calcium and phosphorus metabolism but also acts as an immunomodulatory role by binding to nuclear vitamin D receptors to regulate the expression of transcription factors. Increasing evidence has shown that vitamin D has immunoregulation and anti-inflammatory effects, and it may play a role in T cell regulatory responses due to downregulation in the expression of cathepsin G and inhibition of CD4+ T cell activation and protection of β cells from immune attack and is beneficial in decreasing oxidative stress in T1DM patients. Epidemiologic evidence demonstrates involvement of vitamin D deficiency in T1DM pathogenesis, with the immune system improperly targeting and destroying its own islet β cells. In addition, polymorphisms in genes critical for vitamin D metabolism may increase the risk of islet autoimmunity and T1DM. In this paper, the relationship between vitamin D deficiency and the molecular mechanism of T1DM was discussed.
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Affiliation(s)
- Lian-Ping He
- School of Medicine, Taizhou University, Jiaojiang, 318000 Zhejiang, China
| | - Yu-Xin Song
- School of Medicine, Taizhou University, Jiaojiang, 318000 Zhejiang, China
| | - Ting Zhu
- Children's Hospital of Nanjing Medical University, Nanjing, 210008 Jiangsu, China
| | - Wei Gu
- Children's Hospital of Nanjing Medical University, Nanjing, 210008 Jiangsu, China
| | - Chang-Wei Liu
- Children's Hospital of Nanjing Medical University, Nanjing, 210008 Jiangsu, China
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19
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Chen X, Fu J, Qian Y, Zhi X, Pu L, Gu C, Shu J, Lv L, Cai C. Vitamin D levels and Vitamin D-related gene polymorphisms in Chinese children with type 1 diabetes. Front Pediatr 2022; 10:965296. [PMID: 36275052 PMCID: PMC9581124 DOI: 10.3389/fped.2022.965296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/20/2022] [Indexed: 11/30/2022] Open
Abstract
Low vitamin D levels may play a role in type 1 diabetes (T1D) susceptibility. Since 25(OH)D synthesis is genetically regulated, single nucleotide polymorphisms (SNPs) of important genes have also been shown to modulate the risk of T1D, so this study aimed to investigate the relationship between five SNPs in CYP2R1, DHCR7, CYP24A1, VDR genes, serum 25(OH)D levels and T1D in Chinese children. This case-control study included 141 T1D patients and 200 age-matched healthy children.25 (OH) D concentration was determined, genotyping was performed by High resolution melting (HRM). There was a significant difference in the prevalence of vitamin D deficiency, insufficiency, and sufficiency between T1D and healthy controls. (χ 2 = 10.86, p = 0.004), however no evidence of the association between any group of SNPs and circulating 25(OH) D levels was observed. The allele distribution of CYP2R1(rs1993116) was significantly different between T1D and control group (p = 0.040), and the C allele carriers of rs1993116 had a higher risk of T1D than the T allele carriers, Carriers of the CC and CT genotypes of rs1993116 have higher T1D risk than those carrying the TT genotype. GMDR analysis revealed a significant interaction between CYP2R1(rs12794714) and CYP2R1(rs1993116) in the risk of T1D with a maximum testing balance accuracy of 60.39%.
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Affiliation(s)
- Xiaofang Chen
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Tianjin, China.,Graduate College of Tianjin Medical University, Tianjin Medical University, Tianjin, China
| | - Jia Fu
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Tianjin, China.,Graduate College of Tianjin Medical University, Tianjin Medical University, Tianjin, China
| | - Ying Qian
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital (Tianjin University Children's Hospital), Tianjin, China.,Department of Endocrinology, Tianjin Children's Hospital (Tianjin University Children's Hospital), Tianjin, China
| | - Xiufang Zhi
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Tianjin, China.,Graduate College of Tianjin Medical University, Tianjin Medical University, Tianjin, China
| | - Linjie Pu
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Tianjin, China.,Graduate College of Tianjin Medical University, Tianjin Medical University, Tianjin, China
| | - Chunyu Gu
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Tianjin, China.,Graduate College of Tianjin Medical University, Tianjin Medical University, Tianjin, China
| | - Jianbo Shu
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Tianjin, China.,Tianjin Pediatric Research Institute, Tianjin Children's Hospital (Tianjin University Children's Hospital), Tianjin, China.,Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Tianjin, China
| | - Ling Lv
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital (Tianjin University Children's Hospital), Tianjin, China.,Department of Endocrinology, Tianjin Children's Hospital (Tianjin University Children's Hospital), Tianjin, China
| | - Chunquan Cai
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Tianjin, China.,Tianjin Pediatric Research Institute, Tianjin Children's Hospital (Tianjin University Children's Hospital), Tianjin, China.,Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Tianjin, China
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20
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Najjar L, Sutherland J, Zhou A, Hyppönen E. Vitamin D and Type 1 Diabetes Risk: A Systematic Review and Meta-Analysis of Genetic Evidence. Nutrients 2021; 13:nu13124260. [PMID: 34959812 PMCID: PMC8707565 DOI: 10.3390/nu13124260] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/25/2021] [Accepted: 11/25/2021] [Indexed: 12/16/2022] Open
Abstract
Several observational studies have examined vitamin D pathway polymorphisms and their association with type 1 diabetes (T1D) susceptibility, with inconclusive results. We aimed to perform a systematic review and meta-analysis assessing associations between selected variants affecting 25-hydroxyvitamin D [25(OH)D] and T1D risk. We conducted a systematic search of Medline, Embase, Web of Science and OpenGWAS updated in April 2021. The following keywords “vitamin D” and/or “single nucleotide polymorphisms (SNPs)” and “T1D” were selected to identify relevant articles. Seven SNPs (or their proxies) in six genes were analysed: CYP2R1 rs10741657, CYP2R1 (low frequency) rs117913124, DHCR7/NADSYN1 rs12785878, GC rs3755967, CYP24A1 rs17216707, AMDHD1 rs10745742 and SEC23A rs8018720. Seven case-control and three cohort studies were eligible for quantitative synthesis (n = 10). Meta-analysis results suggested no association with T1D (range of pooled ORs for all SNPs: 0.97–1.02; p > 0.01). Heterogeneity was found in DHCR7/NADSYN1 rs12785878 (I2: 64.8%, p = 0.02). Sensitivity analysis showed exclusion of any single study did not alter the overall pooled effect. No association with T1D was observed among a Caucasian subgroup. In conclusion, the evidence from the meta-analysis indicates a null association between selected variants affecting serum 25(OH)D concentrations and T1D.
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Affiliation(s)
- Liana Najjar
- Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, P.O. Box 2471, Adelaide, SA 5001, Australia; (L.N.); (J.S.); (A.Z.)
| | - Joshua Sutherland
- Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, P.O. Box 2471, Adelaide, SA 5001, Australia; (L.N.); (J.S.); (A.Z.)
| | - Ang Zhou
- Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, P.O. Box 2471, Adelaide, SA 5001, Australia; (L.N.); (J.S.); (A.Z.)
- South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Elina Hyppönen
- Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, P.O. Box 2471, Adelaide, SA 5001, Australia; (L.N.); (J.S.); (A.Z.)
- South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
- Correspondence: ; Tel.: +61-(08)-83022518
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21
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Krasniqi E, Boshnjaku A, Wagner KH, Wessner B. Association between Polymorphisms in Vitamin D Pathway-Related Genes, Vitamin D Status, Muscle Mass and Function: A Systematic Review. Nutrients 2021; 13:3109. [PMID: 34578986 PMCID: PMC8465200 DOI: 10.3390/nu13093109] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/27/2021] [Accepted: 09/02/2021] [Indexed: 12/13/2022] Open
Abstract
An association between vitamin D level and muscle-related traits has been frequently reported. Vitamin D level is dependent on various factors such as sunlight exposure and nutrition. But also on genetic factors. We, therefore, hypothesize that single nucleotide polymorphisms (SNPs) within the vitamin D pathway-related genes could contribute to muscle mass and function via an impact on vitamin D level. However, the integration of studies investigating these issues is still missing. Therefore, this review aimed to systematically identify and summarize the available evidence on the association between SNPs within vitamin D pathway-related genes and vitamin D status as well as various muscle traits in healthy adults. The review has been registered on PROSPERO and was conducted following PRISMA guidelines. In total, 77 studies investigating 497 SNPs in 13 different genes were included, with significant associations being reported for 59 different SNPs. Variations in GC, CYP2R1, VDR, and CYP24A1 genes were reported most frequently, whereby especially SNPs in the GC (rs2282679, rs4588, rs1155563, rs7041) and CYP2R1 genes (rs10741657, rs10766197, rs2060793) were confirmed to be associated with vitamin D level in more than 50% of the respective studies. Various muscle traits have been investigated only in relation to four different vitamin D receptor (VDR) polymorphisms (rs7975232, rs2228570, rs1544410, and rs731236). Interestingly, all of them showed only very low confirmation rates (6-17% of the studies). In conclusion, this systematic review presents one of the most comprehensive updates of the association of SNPs in vitamin D pathway-related genes with vitamin D status and muscle traits in healthy adults. It might be used for selecting candidate SNPs for further studies, but also for personalized strategies in identifying individuals at risk for vitamin D deficiency and eventually for determining a potential response to vitamin D supplementation.
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Affiliation(s)
- Ermira Krasniqi
- Research Platform Active Ageing, University of Vienna, Althanstraße 14, 1090 Vienna, Austria; (E.K.); (K.-H.W.)
- Centre for Sport Science and University Sports, University of Vienna, Auf der Schmelz 6, 1150 Vienna, Austria;
- Department of Nutritional Sciences, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
| | - Arben Boshnjaku
- Centre for Sport Science and University Sports, University of Vienna, Auf der Schmelz 6, 1150 Vienna, Austria;
- Faculty of Medicine, University “Fehmi Agani” in Gjakova, Ismail Qemali n.n., 50000 Gjakovë, Kosovo
| | - Karl-Heinz Wagner
- Research Platform Active Ageing, University of Vienna, Althanstraße 14, 1090 Vienna, Austria; (E.K.); (K.-H.W.)
- Department of Nutritional Sciences, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
| | - Barbara Wessner
- Research Platform Active Ageing, University of Vienna, Althanstraße 14, 1090 Vienna, Austria; (E.K.); (K.-H.W.)
- Centre for Sport Science and University Sports, University of Vienna, Auf der Schmelz 6, 1150 Vienna, Austria;
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22
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Pillar S, Amer R. The association between vitamin D and uveitis: A comprehensive review. Surv Ophthalmol 2021; 67:321-330. [PMID: 34343538 DOI: 10.1016/j.survophthal.2021.07.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/15/2022]
Abstract
Vitamin D plays an important role in both the innate and adaptive immune systems. We review published data on the relationship between uveitis and vitamin D levels or vitamin D-associated gene polymorphisms. A search of the PubMed and Medline databases was conducted to identify relevant articles concerning vitamin D and uveitis. Sixteen studies were included in this review, and the evidence they present, linking low vitamin D levels with uveitis, is compelling. The uveitic entities shown to be modulated by hypovitaminosis D include, but are not limited to, HLA-B27-associated acute anterior uveitis, Vogt-Koyanagi-Harada (VKH) disease, sarcoidosis-associated uveitis, and juvenile idiopathic arthritis-associated uveitis. Specific polymorphisms of vitamin D family genes were found to correlate with uveitis in ankylosing spondylitis, Behçet's disease, VKH, and HLA B27-positive patients. Further understanding of the role of vitamin D, a known regulator of inflammatory processes, in noninfectious uveitis may advance capabilities in the fields of disease prevention and treatment.
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Affiliation(s)
- Shani Pillar
- Department of Ophthalmology, Hadassah Medical Organization, Hebrew University of Jerusalem, Israel.
| | - Radgonde Amer
- Department of Ophthalmology, Hadassah Medical Organization, Hebrew University of Jerusalem, Israel
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23
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Kawai VK, Shi M, Liu G, Feng Q, Wei W, Chung CP, Walunas TL, Gordon AS, Linneman JG, Hebbring SJ, Harley JB, Cox NJ, Roden DM, Stein CM, Mosley JD. Pleiotropy of systemic lupus erythematosus risk alleles and cardiometabolic disorders: A phenome-wide association study and inverse-variance weighted meta-analysis. Lupus 2021; 30:1264-1272. [PMID: 33977795 PMCID: PMC8205989 DOI: 10.1177/09612033211014952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
OBJECTIVES To test the hypothesis that genetic predisposition to systemic lupus erythematosus (SLE) increases the risk of cardiometabolic disorders. METHODS Using 41 single nucleotide polymorphisms (SNPs) associated with SLE, we calculated a weighted genetic risk score (wGRS) for SLE. In a large biobank we tested the association between this wGRS and 9 cardiometabolic phenotypes previously associated with SLE: atrial fibrillation, ischemic stroke, coronary artery disease, type 1 and type 2 diabetes, obesity, chronic kidney disease, hypertension, and hypercholesterolemia. Additionally, we performed a phenome-wide association analysis (pheWAS) to discover novel clinical associations with a genetic predisposition to SLE. Findings were replicated in the Electronic Medical Records and Genomics (eMERGE) Network. To further define the association between SLE-related risk alleles and the selected cardiometabolic phenotypes, we performed an inverse variance weighted regression (IVWR) meta-analysis. RESULTS The wGRS for SLE was calculated in 74,759 individuals of European ancestry. Among the pre-selected phenotypes, the wGRS was significantly associated with type 1 diabetes (OR [95%CI] =1.11 [1.06, 1.17], P-value = 1.05x10-5). In the PheWAS, the wGRS was associated with several autoimmune phenotypes, kidney disorders, and skin neoplasm; but only the associations with autoimmune phenotypes were replicated. In the IVWR meta-analysis, SLE-related risk alleles were nominally associated with type 1 diabetes (P = 0.048) but the associations were heterogeneous and did not meet the adjusted significance threshold. CONCLUSION A weighted GRS for SLE was associated with an increased risk of several autoimmune-related phenotypes including type I diabetes but not with cardiometabolic disorders.
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Affiliation(s)
- Vivian K. Kawai
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Mingjian Shi
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Ge Liu
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - QiPing Feng
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - WeiQi Wei
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Cecilia P. Chung
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Division of Rheumatology, Department of Medicine Vanderbilt University Medical Center, Nashville, TN, USA
- Tennessee Valley Healthcare System - Nashville Campus
| | - Theresa L. Walunas
- Center for Health Information Partnerships, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Adam S. Gordon
- Center for Genetic Medicine, Northwestern University, Chicago, IL
| | - James G. Linneman
- Office of Research, Computing, and Analytics, Marshfield Clinic Research Institute, Marshfield, WI
| | - Scott J. Hebbring
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, Wisconsin USA
| | - John B. Harley
- Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Cincinnati VA Medical Center, Cincinnati, OH, USA
| | - Nancy J. Cox
- Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Dan M. Roden
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - C. Michael Stein
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jonathan D. Mosley
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA
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24
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Al-Kashwan TA, Algenabi AHA, Omara AM, Kaftan AN. Association of vitamin D receptor gene polymorphisms BsmI (rs 1544410) and TaqI rs (731236) with the type 2 diabetes mellitus in Iraqi Patients from the middle Euphrates region. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100854] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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25
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Izzo M, Carrizzo A, Izzo C, Cappello E, Cecere D, Ciccarelli M, Iannece P, Damato A, Vecchione C, Pompeo F. Vitamin D: Not Just Bone Metabolism but a Key Player in Cardiovascular Diseases. Life (Basel) 2021; 11:life11050452. [PMID: 34070202 PMCID: PMC8158519 DOI: 10.3390/life11050452] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/03/2021] [Accepted: 05/13/2021] [Indexed: 12/12/2022] Open
Abstract
Vitamin D is the first item of drug expenditure for the treatment of osteoporosis. Its deficiency is a condition that affects not only older individuals but also young people. Recently, the scientific community has focused its attention on the possible role of vitamin D in the development of several chronic diseases such as cardiovascular and metabolic diseases. This review aims to highlight the possible role of vitamin D in cardiovascular and metabolic diseases. In particular, here we examine (1) the role of vitamin D in diabetes mellitus, metabolic syndrome, and obesity, and its influence on insulin secretion; (2) its role in atherosclerosis, in which chronic vitamin D deficiency, lower than 20 ng/mL (50 nmol/L), has emerged among the new risk factors; (3) the role of vitamin D in essential hypertension, in which low plasma levels of vitamin D have been associated with both an increase in the prevalence of hypertension and diastolic hypertension; (4) the role of vitamin D in peripheral arteriopathies and aneurysmal pathology, reporting that patients with peripheral artery diseases had lower vitamin D values than non-suffering PAD controls; (5) the genetic and epigenetic role of vitamin D, highlighting its transcriptional regulation capacity; and (6) the role of vitamin D in cardiac remodeling and disease. Despite the many observational studies and meta-analyses supporting the critical role of vitamin D in cardiovascular physiopathology, clinical trials designed to evaluate the specific role of vitamin D in cardiovascular disease are scarce. The characterization of the importance of vitamin D as a marker of pathology should represent a future research challenge.
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Affiliation(s)
- Marcello Izzo
- Department of Mathematics for Technology, Medicine and Biosciences Research Center, University of Ferrara, 44121 Ferrara, Italy
- Specialist Medical Center-Via Cimitile, 80035 Nola, Italy
- Correspondence:
| | - Albino Carrizzo
- IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (E.C.); (D.C.); (A.D.); (C.V.); (F.P.)
- Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy; (C.I.); (M.C.); (P.I.)
| | - Carmine Izzo
- Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy; (C.I.); (M.C.); (P.I.)
| | - Enrico Cappello
- IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (E.C.); (D.C.); (A.D.); (C.V.); (F.P.)
| | - Domenico Cecere
- IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (E.C.); (D.C.); (A.D.); (C.V.); (F.P.)
| | - Michele Ciccarelli
- Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy; (C.I.); (M.C.); (P.I.)
| | - Patrizia Iannece
- Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy; (C.I.); (M.C.); (P.I.)
| | - Antonio Damato
- IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (E.C.); (D.C.); (A.D.); (C.V.); (F.P.)
| | - Carmine Vecchione
- IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (E.C.); (D.C.); (A.D.); (C.V.); (F.P.)
- Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy; (C.I.); (M.C.); (P.I.)
| | - Francesco Pompeo
- IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (E.C.); (D.C.); (A.D.); (C.V.); (F.P.)
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26
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Tangjittipokin W, Umjai P, Khemaprasit K, Charoentawornpanich P, Chanprasert C, Teerawattanapong N, Narkdontri T, Santiprabhob J. Vitamin D pathway gene polymorphisms, vitamin D level, and cytokines in children with type 1 diabetes. Gene 2021; 791:145691. [PMID: 33961971 DOI: 10.1016/j.gene.2021.145691] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 04/05/2021] [Accepted: 04/30/2021] [Indexed: 02/06/2023]
Abstract
AIMS The study aimed to examine genetic polymorphism of vitamin D-related genes and association between those genes and vitamin D and cytokines levels in children with type 1 diabetes (T1D). MATERIALS AND METHODS This study was conducted among 100 T1D children and 100 controls at Division of Endocrinology and Metabolism, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, during 2016 to 2018. Vitamin D metabolite levels were measured by liquid chromatography-tandem mass spectrometry method, serum cytokine levels of IFN- ɣ, IL-10, IL-13, IL-17α, IL-2, IL-4, IL-6, and TNF-α by immunoassay, and genetic variations at VDR, CYP2R1, CYP27B1, GC, DHCR7, and CYP24A1 by polymerase chain reaction-restriction fragment length polymorphism method. RESULTS A relationship between studied single nucleotide polymorphisms and T1D was found in CYP2R1 (rs10741657) (GA, OR: 1.83, 95% CI: 1.01-3.31; p = 0.04). VDR haplotypes were also remarkably different between T1D patients and controls. Controls had higher frequency of haplotype TACT than T1D patients (p = 0.02). Vitamin D and all cytokine levels, except for IL-17α, were significantly increased in T1D compared to controls. The polymorphism of DHCR7 (rs12785878) was positively associated with 25OHD3 and 3epi25OHD3 levels and was negatively associated with 25OHD2 level. On the other hand, polymorphism of CYP27B1 (rs4646536) was negatively associated with 3epi25OHD3 level. Polymorphisms of CYP27B1 (rs4646536) and GC (rs2282679) were positively associated with TNF-α levels. VDR variation of rs1544410, rs731236, and rs7975232 also showed negative association with IL-10 levels. In contrast, the level of IL-10 was positively associated with DHCR7 (rs12785878). CONCLUSION Relationships between T1D and CYP2R1 polymorphism and VDR haplotype were found. Vitamin D gene-related variations were associated with vitamin D and circulating cytokine levels in children with T1D.
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Affiliation(s)
- Watip Tangjittipokin
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pichakorn Umjai
- Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Khwanhatai Khemaprasit
- Siriraj Diabetes Center of Excellence, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Parichat Charoentawornpanich
- Division of Endocrinology and Metabolism, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chutima Chanprasert
- Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nipaporn Teerawattanapong
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tassanee Narkdontri
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Jeerunda Santiprabhob
- Siriraj Diabetes Center of Excellence, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Endocrinology and Metabolism, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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27
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McCullough ML, Wan N, Pezzolesi MG, Collins TW, Grineski SE, Wei YD, Lazaro-Guevara J, Frodsham SG, Vanderslice JA, Holmen JR, Srinivas TR, Clements SA. Type 1 Diabetes incidence among youth in Utah: A geographical analysis. Soc Sci Med 2021; 278:113952. [PMID: 33933801 DOI: 10.1016/j.socscimed.2021.113952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 03/23/2021] [Accepted: 04/15/2021] [Indexed: 12/15/2022]
Abstract
Type 1 Diabetes (T1D) poses an increasing threat to public health, as incidence rates continue to rise globally. However, the etiology of T1D is still poorly understood, especially from the perspective of geography. The objective of this research is to examine the incidence of T1D among youth and to identify high-risk clusters and their association with socio-demographic and geographic variables. The study area was the entire state of Utah and included youth with T1D from birth to 19 years of age from 1998 to 2015 (n = 4161). Spatial clustering was measured both globally and locally using the Moran's I statistic and spatial scan statistic. Ordinary least squares (OLS) regression was used to measure the association of high-risk clusters with certain risk factors at the Census Block Group (CBG) level. The mean age at diagnosis was 9.3 years old. The mean incidence rate was 25.67 per 100,000 person-years (95% CI, 24.57-26.75). The incidence rate increased by 14%, from 23.94 per100,000 person-years in 1998 to 27.98 per 100,000 person-years in 2015, with an annual increase of 0.80%. The results of the spatial scan statistic found 42 high-risk clusters throughout the state. OLS regression analysis found a significant association with median household income, population density, and latitude. This study provides evidence that incidence rates of T1D are increasing annually in the state of Utah and that significant geographic high-risk clusters are associated with socio-demographic and geographic factors.
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Affiliation(s)
| | - Neng Wan
- Department of Geography, University of Utah, Salt Lake City, UT, USA
| | - Marcus G Pezzolesi
- Diabetes and Metabolism Research Center, University of Utah School of Medicine, Salt Lake City, UT, USA; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Timothy W Collins
- Department of Geography, University of Utah, Salt Lake City, UT, USA
| | | | - Yehua Dennis Wei
- Department of Geography, University of Utah, Salt Lake City, UT, USA
| | - Jose Lazaro-Guevara
- Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Scott G Frodsham
- Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - James A Vanderslice
- Division of Public Health, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - John R Holmen
- Medical Informatics Department, Intermountain Healthcare, Salt Lake City, UT, USA
| | - Titte R Srinivas
- Division of Nephrology and Hypertension, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Scott A Clements
- Department of Pediatrics, University of Utah, Salt Lake City, UT, USA
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28
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Manousaki D, Harroud A, Mitchell RE, Ross S, Forgetta V, Timpson NJ, Smith GD, Polychronakos C, Richards JB. Vitamin D levels and risk of type 1 diabetes: A Mendelian randomization study. PLoS Med 2021; 18:e1003536. [PMID: 33630834 PMCID: PMC7906317 DOI: 10.1371/journal.pmed.1003536] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 01/12/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Vitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR). METHODS AND FINDINGS For our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D-insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations. CONCLUSIONS Our findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects.
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Affiliation(s)
- Despoina Manousaki
- Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
- Research Center of the Sainte-Justine University Hospital, Montreal, Quebec, Canada
- * E-mail:
| | - Adil Harroud
- Department of Neurology, University of California San Francisco, San Francisco, California, United States of America
- Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, United States of America
| | - Ruth E. Mitchell
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Stephanie Ross
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Vince Forgetta
- Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
| | - Nicholas J. Timpson
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
| | - George Davey Smith
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Constantin Polychronakos
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
- Department of Pediatrics, McGill University, Montreal, Quebec, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, Quebec, Canada
| | - J Brent Richards
- Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
- Department of Medicine, McGill University, Montreal, Quebec, Canada
- Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada
- Department of Twin Research and Genetic Epidemiology, King’s College London, United Kingdom
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Kraus AU, Penna-Martinez M, Shoghi F, Meyer G, Badenhoop K. Monocytic Cytokines in Autoimmune Polyglandular Syndrome Type 2 Are Modulated by Vitamin D and HLA-DQ. Front Immunol 2020; 11:583709. [PMID: 33365026 PMCID: PMC7750404 DOI: 10.3389/fimmu.2020.583709] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 10/30/2020] [Indexed: 12/16/2022] Open
Abstract
Context Autoimmune polyglandular syndrome (APS-2: autoimmune Addison’s disease or type 1 diabetes) is conferred by predisposing HLA molecules, vitamin D deficiency, and heritable susceptibility. Organ destruction is accompanied by cytokine alterations. We addressed the monocytic cytokines of two distinct APS-2 cohorts, effects of vitamin D and HLA DQ risk. Methods APS-2 patients (n = 30) and healthy controls (n = 30) were genotyped for HLA DQA1/DQB1 and their CD14+ monocytes stimulated with IL1β and/or 1,25(OH)2D3 for 24 h. Immune regulatory molecules (IL-6, IL-10, IL-23A, IL-15, CCL-2, PD-L1), vitamin D pathway gene transcripts (CYP24A1, CYP27B1, VDR), and CD14 were analyzed by enzyme-linked immunosorbent assay and RTqPCR. Results Pro-inflammatory CCL-2 was higher in APS-2 patients than in controls (p = 0.001), whereas IL-6 showed a trend – (p = 0.1). In vitro treatment with 1,25(OH)2D3 reduced proinflammatory cytokines (IL-6, CCL-2, IL-23A, IL-15) whereas anti-inflammatory cytokines (IL-10 and PD-L1) rose both in APS-type 1 diabetes and APS-Addison´s disease. Patients with adrenal autoimmunity showed a stronger response to vitamin D. Expression of IL-23A and vitamin D pathway genes VDR and CYP27B1 varied by HLA genotype and was lower in healthy individuals with high-risk HLA (p = 0.0025; p = 0.04), while healthy controls with low-risk HLA showed a stronger IL-10 and CD14 expression (p = 0.01; p = 0.03). Conclusion 1,25(OH)2D3 regulates the monocytic response in APS-2 disorders type 1 diabetes or Addison´s disease. The monocytic cytokine profile of individuals carrying HLA high-risk alleles is proinflammatory, enhances polyglandular autoimmunity and can be targeted by vitamin D.
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Affiliation(s)
- Anna U Kraus
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Marissa Penna-Martinez
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Firouzeh Shoghi
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Gesine Meyer
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Klaus Badenhoop
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
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Savastio S, Cadario F, D'Alfonso S, Stracuzzi M, Pozzi E, Raviolo S, Rizzollo S, Gigliotti L, Boggio E, Bellomo G, Basagni C, Bona G, Rabbone I, Dianzani U, Prodam F. Vitamin D Supplementation Modulates ICOS+ and ICOS- Regulatory T Cell in Siblings of Children With Type 1 Diabetes. J Clin Endocrinol Metab 2020; 105:5897243. [PMID: 32844222 DOI: 10.1210/clinem/dgaa588] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 08/21/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Vitamin D plays an immunoregulatory activity. The aim of this study was to assess the correlation between blood serum 25(OH)D levels and Th17 and Treg circulating subsets, mainly Treg/inducible costimulatory-positive (ICOS+), which seems to have a protective role in autoimmunity, in children with type 1 diabetes mellitus (T1D) and their healthy siblings (S). The secondary aim was to evaluate the impact of vitamin D supplementation on these subsets. PATIENTS AND METHODS 22 T1D and 33 S were enrolled. Glucose, hemoglobin A1c, 25 OH vitamin D (25[OH]D), T helper type 17 (Th17; CD4+CCR6+), regulatory T cells (Treg; CD4+CD25+Foxp3+), and Treg/ICOS+ cells were evaluated. According to human leukocyte antigen (HLA) haplotypes, subjects were classified as "at risk" (HLA+), "protective haplotypes" (HLA-; "nested controls"), and "undetermined" (HLAUND). T1D and S subjects were supplemented with cholecalciferol 1000 IU/die and evaluated after 6 months. RESULTS Vitamin D insufficiency (74.4%) and deficiency (43%) were frequent. S subjects with 25(OH)D levels <25 nmol/L had Th17, Treg (p < 0.01), and Treg/ICOS+ (P < 0.05) percentages higher than subjects with 25(OH)D >75 nmol/L. Treg/ICOS+ percentages (P < 0.05) were higher in HLA- S subjects compared to percentages observed in S with T1D. At baseline, in S subjects, a decreasing trend in Th17 and Treg/ICOS+ values (P < 0.05) from vitamin D deficiency to sufficiency was observed; 25(OH)D levels were negative predictors of Treg/ICOS+ (R2 = 0.301) and Th17 percentages (R2 = 0.138). After 6 months, supplemented S subjects showed higher 25(OH)D levels (P < 0.0001), and lower Th17 (P < 0.0001) and Treg/ICOS+ (P < 0.05) percentages than at baseline; supplemented T1D patients only had a decrease in Th17 levels (P < 0.05). CONCLUSION Serum 25(OH)D levels seem to affect Th17 and Treg cell subsets in S subjects, consistent with its immunomodulating role. HLA role should be investigated in a larger population.
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Affiliation(s)
- Silvia Savastio
- SCDU of Pediatrics, University Hospital Maggiore della Carità, Novara, Italy
| | - Francesco Cadario
- SCDU of Pediatrics, University Hospital Maggiore della Carità, Novara, Italy
- Interdisciplinary Research Center of Autoimmune Diseases, Università del Piemonte Orientale, Novara, Italy
| | - Sandra D'Alfonso
- Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
| | - Marta Stracuzzi
- SCDU of Pediatrics, University Hospital Maggiore della Carità, Novara, Italy
| | - Erica Pozzi
- SCDU of Pediatrics, University Hospital Maggiore della Carità, Novara, Italy
| | - Silvia Raviolo
- SCDU of Pediatrics, University Hospital Maggiore della Carità, Novara, Italy
| | - Stefano Rizzollo
- SCDU of Pediatrics, University Hospital Maggiore della Carità, Novara, Italy
| | - Luca Gigliotti
- Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
| | - Elena Boggio
- Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
| | - Giorgio Bellomo
- Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
| | - Chiara Basagni
- Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
| | - Gianni Bona
- Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
| | - Ivana Rabbone
- SCDU of Pediatrics, University Hospital Maggiore della Carità, Novara, Italy
- Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
| | - Umberto Dianzani
- Interdisciplinary Research Center of Autoimmune Diseases, Università del Piemonte Orientale, Novara, Italy
- Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
- SCDU of Clinical Biochemistry, University Hospital Maggiore della Carità, Novara, Italy
| | - Flavia Prodam
- SCDU of Pediatrics, University Hospital Maggiore della Carità, Novara, Italy
- Interdisciplinary Research Center of Autoimmune Diseases, Università del Piemonte Orientale, Novara, Italy
- Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
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Giustina A, Bouillon R, Binkley N, Sempos C, Adler RA, Bollerslev J, Dawson-Hughes B, Ebeling PR, Feldman D, Heijboer A, Jones G, Kovacs CS, Lazaretti-Castro M, Lips P, Marcocci C, Minisola S, Napoli N, Rizzoli R, Scragg R, White JH, Formenti AM, Bilezikian JP. Controversies in Vitamin D: A Statement From the Third International Conference. JBMR Plus 2020; 4:e10417. [PMID: 33354643 PMCID: PMC7745884 DOI: 10.1002/jbm4.10417] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 08/18/2020] [Accepted: 09/20/2020] [Indexed: 12/19/2022] Open
Abstract
The Third International Conference on Controversies in Vitamin D was held in Gubbio, Italy, September 10–13, 2019. The conference was held as a follow‐up to previous meetings held in 2017 and 2018 to address topics of controversy in vitamin D research. The specific topics were selected by the steering committee of the conference and based upon areas that remain controversial from the preceding conferences. Other topics were selected anew that reflect specific topics that have surfaced since the last international conference. Consensus was achieved after formal presentations and open discussions among experts. As will be detailed in this article, consensus was achieved with regard to the following: the importance and prevalence of nutritional rickets, amounts of vitamin D that are typically generated by sun exposure, worldwide prevalence of vitamin D deficiency, the importance of circulating concentrations of 25OHD as the best index of vitamin D stores, definitions and thresholds of vitamin D deficiency, and efficacy of vitamin D analogues in the treatment of psoriasis. Areas of uncertainly and controversy include the following: daily doses of vitamin D needed to maintain a normal level of 25OHD in the general population, recommendations for supplementation in patients with metabolic bone diseases, cutaneous production of vitamin D by UVB exposure, hepatic regulation of 25OHD metabolites, definition of vitamin D excess, vitamin D deficiency in acute illness, vitamin D requirements during reproduction, potential for a broad spectrum of cellular and organ activities under the influence of the vitamin D receptor, and potential links between vitamin D and major human diseases. With specific regard to the latter area, the proceedings of the conference led to recommendations for areas in need of further investigation through appropriately designed intervention trials. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Andrea Giustina
- Institute of Endocrine and Metabolic Sciences, San Raffaele, Vita-Salute University and IRCCS Hospital Milan Italy
| | - Roger Bouillon
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases Metabolism and Ageing KU Leuven Leuven Belgium
| | - Neil Binkley
- Osteoporosis Clinical Research Program on Aging, University of Wisconsin Madison WI USA
| | | | - Robert A Adler
- McGuire Veterans Affairs Medical Center and Virginia Commonwealth University School of Medicine Richmond VA USA
| | - Jens Bollerslev
- Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Rikshospitalet, Oslo, Norway, and Faculty of Medicine University of Oslo Oslo Norway
| | - Bess Dawson-Hughes
- Jean Mayer USDA Nutrition Research Center on Aging Tufts University Boston MA USA
| | - Peter R Ebeling
- Department of Medicine, School of Clinical Sciences Monash University Calyton Victoria Australia
| | - David Feldman
- Department of Medicine Stanford University School of Medicine Stanford CA USA
| | - Annemieke Heijboer
- Endocrine Laboratory, Department of Clinical Chemistry Amsterdam UMC, Vrije Universiteit Amsterdam and University of Amsterdam, Amsterdam Gastroenterology & Metabolism Amsterdam The Netherlands
| | - Glenville Jones
- Department of Biomedical and Molecular Sciences Queen's University Kingston Ontario Canada
| | - Christopher S Kovacs
- Faculty of Medicine Memorial University of Newfoundland St. John's Newfoundland and Labrador Canada
| | - Marise Lazaretti-Castro
- Division of Endocrinology Escola Paulista de Medicina-Universidade Federal de Sao Paulo (EPM-UNIFESP) São Paulo Brazil
| | - Paul Lips
- Department of Internal Medicine, Endocrine Section Amsterdam University Medical Center Amsterdam The Netherlands
| | - Claudio Marcocci
- Department of Clinical and Experimental Medicine University of Pisa Pisa Italy
| | - Salvatore Minisola
- Department of Internal Medicine and Medical Disciplines University of Rome "Sapienza" Rome Italy
| | - Nicola Napoli
- Unit of Endocrinology and Diabetes Campus Bio-Medico, University of Rome Rome Italy.,Division of Bone and Mineral Diseases Washington University in St. Louis St. Louis MO USA
| | - Rene Rizzoli
- Service of Bone Diseases Geneva University Hospitals and Faculty of Medicine Geneva Switzerland
| | - Robert Scragg
- School of Population Health University of Auckland Auckland New Zealand
| | - John H White
- Department of Physiology McGill University Montreal Quebec Canada
| | - Anna Maria Formenti
- Institute of Endocrine and Metabolic Sciences, San Raffaele, Vita-Salute University and IRCCS Hospital Milan Italy
| | - John P Bilezikian
- Department of Medicine, Endocrinology Division, College of Physicians and Surgeons Columbia University New York NY USA
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Ferrari D, Locatelli M, Briguglio M, Lombardi G. Is there a link between vitamin D status, SARS-CoV-2 infection risk and COVID-19 severity? Cell Biochem Funct 2020; 39:35-47. [PMID: 33137851 DOI: 10.1002/cbf.3597] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/12/2020] [Accepted: 10/18/2020] [Indexed: 01/08/2023]
Abstract
The outbreak of COVID-19 emerged in December 2019 rapidly spread across the globe and has become pandemic. Little is known about the protective factors of this infection, which is equally distributed between genders and different ages while severe and poor prognosis cases are strongly associated to old males and the presence of comorbidities. Thus, preventive measures aiming at reducing the number of infection and/or their severity are strongly needed. Vitamin D has got great attention and has been claimed as potentially protective against the infection since it may be associated with immunocompetence, inflammation, aging, and those diseases involved in determining the outcomes of COVID-19. This narrative review aims at collecting the literature available on the involvement of the vitamin D status in the pathogenesis of COVID-19 and the putative utility of vitamin D supplementation in the therapeutics. It emerges that a poor vitamin D status seems to associate with an increased risk of infection whereas age, gender and comorbidities seem to play a more important role in COVID-19 severity and mortality. While randomized control trials are needed to better inquire into this topic, vitamin D supplementation may be useful beside its potential effects on SARS-CoV-2 infection and COVID-19.
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Affiliation(s)
| | | | - Matteo Briguglio
- Scientific Direction, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy.,Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland
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Ma X, Xie Z, Qin J, Luo S, Zhou Z. Association of Vitamin D Pathway Gene CYP27B1 and CYP2R1 Polymorphisms with Autoimmune Endocrine Disorders: A Meta-Analysis. J Clin Endocrinol Metab 2020; 105:5892993. [PMID: 32915988 DOI: 10.1210/clinem/dgaa525] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 08/07/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Studies on organ-specific autoimmune endocrine disorders showed correlations between disease risks and vitamin D pathways gene variants, such as CYP27B1 rs10877012 and rs4646536, or CYP2R1 rs10741657 single nucleotide polymorphisms. However, previous works presented inconsistent conclusions. Our study aimed at assessing the association of CYP27B1 and CYP2R1 polymorphisms with autoimmune endocrine disorder susceptibility using the meta-analysis method. METHODS Case-control studies of the subject of interest were identified from the databases Pubmed, Embase, Cochrane Library, and China National Knowledge Infrastructure. Studies that met inclusion and quality criteria were pooled. Observational outcomes were diagnosis of autoimmune Addison's disease, Graves disease, Hashimoto thyroiditis, or type 1 diabetes mellitus. Statistical analysis was performed using software STATA 16.0. RESULTS A total of 14 studies involving 12 929 patients (2243 autoimmune Addison disease, 1253 Graves disease, 612 Hashimoto thyroiditis, 8821 type 1 diabetes), and 12 907 healthy control subjects were pooled for meta-analysis. The rs10877012 minor allele A and its homozygote and heterozygote conferred low overall disease risk (OR [odds ratio] = 0.748, 95% CI [confidence interval] 0.620-0.902 in dominant model; OR = 0.709, 95% CI 0.571-0.879 in recessive model; OR = 0.777, 95% CI 0.674-0.895 in the allele model). The population carrying rs4646536 minor allele C and its homozygote and heterozygote showed decreased overall autoimmune endocrine disorders risk (OR = 0.849, 95% CI 0.748-0.963; OR = 0.868, 95% CI 0.790-0.955; OR = 0.915, 95% CI 0.875-0.957 in the dominant, recessive, and allele model, respectively). No significant genetic association was found for rs10741657. CONCLUSION Our study suggested CYP27B1 polymorphisms rs10877012 minor allele A and rs4646536 minor allele C were negatively related to susceptibilities of organ-specific autoimmune endocrine diseases.
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Affiliation(s)
- Xiaoxi Ma
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, China
- National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Zhiguo Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, China
- National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Jiabi Qin
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Shuoming Luo
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, China
- National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, China
- National Clinical Research Center for Metabolic Diseases, Changsha, China
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Segovia-Ortí R, Bennassar AB, de Sotto-Esteban D, Cortés PS. Vitamin D status is related to severity at onset of diabetes and worse glycemic control. J Pediatr Endocrinol Metab 2020; 33:1265-1271. [PMID: 32853168 DOI: 10.1515/jpem-2020-0149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/04/2020] [Indexed: 01/08/2023]
Abstract
Objectives Our aim is to evaluate whether 25-hydroxyvitamin D at onset of type 1 diabetes mellitus (T1DM) would influence analytical variables of worse prognosis of the disease at the beginning and after one year of development. Methods A retrospective study of pediatric patients (0-14 years) diagnosed with T1DM with initial measurements of 25-hydroxyvitamin D was performed at Son Espases Hospital, between March 2012 and April 2019 (n=67). Results Vitamin D insufficiency was related to age, glycosylated hemoglobin, and creatinine. An improvement in glycosylated hemoglobin was found in subjects whose baseline serum 25(OH)D was >30 ng/mL. Bivariate correlation analysis adjusted by age showed a significantly positive correlation of vitamin D with pH (r=0.279), bicarbonate (r=0.338), and free levothyroxine (r=0.293). Independent variables associated with vitamin D insufficiency were age (odds ratio [OR]=1.2) and winter season (OR=10.52). Conclusion Hypovitaminosis D is related to biochemical variables showing greater severity and higher glycosylated hemoglobin at diagnosis: higher creatinine, lower free levothyroxine, pH, and bicarbonate. Unsupplemented patients with baseline deficiency showed persistently worse glycemic control vs. those with baseline repletion.
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Totonchi H, Rezaei R, Noori S, Azarpira N, Mokarram P, Imani D. Vitamin D Receptor Gene Polymorphisms and the Risk of Metabolic Syndrome (MetS): A Meta-Analysis. Endocr Metab Immune Disord Drug Targets 2020; 21:943-955. [PMID: 32767922 DOI: 10.2174/1871530320666200805101302] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 05/09/2020] [Accepted: 06/24/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Several studies have assessed the association between the vitamin D receptor (VDR) polymorphism and the risk of metabolic syndrome (MetS). However, the results were inconsistent and inconclusive. Therefore, we conducted a meta-analysis to clarify the exact association between the vitamin D receptor (VDR) polymorphisms and the risk of MetS. METHODS All accessible studies reporting the association between the FokI (rs2228570) or/and TaqI (rs731236) or/and BsmI (rs1544410) or/and ApaI (rs7975232 polymorphisms of the Vitamin D Receptor and susceptibility to MetS published prior to February 2019 were systematically searched in Web of Science, Scopus, and PubMed. After that, Odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated to evaluate the strength of the association in five genetic models. RESULTS A total of 9 articles based on four gene variations, and comprising 3348 participants with 1779 metabolic syndrome patients were included. The overall results suggested a significant association between BsmI (rs1544410) polymorphism and MetS susceptibility in recessive model (OR, 0.72, 95% CI, 0.55-0.95, fixed effect model), allelic model (OR, 0.83, 95% CI, 0.72-0.95, fixed effect model), and bb vs BB (OR, 0.65, 95% CI, 0.46-0.93, fixed effect). However, no significant association was identified between TaqI (rs731236) polymorphism, ApaI (rs7975232) polymorphism, and FokI (rs2228570) polymorphism and MetS. CONCLUSION This meta-analysis suggested an association between the BsmI (rs1544410) polymorphism and MetS. Indeed, BsmI (rs1544410) acts as a protective factor in the MetS. As a result, the VDR gene could be regarded as a promising pharmacological and physiological target in the prevention or treatment of the MetS.
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Affiliation(s)
- Hamidreza Totonchi
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Ramazan Rezaei
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shokoofe Noori
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Negar Azarpira
- Shiraz Transplant Research Center, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Pooneh Mokarram
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Danyal Imani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Vitamin D Pathway Genetic Variation and Type 1 Diabetes: A Case-Control Association Study. Genes (Basel) 2020; 11:genes11080897. [PMID: 32764491 PMCID: PMC7465037 DOI: 10.3390/genes11080897] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 07/27/2020] [Accepted: 08/01/2020] [Indexed: 12/16/2022] Open
Abstract
Vitamin D has immunomodulatory effects, and its deficiency has been implicated in the autoimmune process of type 1 diabetes. Serum vitamin D levels are influenced by variants in genes involved in the synthesis, transport, hydroxylation and degradation of vitamin D. The aim of this study was to assess if single nucleotide polymorphisms (SNPs) at the DHCR7 (rs12785878), GC (rs2282679), CYP2R1 (rs2060793) and CYP24A1 (rs6013897) loci are associated with type 1 diabetes in the Portuguese population. Genotype and allele frequencies were determined in 350 cases of type 1 diabetes and in 490 controls. The frequency of each SNP alone was not significantly different between patients and controls. However, the combined analysis of the four SNPs showed that minor alleles of these variants clustered more frequently in patients. The proportion of individuals with three or more minor alleles was significantly higher in patients than in controls (56.3% vs. 48.5; odds ratio (OR) 1.37; 95% confidence interval (CI) 1.04-1.81; p-value 0.027). These results suggest a cumulative effect of SNPs at the DHCR7, GC, CYP2R1 and CYP24A1 loci on the susceptibility to type 1 diabetes, due to the roles of these genes in the vitamin D metabolic pathway.
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Association of common genetic variants with vitamin D status in Malaysian children with epilepsy. Seizure 2020; 79:103-111. [PMID: 32464532 DOI: 10.1016/j.seizure.2020.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 04/27/2020] [Accepted: 05/08/2020] [Indexed: 01/08/2023] Open
Abstract
PURPOSE Children with epilepsy (CWE) are at risk of vitamin D deficiency. Single nucleotide polymorphisms (SNPs) affecting the vitamin D pathway are potentially important risk factors for serum 25-hydroxyvitamin D [25(OH)D] concentration. The aims of our study were to evaluate the association of vitamin d-related SNPs to serum 25(OH)D concentrations in Malaysian CWE. METHODS Cross-sectional study of Malaysian ambulant CWE on antiseizure medication for >1 year. Sixteen SNPs in 8 genes (GC, VDR, CYP2R1, CYP24A1, CYP27B1, CYP27A1, CYP3A4, NADSYN1/DHCR7) were genotyped. Linear and logistic regression models and co-variates adjusted analyses were used. SNPs with significant associations were further analysed in a group of ethnically-matched healthy Malaysian children. RESULTS 239 CWE were recruited (52.7% Malay, 24.3% Chinese and 23.0% Indian) with mean serum 25(OH)D of 58.8 nmol/L (SD 25.7). Prevalence of vitamin D deficiency (≤37.5 nmol/L) was 23.0%. Minor allele of GC-rs4588-A was associated with lower serum 25(OH)D in the meta-analysis of both CWE (β -8.11, P = 0.002) and Malaysian healthy children (β -5.08, P < 0.001), while VDR-rs7975232-A was significantly associated with reduced odds of vitamin D deficiency in Malay subgroup of CWE (OR: 0.16; 95% CI: 0.06-0.49; P = 0.001) and this association was not found in the healthy children group. CONCLUSIONS Our results suggest that GC-rs4588 is associated with lower serum 25(OH)D concentration in both Malaysian CWE and healthy children, while VDR-rs7975232A is associated with lower risk of vitamin D deficiency in Malaysian CWE of Malay ethnicity. Our findings may assist in the genetic risk stratification of low vitamin D status among CWE.
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Shaat N, Katsarou A, Shahida B, Prasad RB, Kristensen K, Planck T. Association between the rs1544410 polymorphism in the vitamin D receptor (VDR) gene and insulin secretion after gestational diabetes mellitus. PLoS One 2020; 15:e0232297. [PMID: 32407388 PMCID: PMC7224565 DOI: 10.1371/journal.pone.0232297] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 04/11/2020] [Indexed: 12/12/2022] Open
Abstract
Background and aims Genetic variants involved in vitamin D metabolism have been associated with diabetes and related syndromes/diseases. We wanted to investigate possible associations of polymorphisms in genes involved in vitamin D metabolism with indices of insulin resistance and insulin secretion, and also with development of diabetes after gestational diabetes mellitus (GDM). Materials and methods We have studied 376 women with previous GDM. Eight single nucleotide polymorphisms (SNPs) in the genes for vitamin D receptor (VDR) [rs731236, rs7975232, rs10735810, and rs1544410], vitamin D binding protein (DBP) [rs7041 and rs4588], and cytochrome P450 family 27 subfamily B member 1 (CYP27B1) [rs10877012 and rs4646536] were genotyped by TaqMan Allelic Discrimination Assay using the Quantstudio 7 Flex system. A 75-g oral glucose tolerance test (OGTT) was performed 1–2 years postpartum. The homeostasis model assessment of insulin resistance (HOMA-IR) and the disposition index [(insulinogenic index: I30/G30)/HOMA-IR] were used to calculate insulin resistance and insulin secretion, respectively. Serum samples for determination of 25(OH)D3 were collected at the time of the OGTT. Manifestation of diabetes was followed up to five years postpartum. Results After adjustment for BMI, age, and ethnicity, the A-allele of the VDR rs1544410 polymorphism was found to be associated with increased disposition index (difference per allele = 3.56, 95% CI: 0.4567–6.674; p = 0.03). The A-allele of the DBP rs7041 polymorphism was found to be associated with 25(OH)D3 levels (difference [in nmol/L] per allele = −5.478, 95% CI: -8.315 to −2.641; p = 0.0002), as was the T-allele of the DBP rs4588 polymorphism (OR = −6.319, 95% CI: −9.466 to −3.171; p = 0.0001). None of the SNPs were significantly associated with HOMA-IR or postpartum diabetes. Conclusions This study provides evidence that the rs1544410 polymorphism of the VDR gene may be associated with increased insulin secretion in women after pregnancy complicated by GDM. Further studies in other populations are needed to confirm the results.
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Affiliation(s)
- Nael Shaat
- Department of Clinical Sciences, Genomics, Diabetes and Endocrinology, Lund University, Malmö, Sweden
- Department of Endocrinology, Skåne University Hospital, Malmö, Sweden
- * E-mail:
| | - Anastasia Katsarou
- Department of Clinical Sciences, Genomics, Diabetes and Endocrinology, Lund University, Malmö, Sweden
- Department of Endocrinology, Skåne University Hospital, Malmö, Sweden
| | - Bushra Shahida
- Department of Clinical Sciences, Genomics, Diabetes and Endocrinology, Lund University, Malmö, Sweden
| | - Rashmi B. Prasad
- Department of Clinical Sciences, Genomics, Diabetes and Endocrinology, Lund University, Malmö, Sweden
| | - Karl Kristensen
- Department of Clinical Sciences, Genomics, Diabetes and Endocrinology, Lund University, Malmö, Sweden
- Department of Obstetrics and Gynaecology, Skåne University Hospital, Malmö, Sweden
| | - Tereza Planck
- Department of Clinical Sciences, Genomics, Diabetes and Endocrinology, Lund University, Malmö, Sweden
- Department of Endocrinology, Skåne University Hospital, Malmö, Sweden
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Lu X, Vick S, Chen Z, Chen J, Watsky MA. Effects of Vitamin D Receptor Knockout and Vitamin D Deficiency on Corneal Epithelial Wound Healing and Nerve Density in Diabetic Mice. Diabetes 2020; 69:1042-1051. [PMID: 32139594 PMCID: PMC7171964 DOI: 10.2337/db19-1051] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 02/23/2020] [Indexed: 12/20/2022]
Abstract
Diabetic keratopathy occurs in ∼70% of all people with diabetes. This study was designed to examine the effects of vitamin D receptor knockout (VDR-/-) and vitamin D deficiency (VDD) on corneal epithelial wound healing and nerve density in diabetic mice. Diabetes was induced using the low-dose streptozotocin method. Corneal epithelial wounds were created using an Algerbrush, and wound healing was monitored over time. Corneal nerve density was measured in unwounded mice. VDR-/- and VDD diabetic mice (diabetic for 8 and 20 weeks, respectively) had slower healing ratios than wild-type diabetic mice. VDR-/- and VDD diabetic mice also showed significantly decreased nerve density. Reduced wound healing ratios and nerve densities were not fully rescued by a supplemental diet rich in calcium, lactose, and phosphate. We conclude that VDR-/- and VDD significantly reduce both corneal epithelial wound healing and nerve density in diabetic mice. Because the supplemental diet did not rescue wound healing or nerve density, these effects are likely not specifically related to hypocalcemia. This work supports the hypothesis that low vitamin D levels can exacerbate preexisting ophthalmic conditions, such as diabetes.
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Affiliation(s)
- Xiaowen Lu
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA
| | - Sarah Vick
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA
| | - Zhong Chen
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA
| | - Jie Chen
- Biostatistics and Data Science, Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, GA
| | - Mitchell A Watsky
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA
- The Graduate School, Augusta University, Augusta, GA
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Vitamin D's Effect on Immune Function. Nutrients 2020; 12:nu12051248. [PMID: 32353972 PMCID: PMC7281985 DOI: 10.3390/nu12051248] [Citation(s) in RCA: 227] [Impact Index Per Article: 45.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 04/24/2020] [Accepted: 04/26/2020] [Indexed: 02/06/2023] Open
Abstract
Ever since its discovery by Windhaus, the importance of the active metabolite of vitamin D (1,25-dihydroxyvitamin D3; 1,25-(OH)2D3) has been ever expanding. In this review, the attention is shifted towards the importance of the extra-skeletal effects of vitamin D, with special emphasis on the immune system. The first hint of the significant role of vitamin D on the immune system was made by the discovery of the presence of the vitamin D receptor on almost all cells of the immune system. In vitro, the overwhelming effect of supra-physiological doses of vitamin D on the individual components of the immune system is very clear. Despite these promising pre-clinical results, the translation of the in vitro observations to solid clinical effects has mostly failed. Nevertheless, the evidence of a link between vitamin D deficiency and adverse outcomes is overwhelming and clearly points towards avoidance of vitamin D deficiency especially in early life.
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Płazińska MT, Czarnywojtek A, Sawicka-Gutaj N, Zgorzalewicz-Stachowiak M, Czarnocka B, Gut P, Karlinska M, Fichna M, Stachowski A, Ruchała M, Krela-Kaźmierczak I, Królicki L. Vitamin D deficiency and thyroid autoantibody fluctuations in patients with Graves' disease - A mere coincidence or a real relationship? Adv Med Sci 2020; 65:39-45. [PMID: 31884304 DOI: 10.1016/j.advms.2019.11.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 09/07/2019] [Accepted: 11/26/2019] [Indexed: 12/24/2022]
Abstract
PURPOSE The aim of this study was to evaluate the association between vitamin D (vitD) and changes in the titers of anti-TSH receptor (TSHR-Abs), antithyroglobulin (Tg-Abs), and antiperoxidase (TPO-Abs) autoantibodies. MATERIALS/METHODS The study involved 269 patients with Graves' disease (GD), divided into four subgroups (1-4), i.e. 65 smokers treated with vitD(+) (1), 76 smokers not treated with vitD(-) (2), 61 non-smokers treated with vitD(+) (3) and 67 non-smokers with vitD(-) (4). All thyroid parameters were analyzed at entry and 1, 3, 6, 9 and 12 months later. RESULTS The titer of TSHR-Abs in group 3 was significantly lower than in groups 1 and 2 across all time points. At 3, 6 and 12 months, the titers of TSHR-Abs were also lower in group 4 compared to groups 1 and 2. At 9 months, the titers in group 3 were lower than in all other groups. There was a significant inverse correlation between baseline levels of vitD and baseline titers of Tg-Abs (in group 1 only), Tg-Abs after 12 months (in group 1 only), TPO-Abs after 12 months (in groups 1 and 3), fT4 (in group 4 only), and a significant positive correlation with TPO-Abs (in group 2 only). VitD levels at 12 months were inversely correlated with Tg-Abs in group 1. CONCLUSIONS VitD measurements in patients with GD, especially smokers with an increased TSHR-Ab titers before 131I therapy, are recommended. Immunological remission is more likely in patients with GD who receive vitD, particularly smokers.
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Effect of genetic factors on the response to vitamin D 3 supplementation in the VIDARIS randomized controlled trial. Nutrition 2020; 75-76:110761. [PMID: 32289634 DOI: 10.1016/j.nut.2020.110761] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/09/2019] [Accepted: 12/18/2019] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Supplementation provides the best means of improving vitamin D status; however, individual responses vary partly owing to genetics. The aim of this study was to determine whether 28 single nucleotide polymorphisms (SNPs) in six key vitamin D pathway genes (GC, DHCR7, CYP2 R1, CYP24 A1, CYP27 B1, VDR) were associated with differences in response to supplementation. METHODS Participants (N = 313; n = 160 vitamin D, n = 153 placebo) were part of VIDARIS (Vitamin D and Acute Respiratory Infections Study), a double-blind, randomized controlled trial involving oral monthly supplementation of either vitamin D3 (200 000 IU each for the first 2 mo, thereafter 100 000 IU monthly) or placebo for 18 mo. Circulating 25-hydroxyvitamin D (25[OH]D) concentrations at baseline and 2, 6, 12, and 18 mo, and vitamin D binding protein (Gc-globulin) and calculated free 25(OH)D concentrations at baseline and 2 mo were obtained. Multiple regression was used to model associations between genetic variants and 25(OH)D, Gc-globulin, and free 25(OH)D concentrations. RESULTS SNPs within GC, CYP2 R1, and CYP27 B1 were associated with 25(OH)D concentrations following supplementation. However, only two GC gene SNPs (rs2282679, rs1155563) were significant after adjustment for multiple testing. This effect disappeared after more than 2 mo of supplementation. None of the SNPs were significantly associated with Gc-globulin concentrations; however, there was a significant interaction with one SNP in DHCR7 (rs12785878), which was associated with reduced free 25(OH)D concentrations in the supplemented arm. CONCLUSION Only variants of GC were associated with 25(OH)D concentrations after supplementation. This effect was modest and disappeared after >2 mo of supplementation, suggesting it may be time/dose-dependent and saturable.
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Tajiri M, Nakahashi O, Kagawa T, Masuda M, Ohminami H, Iwano M, Takeda E, Taketani Y, Yamamoto H. Association of increased renal Cyp24a1 gene expression with low plasma 1,25-dihydroxyvitamin D levels in rats with streptozotocin-induced diabetes. J Clin Biochem Nutr 2020; 66:49-56. [PMID: 32001956 PMCID: PMC6983441 DOI: 10.3164/jcbn.19-79] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 09/05/2019] [Indexed: 12/12/2022] Open
Abstract
Decreases in plasma vitamin D concentrations have been reported in diabetes, although the mechanism involved in this decrease is unclear. Here, we investigated the association between Cyp24a1, a vitamin D catabolic enzyme, and abnormalities in vitamin D metabolism in streptozotocin-induced diabetes rats, an animal model of type 1 diabetes. Plasma 1,25-dihydroxyvitamin D [1,25(OH)2D] levels were significantly lower in streptozotocin-induced diabetes rats and renal Cyp24a1 mRNA expression levels were increased. Western blotting analysis of streptozotocin-induced diabetes rats kidney tissues with anti-CYP24A1 antibody showed a strong signal around 40 kDa, which differs from the predicted 50–55 kDa molecular weight for full-length Cyp24a1 and could represent the Cyp24a1-splicing variant that lacks exons 1 and 2. We observed high levels of renal Cyp24a1-splicing variant mRNA expression in streptozotocin-induced diabetes rats. We also confirmed transcriptional up-regulation of endogenous Cyp24a1 mRNA expression through glucocorticoid receptors by glucocorticoid in opossum kidney proximal cells. Taken together, our results indicated that high Cyp24a1 expression levels may play a role in the decrease of plasma 1,25(OH)2D levels in streptozotocin-induced diabetes rats. High plasma corticosterone levels in diabetes may affect transcriptional regulation to promote increases in Cyp24a1 expression.
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Affiliation(s)
- Mari Tajiri
- Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Otoki Nakahashi
- Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.,Division of Functional Food Chemistry, Institute for Health Science, Tokushima Bunri University, 180 Nishihamahoji, Yamashiro-cho, Tokushima 770-8514, Japan
| | - Tomohiro Kagawa
- Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Masashi Masuda
- Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Hirokazu Ohminami
- Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Masayuki Iwano
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka, Shimoaizuki, Eiheiji-cho, Fukui 910-1193, Japan
| | - Eiji Takeda
- Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Yutaka Taketani
- Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Hironori Yamamoto
- Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.,Department of Nephrology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka, Shimoaizuki, Eiheiji-cho, Fukui 910-1193, Japan.,Department of Health and Nutrition, Faculty of Human Life, Jin-ai University, 3-1-1 Ohde-cho, Echizen-city, Fukui 915-8586, Japan
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Kamiński M, Molenda M, Banaś A, Uruska A, Zozulińska-Ziółkiewicz D. Determinants of Vitamin D Supplementation among Individuals with Type 1 Diabetes. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17030715. [PMID: 31979092 PMCID: PMC7036832 DOI: 10.3390/ijerph17030715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/17/2020] [Accepted: 01/19/2020] [Indexed: 11/23/2022]
Abstract
Half of the individuals with type 1 diabetes (T1DM) may present Vitamin D (VD) deficiency. There is little known about factors determining a decision on VD supplementation. The study aimed to determine the factors affecting vitamin D supplementation in people with T1DM. A cross-sectional survey study using the authors’ questionnaire paper and its digital version was performed. The questions involved data on the basic characteristics of the respondent, medical history, VD supplementation status, influence of the social environment, self-education, and the most important personal motivator for VD supplement use. Multivariate logistic regression analysis was performed. We collected a total of n = 184 papers and n = 550 digital complete surveys. From 734 total respondents, 62.0% declared VD supplementation. The main personal rationale for VD supplementation were recommendation of medical specialist 172 (37.8%) and self-education 135 (29.7%). The main reasons for non-supplementation of VD were lack of knowledge about VD 159 (57.0%) and lack of motivation 77 (27.6%). VD supplementation was independently associated with a family doctor (odds ratio (OR), 95% confidence interval (CI): 4.67, 2.32–9.40) or medical specialist recommendation (16.20, 9.57–27.43), and self-education (5.97, 3.90–9.13). Most Polish individuals with T1DM use VD supplements, and the decision is related to physicians’ recommendations and self-education.
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Harrison SR, Li D, Jeffery LE, Raza K, Hewison M. Vitamin D, Autoimmune Disease and Rheumatoid Arthritis. Calcif Tissue Int 2020; 106:58-75. [PMID: 31286174 PMCID: PMC6960236 DOI: 10.1007/s00223-019-00577-2] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 06/18/2019] [Indexed: 02/06/2023]
Abstract
Vitamin D has been reported to influence physiological systems that extend far beyond its established functions in calcium and bone homeostasis. Prominent amongst these are the potent immunomodulatory effects of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). The nuclear vitamin D receptor (VDR) for 1,25-(OH)2D3 is expressed by many cells within the immune system and resulting effects include modulation of T cell phenotype to suppress pro-inflammatory Th1 and Th17 CD4+ T cells and promote tolerogenic regulatory T cells. In addition, antigen-presenting cells have been shown to express the enzyme 1α-hydroxylase that converts precursor 25-hydroxyvitamin D3 (25-OHD3) to 1,25-(OH)2D3, so that immune microenvironments are able to both activate and respond to vitamin D. As a consequence of this local, intracrine, system, immune responses may vary according to the availability of 25-OHD3, and vitamin D deficiency has been linked to various autoimmune disorders including rheumatoid arthritis (RA). The aim of this review is to explore the immune activities of vitamin D that impact autoimmune disease, with specific reference to RA. As well as outlining the mechanisms linking vitamin D with autoimmune disease, the review will also describe the different studies that have linked vitamin D status to RA, and the current supplementation studies that have explored the potential benefits of vitamin D for prevention or treatment of RA. The overall aim of the review is to provide a fresh perspective on the potential role of vitamin D in RA pathogenesis and treatment.
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Affiliation(s)
- Stephanie R Harrison
- Institute of Metabolism and Systems Research, The University of Birmingham, Birmingham, B15 2TT, UK
- Department of Rheumatology, Sandwell and West, Birmingham Hospitals NHS Trust, Birmingham, B18 7QH, UK
| | - Danyang Li
- Institute of Metabolism and Systems Research, The University of Birmingham, Birmingham, B15 2TT, UK
| | - Louisa E Jeffery
- Institute of Translation Medicine, The University of Birmingham, Birmingham, B15 2TT, UK
| | - Karim Raza
- Department of Rheumatology, Sandwell and West, Birmingham Hospitals NHS Trust, Birmingham, B18 7QH, UK
- Institute of Inflammation and Ageing, Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence and MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, B15 2TT, UK
| | - Martin Hewison
- Institute of Metabolism and Systems Research, The University of Birmingham, Birmingham, B15 2TT, UK.
- Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TT, UK.
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Jorde R, Wilsgaard T, Grimnes G. Polymorphisms in the vitamin D system and mortality - The Tromsø study. J Steroid Biochem Mol Biol 2019; 195:105481. [PMID: 31541730 DOI: 10.1016/j.jsbmb.2019.105481] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/09/2019] [Accepted: 09/18/2019] [Indexed: 01/08/2023]
Abstract
Vitamin D deficiency is associated with diabetes, cancer, immunological and cardiovascular diseases as well as increased mortality. It has, however, been difficult to show a causal relation in randomized, controlled trials. Mendelian randomization studies provide another option for testing causality, and results indicate relations between the serum 25-hydroxyvitamin D (25(OH)D) level and some diseases, including mortality. We have from the Tromsø Study in 2012 published non-significant relations been vitamin D related single nucleotide polymorphisms (SNPs) and mortality, but have since then genotyped additional subjects, the observation time is longer and new SNPs have been included. For the present study genotyping was performed for SNPs in the NADSYN1, CYP2R1, GC and CYP24A1, VDR, CUBILIN and MEGALIN genes in 11 897 subjects who participated in the fourth survey of the Tromsø Study in 1994-1995. Serum 25(OH)D levels were measured in 6733 of these subjects. Genetic scores based on SNPs related to the serum 25(OH)D level (NADSYN1 and CYP2R1 SNPs (synthesis score) and GC and CYP24A1 SNPs (metabolism score)) and serum 25(OH)D percentile groups were created. Mortality data was updated till end of March 2017 and survival analysed with Cox regression adjusted for sex and age. During the observation period 5491 subjects died. The 25(OH)D synthesis (but not the metabolism) genetic score and the serum 25(OH)D percentile groups were (without Bonferroni correction) significantly related to mortality in favour of high serum 25(OH)D. None of the SNPs in the VDR or MEGALIN genes were related to mortality. However, for the rs12766939 in the CUBILIN gene with the major homozygote as reference, the hazard ratio for mortality for the minor homozygote genotype was 1.17 (1.06-1.29), P < 0.002. This should be viewed with caution, as rs12766939 was not in Hardy-Weinberg equilibrium. In conclusion, our study confirms a probable causal but weak relation between serum 25(OH)D level and mortality. The relation between rs12766939 and mortality needs confirmation in more homogenous cohorts.
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Affiliation(s)
- Rolf Jorde
- Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway; Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway.
| | - Tom Wilsgaard
- Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway
| | - Guri Grimnes
- Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway; Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
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Chen C, Chen Y, Weng P, Xia F, Li Q, Zhai H, Wang N, Lu Y. Association of 25-hydroxyvitamin D with cardiometabolic risk factors and metabolic syndrome: a mendelian randomization study. Nutr J 2019; 18:61. [PMID: 31660975 PMCID: PMC6819483 DOI: 10.1186/s12937-019-0494-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 10/14/2019] [Indexed: 12/17/2022] Open
Abstract
Background Low circulating vitamin D levels have been associated with increased risk of metabolic syndrome (MS) and cardiometabolic risk factors in multiple epidemiology studies. However, whether this association is causal is still unclear. We aimed to test whether genetically lowered vitamin D levels were associated with MS and its metabolic traits, using mendelian randomization (MR) methodology. Methods Ten thousand six hundred fifty-five participants were enrolled from the SPECT-China study, which was performed in 23 sites in East China during 2014 to 2016. Using four single-nucleotide polymorphisms (SNPs) in the DHCR7, CYP2R1, GC and CYP24A1 genes with known effects on 25(OH) D concentrations, we created a genetic risk score (GRS) as instrumental variable (IV) to estimate the effect of genetically lowered 25(OH) D on MS and cardiometabolic risk factors. MS was defined according to the International Diabetes Federation criteria. Results Lower measured 25(OH)D levels were associated with MS (OR 0.921, 95% CI 0.888, 0.954) after multivariable adjustment. However, the MR-derived odds ratio of genetically determined 25(OH) D for risk of MS was 0.977 (95% CI 0.966, 1.030). The MR-derived estimates for raised fasting plasma glucose was 0.578 (95% CI 0.321, 0.980) per 10 nmol/L GRSsynthesis determined increase of 25(OH) D levels. Conclusions We found no evidence that genetically determined reduction in 25(OH)D conferred an increased risk of MS and its metabolic traits. However, we created our GRS only on the basis of common variants, which represent limited amount of variance in 25(OH)D. MR studies using rare variants, and large-scale well-designed RCTs about the effect of vitamin D supplementation on MS are warranted to further validate the findings.
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Affiliation(s)
- Chi Chen
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China
| | - Yi Chen
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China
| | - Pan Weng
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China
| | - Fangzhen Xia
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China
| | - Qin Li
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China
| | - Hualing Zhai
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China
| | - Ningjian Wang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China.
| | - Yingli Lu
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China.
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Infante M, Ricordi C, Sanchez J, Clare-Salzler MJ, Padilla N, Fuenmayor V, Chavez C, Alvarez A, Baidal D, Alejandro R, Caprio M, Fabbri A. Influence of Vitamin D on Islet Autoimmunity and Beta-Cell Function in Type 1 Diabetes. Nutrients 2019; 11:E2185. [PMID: 31514368 PMCID: PMC6769474 DOI: 10.3390/nu11092185] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/05/2019] [Accepted: 09/06/2019] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease leading to immune-mediated destruction of pancreatic beta cells, resulting in the need for insulin therapy. The incidence of T1D is increasing worldwide, thus prompting researchers to investigate novel immunomodulatory strategies to halt autoimmunity and modify disease progression. T1D is considered as a multifactorial disease, in which genetic predisposition and environmental factors interact to promote the triggering of autoimmune responses against beta cells. Over the last decades, it has become clear that vitamin D exerts anti-inflammatory and immunomodulatory effects, apart from its well-established role in the regulation of calcium homeostasis and bone metabolism. Importantly, the global incidence of vitamin D deficiency is also dramatically increasing and epidemiologic evidence suggests an involvement of vitamin D deficiency in T1D pathogenesis. Polymorphisms in genes critical for vitamin D metabolism have also been shown to modulate the risk of T1D. Moreover, several studies have investigated the role of vitamin D (in different doses and formulations) as a potential adjuvant immunomodulatory therapy in patients with new-onset and established T1D. This review aims to present the current knowledge on the immunomodulatory effects of vitamin D and summarize the clinical interventional studies investigating its use for prevention or treatment of T1D.
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Affiliation(s)
- Marco Infante
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
| | - Camillo Ricordi
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Janine Sanchez
- Pediatric Endocrinology, University of Miami Miller School of Medicine, 1601 NW 12th Avenue, Miami, FL 33136, USA.
| | - Michael J Clare-Salzler
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, 1600 SW Archer Rd, Gainesville, FL 32610, USA.
| | - Nathalia Padilla
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Virginia Fuenmayor
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Carmen Chavez
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Ana Alvarez
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - David Baidal
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Rodolfo Alejandro
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Massimiliano Caprio
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00133 Rome, Italy.
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy.
| | - Andrea Fabbri
- Department of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
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Nam HK, Rhie YJ, Lee KH. Vitamin D level and gene polymorphisms in Korean children with type 1 diabetes. Pediatr Diabetes 2019; 20:750-758. [PMID: 31206955 DOI: 10.1111/pedi.12878] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 05/18/2019] [Accepted: 06/10/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Vitamin D metabolism has been associated with type 1 diabetes. OBJECTIVE We aimed to clarify the association of 25-hydroxylase (CYP2R1) and 1α-hydroxylase (CYP27B1) with risk of developing type 1 diabetes in Korean children. METHODS In total, 252 children (96 type 1 diabetes and 156 healthy controls) under the age of 20 years were recruited. Serum 25-hydroxyvitamin D (25OHD) and 1α,25-dihydroxyvitamin D [1α,25(OH)2 D] levels were determined. Allelic, genotypic, and haplotypic distribution of CYP2R1 (rs12794714, rs10766196, rs10741657, rs2060793, and rs10766197) and CYP27B1 (rs4646536, rs10877012, and rs3782130) polymorphisms were determined. Clinical and biochemical data were analyzed according to genotype. RESULTS Mean vitamin D level was considerably lower, and vitamin D deficiency was more prevalent in children with type 1 diabetes than in healthy controls. The GG genotype of CYP2R1 rs12794714 and AA genotype of CYP2R1 rs10766196 were significantly associated with risk of developing type 1 diabetes (odds ratio 2.00, 95% confidence interval 1.176-3.413 and odds ratio 1.88, 95% confidence interval 1.103-3.195, respectively). The GG+GA genotype of CYP2R1 rs12794714 and AA+AG genotype of CYP2R1 rs10766196 were associated with prevalent vitamin D deficiency in children with type 1 diabetes. These genotypes did not differ with respect to glycosylated hemoglobin and daily insulin requirement. CONCLUSIONS Serum 25OHD and 1α,25(OH)2 D levels were lower in children with type 1 diabetes than in healthy controls. CYP2R1 rs12794714 and rs10766196 polymorphisms were associated with a higher risk of type 1 diabetes. Thus, polymorphisms in vitamin D metabolism may contribute to susceptibility to type 1 diabetes in Korean children.
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Affiliation(s)
- Hyo-Kyoung Nam
- Department of Pediatrics, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Young-Jun Rhie
- Department of Pediatrics, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Gyeonggi-do, Korea
| | - Kee-Hyoung Lee
- Department of Pediatrics, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
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Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, Lips P, Munns CF, Lazaretti-Castro M, Giustina A, Bilezikian J. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev 2019; 40:1109-1151. [PMID: 30321335 PMCID: PMC6626501 DOI: 10.1210/er.2018-00126] [Citation(s) in RCA: 616] [Impact Index Per Article: 102.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023]
Abstract
The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D-deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.
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Affiliation(s)
- Roger Bouillon
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Belgium
| | - Claudio Marcocci
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Geert Carmeliet
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Belgium
| | - Daniel Bikle
- Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California
| | - John H White
- Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - Bess Dawson-Hughes
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
| | - Paul Lips
- Department of Internal Medicine, Endocrine Section, VU University Medical Center, HV Amsterdam, Netherlands
| | - Craig F Munns
- Children’s Hospital at Westmead, Sydney, New South Wales, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Marise Lazaretti-Castro
- Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Andrea Giustina
- Chair of Endocrinology, Vita-Salute San Raffaele University, Milan, Italy
| | - John Bilezikian
- Department of Endocrinology, Columbia University College of Physicians and Surgeons, New York, New York
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