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Zheng TT, Liu JH, Huang WT, Hong B, Wang D, Liu CY, Zhang J, Li SS, Wu SW, Wang Q, Chen L, Jin L. Single-nucleotide polymorphisms in genes involved in folate metabolism or selected other metabolites and risk for gestational diabetes mellitus. World J Diabetes 2025; 16:103602. [DOI: 10.4239/wjd.v16.i5.103602] [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: 12/06/2024] [Revised: 02/09/2025] [Accepted: 03/24/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND There are conflicting results on the potential correlation between folic acid and gestational diabetes mellitus (GDM), and the correlation between genetic factors related to folic acid metabolism pathways and GDM remains to be revealed.
AIM To examine the association between single-nucleotide polymorphisms (SNPs) of enzyme genes in the folate metabolite pathway as well as that between GDM-related genes and risk for GDM.
METHODS A nested case-control study was conducted with GDM cases (n = 412) and healthy controls (n = 412). DNA was extracted blood samples and SNPs were genotyped using Agena Bioscience’s MassARRAY gene mass spectrometry system. The associations between different SNPs of genes and the risk for GDM were estimated using logistic regression models. The generalized multi-factor dimensionality reduction (GMDR) method was used to analyze gene-gene and gene-environment interactions using the GMDR 0.9 software.
RESULTS The variation allele frequency of melatonin receptor 1B (MTNR1B) rs10830963 was higher in the GDM group than in controls (P < 0.05). MTNR1B rs10830963 mutant G was associated with risk for GDM [adjusted odds ratio (aOR): 1.43; 95% confidence interval (95%CI): 1.13-1.80] in the additive model. MTNR1B rs10830963 GG + GC was significantly associated with the risk for GDM (aOR: 1.65; 95%CI: 1.23-2.22) in the dominant model. The two-locus model of MTNR1B rs10830963 and CHEMERIN rs4721 was the best model (P < 0.05) for gene-gene interactions in the GMDR results. The high-risk rs10830963 × rs4721 type of interaction was a risk factor for GDM (aOR: 2.09; 95%CI: 1.49-2.93).
CONCLUSION This study does not find an association between SNPs of folate metabolic enzymes and risk for GDM. The G mutant allele of MTNR1B rs10830963 is identified as a risk factor for GDM in the additive model, and there may be gene-gene interactions between MTNR1B rs10830963 and CHEMERIN rs4721. It is conducive to studying the causes of GDM and provides a new perspective for the precise prevention of this disease.
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Affiliation(s)
- Ting-Ting Zheng
- Department of Obstetrics and Gynecology, The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China
- Department of Gynecology, Jinan Maternal and Child Care Hospital, Jinan 250000, Shandong Province, China
- Department of Obstetrics and Gynecology, The Sixth Medical Center of PLA General Hospital, Beijing 100191, China
| | - Jia-He Liu
- Institute of Reproductive and Child Health, Peking University, Beijing 100191, China
- Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Beijing 100191, China
- State Key Laboratory of Female Fertility Promotion, Peking University, Beijing 100191, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Wan-Tong Huang
- Institute of Reproductive and Child Health, Peking University, Beijing 100191, China
- Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Beijing 100191, China
- State Key Laboratory of Female Fertility Promotion, Peking University, Beijing 100191, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Bo Hong
- Department of Obstetrics and Gynecology, Haidian Maternal and Child Health Care Hospital of Beijing, Beijing 100191, China
| | - Di Wang
- Institute of Reproductive and Child Health, Peking University, Beijing 100191, China
- Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Beijing 100191, China
- State Key Laboratory of Female Fertility Promotion, Peking University, Beijing 100191, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Chun-Yi Liu
- Institute of Reproductive and Child Health, Peking University, Beijing 100191, China
- Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Beijing 100191, China
- State Key Laboratory of Female Fertility Promotion, Peking University, Beijing 100191, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Jie Zhang
- Institute of Reproductive and Child Health, Peking University, Beijing 100191, China
- Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Beijing 100191, China
- State Key Laboratory of Female Fertility Promotion, Peking University, Beijing 100191, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Si-Si Li
- Institute of Reproductive and Child Health, Peking University, Beijing 100191, China
- Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Beijing 100191, China
- State Key Laboratory of Female Fertility Promotion, Peking University, Beijing 100191, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Shao-Wei Wu
- Department of Occupational and Environmental Health, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University Health Science Center, Xi'an 710000, Shaanxi Province, China
| | - Qi Wang
- Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China
| | - Lei Chen
- Department of Obstetrics and Gynecology, The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China
- Department of Obstetrics and Gynecology, The Sixth Medical Center of PLA General Hospital, Beijing 100191, China
| | - Lei Jin
- Institute of Reproductive and Child Health, Peking University, Beijing 100191, China
- Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Beijing 100191, China
- State Key Laboratory of Female Fertility Promotion, Peking University, Beijing 100191, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
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Galchenko AV, Rizzo G, Baroni L. Nutrient Intakes in Vegans, Lacto-Ovo-Vegetarians, Orthodox Fasters, and Omnivores in Russia: A Cross-Sectional Study. Foods 2025; 14:1062. [PMID: 40232088 PMCID: PMC11942464 DOI: 10.3390/foods14061062] [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: 01/21/2025] [Revised: 03/13/2025] [Accepted: 03/14/2025] [Indexed: 04/16/2025] Open
Abstract
In Eastern Europe, the number of vegetarians is growing, and the number of people adhering to Christian Lents is traditionally high. However, data on the nutritional value of plant-based diets in this part of the world are limited. The aim of this study was to compare the nutritional intakes of three groups with different plant-based patterns with that of omnivores in Russia, Moscow region. The nutrient intakes of 46 vegans, 49 lacto-ovo-vegetarians, 42 people who adhered to Orthodox Great Lent, and 48 omnivores were assessed. The food frequency questionnaire method was used for data collection and analysis. The differences in absolute and calorie adjusted nutrient intakes between the groups were analysed. Additionally, a pairwise comparison of the general plant-based group (combined of the vegan, lacto-ovo-vegetarian, and Great Lent samples) and the omnivorous groups was conducted. Vegan diet was the most favourable in micronutrient composition. The intake of many micronutrients increased when switching to a more plant-based diet from a more animal-based one. The opposite association was observed only for selenium and vitamins D and B12. Fasting people consumed more iodine and n-3 polyunsaturated fatty acids; however, after the calorie content was standardized, the omnivores caught up with them. The omnivores had the largest list of dietary inadequacies: they significantly more often than all other groups had inadequate intake of cholesterol (excessive), fibre, potassium, magnesium, iron, and vitamins B1, B6, B9, and E (insufficient). Inadequate intake of polyunsaturated fatty acids, calcium, iodine, chromium, molybdenum, and zinc; or vitamins B2, PP, H, B12, and D was observed rather often in all the studied groups. Although, the vegan diet was richer in most micronutrients, plant products often contain substances that reduce the bioavailability of various nutrients, which can partially affect their status in the body, and, thus, may increase the need in them in vegetarians and fasters.
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Affiliation(s)
- Alexey Vladimirovich Galchenko
- Scientific Society for Vegetarian Nutrition—SSNV, Mestre, 30171 Venice, Italy;
- Earth Philosophical Society “Melodia Vitae”, Toronto, ON M9A4X9, Canada
| | | | - Luciana Baroni
- Scientific Society for Vegetarian Nutrition—SSNV, Mestre, 30171 Venice, Italy;
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Mohammed NO, Ali IA, Elamin BK, Saeed BO. 5,10-methylenetetrahydrofolate reductase C677T gene polymorphism as a risk factor for premature coronary artery disease in patients with type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2025; 15:1502497. [PMID: 39911235 PMCID: PMC11794260 DOI: 10.3389/fendo.2024.1502497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 12/23/2024] [Indexed: 02/07/2025] Open
Abstract
Background Africa, like the rest of the world, is experiencing an increasing prevalence of diabetes mellitus. Diabetes increases the risk for coronary artery disease (CAD) by fourfold compared to people without diabetes. C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) and hyperhomocysteinemia were reported by many studies as risk factors for CAD among patients with type 2 diabetes mellitus (T2DM). Early detection of modifiable risk factors for CAD is an important aspect of management of diabetes. This is the only study in Sudan which investigates the association between MTHFR genotypes and plasma homocysteine levels, and their role in premature CAD (PCAD) among patients with T2DM. Methods This study is a comparative study. We enrolled 226 Sudanese patients with T2DM, age range 25-60 years, recruited from Alshaab and Omdurman teaching hospitals in Khartoum State. 113 patients had CAD confirmed by angiography and electrocardiography (ECG) and 113 had no evidence of CAD. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), using Hinf1 restriction enzyme, were used to determine MTHFR genotypes. Plasma homocysteine levels were determined by enzymatic assay on the Hitachi Cobas Integra® 400 plus. Data was analyzed using statistical package for Social Sciences (SPSS) 23, using Mann-Whtney U test, general linear model, Chi-square test and logistic regression analysis. Results The frequencies of TT, CT, and CC genotypes were 16,40 and 44% among T2DM patients with PCAD. In T2DM patients without PCAD, the frequencies of TT, CT, and CC genotypes were 00,19 and 83%. The T allele showed strong association with PCAD among T2DM patients, p <0.001, odds ratio (OR) 6.2, 95% CI (3.4-11.6). Patients with PCAD showed higher plasma homocysteine levels than patients without PCAD (13.5 µmol/L versus 10 µmol/L, p < 0.001). The T allele had significant effect on homocysteine level, (p <0.001). Plasma homocysteine levels were higher in individuals with TT genotype than those with CT or CC genotypes in patients with PCAD (16.2 + 5.3, 14.3 + 5.7 and 12.9 + 5.02 µmol/L, p=0.017). Homocysteine levels showed a significant association with CAD, p<0.001, OR 3.2, 95% CI (1.9-5.5). Conclusions Our study suggests that C677T polymorphism of MTHFR gene and hyperhomocysteinemia are risk factors for PCAD in Sudanese population with T2DM.
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Affiliation(s)
- Nisreen O. Mohammed
- Ahfad Centre for Science and Technology, Ahfad University for Women, Khartoum, Sudan
| | - Ibtisam A. Ali
- Faculty of Medicine, International University of Africa, Khartoum, Sudan
| | - Bahaelddin K. Elamin
- Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum, Sudan
| | - Bakri Osman Saeed
- Faculty of Medicine, Sudan International University, Khartoum, Sudan
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Kolanis S, Kotanidou EP, Tsinopoulou VR, Georgiou E, Hatzipantelis E, Fidani L, Galli-Tsinopoulou A. MTHFR Gene Polymorphisms and Cancer Risk in Children and Adolescents: A Systematic Review and Meta-Analysis. CHILDREN (BASEL, SWITZERLAND) 2025; 12:108. [PMID: 39857939 PMCID: PMC11764102 DOI: 10.3390/children12010108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/05/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025]
Abstract
Background/Objectives:MTHFR gene polymorphisms (677C>T and 1298A>C) correlate with various types of cancer across all age groups; however, a small number of studies have included solely children and adolescents. The aim of this systematic review and meta-analysis was to present and synthesize all the available evidence on the association between MTHFR gene polymorphisms and the incidence of all types of cancer in children and adolescences. Methods: After a systematic search of all of the available data, original case-control studies involving children or adolescents with a confirmed diagnosis of any type of cancer and a molecular genetic test of MTHFR gene polymorphisms were included. Results: A total of 53 original studies in children and adolescents with cancer were included in the systematic review. Among these, 40 studies reviewed children and adolescents with Acute Lymphoblastic Leukemia (ALL), 4 those with Acute Myeloblastic Leukemia (AML), 8 those with central nervous system (CNS) tumors and 3 those with other types of cancer. Children and adolescents with ALL had less frequent T allele sequences (CT and TT variations) of the 677C>T polymorphism compared to a healthy population (OR: 0.85; CI: 0.80-0.91; p < 0.00001). Concerning the 1298A>C polymorphism, the C allele sequences (AC and CC) did not present a statistically significant difference in frequency compared to a healthy population (OR: 1.01; CI: 0.95-1.08; p = 0.69). Conclusions: Children and adolescents with ALL appeared to have the T allele sequences of the 677C>T polymorphism of the MTHFR gene less frequently compared to a healthy population.
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Affiliation(s)
- Savvas Kolanis
- 2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece; (S.K.); (E.P.K.); (V.R.T.); (E.H.); (L.F.)
| | - Eleni P. Kotanidou
- 2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece; (S.K.); (E.P.K.); (V.R.T.); (E.H.); (L.F.)
| | - Vasiliki Rengina Tsinopoulou
- 2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece; (S.K.); (E.P.K.); (V.R.T.); (E.H.); (L.F.)
| | - Elisavet Georgiou
- Laboratory of Biological Chemistry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Emmanuel Hatzipantelis
- 2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece; (S.K.); (E.P.K.); (V.R.T.); (E.H.); (L.F.)
| | - Liana Fidani
- 2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece; (S.K.); (E.P.K.); (V.R.T.); (E.H.); (L.F.)
- Laboratory of Medical Biology-Genetics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Assimina Galli-Tsinopoulou
- 2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece; (S.K.); (E.P.K.); (V.R.T.); (E.H.); (L.F.)
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Fryar-Williams S, Tucker G, Clements P, Strobel J. Gene Variant Related Neurological and Molecular Biomarkers Predict Psychosis Progression, with Potential for Monitoring and Prevention. Int J Mol Sci 2024; 25:13348. [PMID: 39769114 PMCID: PMC11677369 DOI: 10.3390/ijms252413348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/14/2024] [Accepted: 11/17/2024] [Indexed: 01/11/2025] Open
Abstract
The (MTHFR) C677T gene polymorphism is associated with neurological disorders and schizophrenia. Patients diagnosed with schizophrenia and schizoaffective disorder and controls (n 134) had data collected for risk factors, molecular and neuro-sensory variables, symptoms, and functional outcomes. Promising gene variant-related predictive biomarkers were identified for diagnosis by Receiver Operating Characteristics and for illness duration by linear regression. These were then analyzed using Spearman's correlation in relation to the duration of illness. Significant correlations were ranked by strength and plotted on graphs for each MTHFR C677T variant. Homozygous MTHFR 677 TT carriers displayed a mid-illness switch to depression, with suicidality and a late-phase shift from lower to higher methylation, with activated psychosis symptoms. MTHFR 677 CC variant carriers displayed significant premorbid correlates for family history, developmental disorder, learning disorder, and head injury. These findings align with those of low methylation, oxidative stress, multiple neuro-sensory processing deficits, and disability outcomes. Heterozygous MTHFR 677 CT carriers displayed multiple shifts in mood and methylation with multiple adverse outcomes. The graphically presented ranked biomarker correlates for illness duration allow a perspective of psychosis development across gene variants, with the potential for phase of illness monitoring and new therapeutic insights to prevent or delay psychosis and its adverse outcomes.
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Affiliation(s)
- Stephanie Fryar-Williams
- Youth in Mind Research Institute, Unley, SA 5061, Australia
- Department of Medical Specialities, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
| | - Graeme Tucker
- Department of Public Health, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
| | - Peter Clements
- Department of Paediatrics, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
| | - Jörg Strobel
- Department of Psychiatry, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
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Zhang Y, Zhang Y, Miao R, Fang X, Yin R, Guan H, Tian J. The MTHFR C677T/A1298C polymorphism is associated with increased risk of microangiopathy in type 2 diabetes mellitus: A systematic review and meta-analysis. Nutr Res 2024; 130:34-47. [PMID: 39340999 DOI: 10.1016/j.nutres.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 08/30/2024] [Accepted: 08/30/2024] [Indexed: 09/30/2024]
Abstract
Extensive case-control association studies have been conducted over the past few decades to investigate the relationship between MTHFR polymorphism and type 2 diabetes mellitus (T2DM) microangiopathy. However, the strength of the evidence and clinical significance are unclear. Consequently, a meta-analysis was performed to examine the correlations between two prevalent MTHFR single nucleotide polymorphisms, MTHFR C677T and A1298C, and T2DM microangiopathy. Randomized controlled trials were systematically searched in PubMed, Cochrane, Embase, Web of Science, CNKI, VIP database, China Biology Medicine, and Wanfang until August 2023. A total of 42 studies were included. Random-effect models were utilized to estimate odds ratios (ORs) with 95% confidence intervals (CIs) to assess the association between MTHFR polymorphisms and T2DM microangiopathy susceptibility. T2DM microangiopathy was significantly associated with the MTHFR C677T polymorphism in the overall population (T vs C, OR = 1.43, 95% CI = 1.25-1.64; TT + CT vs CC: OR = 1.56, 95% CI = 1.30-1.88; TT vs CT + CC: OR = 1.66, 95% CI = 1.38-1.99; TT vs CC: OR = 2.03, 95% CI = 1.58-2.60). Additionally, the dominant model revealed that the MTHFR A1298C polymorphism was associated with T2DM microangiopathy (OR = 1.27, 95% CI: 1.09-1.47). This meta-analysis revealed that MTHFR may be involved in the pathogenesis of T2DM microangiopathy, providing a reference for early diagnosis and treatment of T2DM.
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Affiliation(s)
- Yuxin Zhang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Yanjiao Zhang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Runyu Miao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate College, Beijing University of Chinese Medicine, Beijing, China
| | - Xinyi Fang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate College, Beijing University of Chinese Medicine, Beijing, China
| | - Ruiyang Yin
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Huifang Guan
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Jiaxing Tian
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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Zhang X, Hocher B. Parental genetic effects on the offspring's phenotype without transmission of the gene itself-pathophysiology and clinical evidence. Am J Physiol Cell Physiol 2024; 327:C750-C777. [PMID: 39010843 DOI: 10.1152/ajpcell.00359.2024] [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: 05/28/2024] [Revised: 06/20/2024] [Accepted: 07/04/2024] [Indexed: 07/17/2024]
Abstract
Parental genes can influence the phenotype of their offspring through genomic-epigenomic interactions even without the direct inheritance of specific parental genotypes. Maternal genetic variations can affect the ovarian and intrauterine environments and potentially alter lactation behaviors, impacting offspring nutrition and health outcomes independently of the fetal genome. Similarly, paternal genetic changes can affect the endocrine system and vascular functions in the testes, influencing sperm quality and seminal fluid composition. These changes can initiate early epigenetic modifications in sperm, including alterations in microRNAs, tRNA-derived small RNAs (tsRNAs), and DNA methylation patterns. These epigenetic modifications might induce further changes in target organs of the offspring, leading to modified gene expression and phenotypic outcomes without transmitting the original parental genetic alterations. This review presents clinical evidence supporting this hypothesis and discusses the potential underlying molecular mechanisms. Parental gene-offspring epigenome-offspring phenotype interactions have been observed in neurocognitive disorders and cardio-renal diseases.
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Affiliation(s)
- Xiaoli Zhang
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
| | - Berthold Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, People's Republic of China
- IMD-Institut für Medizinische Diagnostik Berlin-Potsdam GbR, Berlin, Germany
- Key Laboratory of Reproductive and Stem Cell Engineering, Central South University, Changsha, People's Republic of China
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Memar Montazerin S, Hassanzadeh S, Najafi H, Shojaei F, Kumanayaka D, Suleiman A. The genetics of spontaneous coronary artery dissection: a scoping review. J Cardiovasc Med (Hagerstown) 2024; 25:569-586. [PMID: 38916232 DOI: 10.2459/jcm.0000000000001634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
BACKGROUND Spontaneous coronary artery dissection (SCAD) is a multifactorial process that involves predisposing factors and precipitating stressors. Genetic abnormality has been implicated to play a mechanistic role in the development of SCAD. This systematic review aims to summarize the current evidence concerning the link between SCAD and genetic abnormalities. METHODS We reviewed original studies published until May 2023 that reported SCAD patients with a genetic mutation by searching PubMed, Embase Ovid, and Google Scholar. Registries, cohort studies, and case reports were included if a definitive SCAD diagnosis was reported, and the genetic analysis was performed. Exclusion criteria included editorials, reviews, letters or commentaries, animal studies, meeting papers, and studies from which we were unable to extract data. Data were extracted from published reports. RESULTS A total of 595 studies were screened and 55 studies were identified. Among 116 SCAD patients with genetic abnormalities, 20% had mutations in the COL gene, 13.70% TLN1 gene, and 8.42% TSR1 gene. Mutations affecting the genes encoding COL and TLN1 were most frequently reported (20 and 13.7%, respectively). Interestingly, 15 genes of this collection were also reported in patients with thoracic aortic diseases as well. The genetic commonality between fibromuscular dysplasia (FMD) and SCAD was also included. CONCLUSION In this review, the inherited conditions and reported genes of undetermined significance from case reports associated with SCAD are collected. A brief description of the encoded protein and the clinical features associated with pathologic genes is provided. Current data suggested that the diagnostic yield of genetic studies for patients with SCAD would be low and routine genetic screening of such patients with no clinical features indicative of associated disorders remains debatable. This review can be used as a guide for clinicians to recognize inherited syndromic and nonsyndromic disorders associated with SCAD.
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Affiliation(s)
- Sahar Memar Montazerin
- Beth Israel Deaconess Medical Center, Harvard Medical School
- Department of Cardiology, Saint Michael's Medical Center, Newark, New Jersey
| | - Shakiba Hassanzadeh
- Department of Pathology, East Carolina University, Greenville, North Carolina, USA
| | - Homa Najafi
- Beth Israel Deaconess Medical Center, Harvard Medical School
| | | | - Dilesha Kumanayaka
- Department of Cardiology, Saint Michael's Medical Center, Newark, New Jersey
| | - Addi Suleiman
- Department of Cardiology, Saint Michael's Medical Center, Newark, New Jersey
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Pham NTN, Huynh CTN, Nguyen ATT, Ho CQ, Duong LM, Bui DT, Nguyen HH. Pre-gestational diabetes mellitus, gestational diabetes mellitus, and its association with the MTHFR C677T polymorphism. Medicine (Baltimore) 2024; 103:e38648. [PMID: 38996094 PMCID: PMC11245254 DOI: 10.1097/md.0000000000038648] [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: 04/24/2024] [Accepted: 05/30/2024] [Indexed: 07/14/2024] Open
Abstract
Gestational diabetes mellitus (GDM) is a common condition during pregnancy and is associated with an increased risk of pre-eclampsia. The methylenetetrahydrofolate reductase (MTHFR) gene plays a crucial role in folate metabolism and has been implicated in GDM. To investigate the relationship between the MTHFR C677T gene polymorphism and the conditions of GDM and gestational prediabetes in pregnant women. A case-control study was conducted in 114 pregnant women with GDM and 96 pregnant women without GDM, from the first trimester to the prenatal examination at Can Tho Obstetrics Hospital. The pregnant women underwent a 1-hour (G1) and 2-hour (G2) oral glucose tolerance test (OGTT) and genetic polymorphism analysis based on real-time PCR technique. In pregnant women with GDM, weight, concentrations of G0, G1, G2, and folic acid were higher than those in the non-GDM group, with P < .05. When analyzing the subgroup without gestational diabetes, we found that the rate of prediabetes was 16.6% (16/96 pregnant women). In this group, blood glucose levels at 1 hour and 2 hours during the OGTT were higher compared to the normal glucose group (P < .05). A 2-hour post-OGTT glucose level of 7.78 mmol/L had a sensitivity of 93.8%, a specificity of 100%, and an area under the curve of 0.987 for diagnosing gestational prediabetes (P < .001). However, there were no statistically significant differences in the CC, CT, and TT polymorphisms of the MTHFR C677T gene among pregnant women with or without pre-gestational and GDM. Both fasting blood glucose and 2-hour glucose concentrations during the OGTT, as well as folic acid concentrations, were higher in both the pre-gestational and GDM groups compared to the non-gestational diabetes cohort. However, the analysis of MTHFR C677T polymorphisms revealed no statistically significant differences among the groups, highlighting the necessity for more extensive investigations to gain deeper insights into this relationship.
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Affiliation(s)
| | | | | | - Chuong Quoc Ho
- University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh, Vietnam
| | - Linh My Duong
- Can Tho University of Medicine and Pharmacy, Can Tho City, Vietnam
| | - Dung The Bui
- University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh, Vietnam
| | - Ha Hong Nguyen
- Can Tho University of Medicine and Pharmacy, Can Tho City, Vietnam
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Pietruszyńska-Reszetarska A, Pietruszyński R, Irzmański R. The Significance of Genetically Determined Methylation and Folate Metabolism Disorders in the Pathogenesis of Coronary Artery Disease: A Target for New Therapies? Int J Mol Sci 2024; 25:6924. [PMID: 39000032 PMCID: PMC11241586 DOI: 10.3390/ijms25136924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 06/18/2024] [Accepted: 06/21/2024] [Indexed: 07/14/2024] Open
Abstract
Methylation is a biochemical process involving the addition of a methyl group (-CH3) to various chemical compounds. It plays a crucial role in maintaining the homeostasis of the endothelium, which lines the interior surface of blood vessels, and has been linked, among other conditions, to coronary artery disease (CAD). Despite significant progress in CAD diagnosis and treatment, intensive research continues into genotypic and phenotypic CAD biomarkers. This review explores the significance of the methylation pathway and folate metabolism in CAD pathogenesis, with a focus on endothelial dysfunction resulting from deficiency in the active form of folate (5-MTHF). We discuss emerging areas of research into CAD biomarkers and factors influencing the methylation process. By highlighting genetically determined methylation disorders, particularly the MTHFR polymorphism, we propose the potential use of the active form of folate (5-MTHF) as a novel CAD biomarker and personalized pharmaceutical for selected patient groups. Our aim is to improve the identification of individuals at high risk of CAD and enhance their prognosis.
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Affiliation(s)
| | - Robert Pietruszyński
- Cardiology Outpatient Clinic, Military Medical Academy Memorial Teaching Hospital of the Medical University of Lodz—Central Veterans’ Hospital, 90-549 Lodz, Poland;
| | - Robert Irzmański
- Department of Internal Medicine, Rehabilitation and Physical Medicine, Medical University of Lodz, 90-645 Lodz, Poland;
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Tsukamoto M, Hishida A, Tamura T, Nagayoshi M, Okada R, Kubo Y, Kato Y, Hamajima N, Nishida Y, Shimanoe C, Ibusuki R, Shibuya K, Takashima N, Nakamura Y, Kusakabe M, Nakamura Y, Koyanagi YN, Oze I, Nishiyama T, Suzuki S, Watanabe I, Matsui D, Otonari J, Ikezaki H, Katsuura-Kamano S, Arisawa K, Kuriki K, Nakatochi M, Momozawa Y, Takeuchi K, Wakai K, Matsuo K. GWAS of Folate Metabolism With Gene-environment Interaction Analysis Revealed the Possible Role of Lifestyles in the Control of Blood Folate Metabolites in Japanese: The J-MICC Study. J Epidemiol 2024; 34:228-237. [PMID: 37517992 PMCID: PMC10999522 DOI: 10.2188/jea.je20220341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 06/30/2023] [Indexed: 08/01/2023] Open
Abstract
BACKGROUND The present genome-wide association study (GWAS) aimed to reveal the genetic loci associated with folate metabolites, as well as to detect related gene-environment interactions in Japanese. METHODS We conducted the GWAS of plasma homocysteine (Hcy), folic acid (FA), and vitamin B12 (VB12) levels in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study participants who joined from 2005 to 2012, and also estimated gene-environment interactions. In the replication phase, we used data from the Yakumo Study conducted in 2009. In the discovery phase, data of 2,263 participants from four independent study sites of the J-MICC Study were analyzed. In the replication phase, data of 573 participants from the Yakumo Study were analyzed. RESULTS For Hcy, MTHFR locus on chr 1, NOX4 on chr 11, CHMP1A on chr 16, and DPEP1 on chr 16 reached genome-wide significance (P < 5 × 10-8). MTHFR also associated with FA, and FUT2 on chr 19 associated with VB12. We investigated gene-environment interactions in both studies and found significant interactions between MTHFR C677T and ever drinking, current drinking, and physical activity >33% on Hcy (β = 0.039, 0.038 and -0.054, P = 0.018, 0.021 and <0.001, respectively) and the interaction of MTHFR C677T with ever drinking on FA (β = 0.033, P = 0.048). CONCLUSION The present GWAS revealed the folate metabolism-associated genetic loci and gene-environment interactions with drinking and physical activity in Japanese, suggesting the possibility of future personalized cardiovascular disease prevention.
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Affiliation(s)
- Mineko Tsukamoto
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Asahi Hishida
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Tamura
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mako Nagayoshi
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Rieko Okada
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoko Kubo
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasufumi Kato
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nobuyuki Hamajima
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuichiro Nishida
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | | | - Rie Ibusuki
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kenichi Shibuya
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Naoyuki Takashima
- Department of Public Health, Shiga University of Medical Science, Otsu, Japan
| | - Yasuyuki Nakamura
- Department of Public Health, Shiga University of Medical Science, Otsu, Japan
| | - Miho Kusakabe
- Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Yohko Nakamura
- Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Yuriko N. Koyanagi
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Isao Oze
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Takeshi Nishiyama
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Sadao Suzuki
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Isao Watanabe
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Daisuke Matsui
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Jun Otonari
- Department of Psychosomatic Medicine, Kyushu University Graduate School of Medical Sciences, Faculty of Medical Sciences, Fukuoka, Japan
| | - Hiroaki Ikezaki
- Department of Comprehensive General Internal Medicine, Kyushu University Graduate School of Medical Sciences, Faculty of Medical Sciences, Fukuoka, Japan
| | - Sakurako Katsuura-Kamano
- Department of Preventive Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Kokichi Arisawa
- Laboratory of Public Health, Division of Nutritional Sciences, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan
| | - Kiyonori Kuriki
- Laboratory of Public Health, Division of Nutritional Sciences, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan
| | - Masahiro Nakatochi
- Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukihide Momozawa
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Kenji Takeuchi
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of International and Community Oral Health, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
- Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Akcılar R, Yalınbaş EE, Mutlu F. MTHFR 677 C > T Gene Polymorphism is Associated with Large for Gestational Age Infants. Fetal Pediatr Pathol 2024; 43:234-245. [PMID: 38743580 DOI: 10.1080/15513815.2024.2352755] [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: 03/22/2024] [Accepted: 05/02/2024] [Indexed: 05/16/2024]
Abstract
BACKGROUND The aim of this study was to investigate the methylenetetrahydrofolate reductase (MTHFR) 677 C > T gene polymorphism in term infants born small (SGA), appropriate (AGA), and large for gestational age (LGA). METHODS The study comprised 165 newborns with SGA, LGA and AGA. Genomic DNA was isolated from the peripheral blood. Samples were genotyped for MTHFR 677 C > T gene polymorphisms using PCR-RFLP. RESULTS There was a statistically significant difference between the genotype and their allelic distribution of AGA, SGA, and LGA. The newborns carrying the TT genotype had higher birth weight than those carrying the CC and CT genotypes. The frequency of MTHFR 677 TT genotype and T allele was significantly higher and was found to be linked with a higher risk in LGA than in the AGA group. CONCLUSIONS The MTHFR 677 C > T gene polymorphism can be used as a genetic marker in Turkish LGA newborns, but not in SGA.
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Affiliation(s)
- Raziye Akcılar
- Faculty of Medicine, Department of Physiology, Kütahya Health Sciences University, Kütahya, Turkey
| | | | - Fezan Mutlu
- Faculty of Medicine, Department of Biostatistics, Eskisehir Osmangazi University, Eskisehir, Turkey
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Ismail AB, Dundar MS, Erguzeloglu CO, Ergoren MC, Alemdar A, Ozemri Sag S, Temel SG. Alzheimer Disease Associated Loci: APOE Single Nucleotide Polymorphisms in Marmara Region. Biomedicines 2024; 12:968. [PMID: 38790930 PMCID: PMC11118074 DOI: 10.3390/biomedicines12050968] [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: 04/06/2024] [Revised: 04/22/2024] [Accepted: 04/24/2024] [Indexed: 05/26/2024] Open
Abstract
Alzheimer's disease (AD) is a major global health challenge, especially among individuals aged 65 or older. According to population health studies, Turkey has the highest AD prevalence in the Middle East and Europe. To accurately determine the frequencies of common and rare APOE single nucleotide polymorphisms (SNPs) in the Turkish population residing in the Marmara Region, we conducted a retrospective study analyzing APOE variants in 588 individuals referred to the Bursa Uludag University Genetic Diseases Evaluation Center. Molecular genotyping, clinical exome sequencing, bioinformatics analysis, and statistical evaluation were employed to identify APOE polymorphisms and assess their distribution. The study revealed the frequencies of APOE alleles as follows: ε4 at 9.94%, ε2 at 9.18%, and ε3 at 80.68%. The gender-based analysis in our study uncovered a tendency for females to exhibit a higher prevalence of mutant genotypes across various SNPs. The most prevalent haplotype observed was ε3/ε3, while rare APOE SNPs were also identified. These findings align with global observations, underscoring the significance of genetic diversity and gender-specific characteristics in comprehending health disparities and formulating preventive strategies.
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Affiliation(s)
- Aya Badeea Ismail
- Department of Medical Genetics, Faculty of Medicine, Near East University, 99138 Nicosia, Cyprus; (A.B.I.); (M.C.E.)
| | - Mehmet Sait Dundar
- Department of Electrıcal and Computer Engineering, Graduate School of Engineering and Sciences, Abdullah Gul University, 38000 Kayseri, Türkiye;
- Halil Bayraktar Health Services Vocational School, Erciyes University, 38030 Kayseri, Türkiye
| | - Cemre Ornek Erguzeloglu
- Department of Translational Medicine, Institute of Health Sciences, Bursa Uludag University, 16059 Bursa, Türkiye; (C.O.E.); (A.A.)
| | - Mahmut Cerkez Ergoren
- Department of Medical Genetics, Faculty of Medicine, Near East University, 99138 Nicosia, Cyprus; (A.B.I.); (M.C.E.)
| | - Adem Alemdar
- Department of Translational Medicine, Institute of Health Sciences, Bursa Uludag University, 16059 Bursa, Türkiye; (C.O.E.); (A.A.)
| | - Sebnem Ozemri Sag
- Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, 16059 Bursa, Türkiye;
| | - Sehime Gulsun Temel
- Department of Translational Medicine, Institute of Health Sciences, Bursa Uludag University, 16059 Bursa, Türkiye; (C.O.E.); (A.A.)
- Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, 16059 Bursa, Türkiye;
- Department of Histology & Embryology, Faculty of Medicine, Bursa Uludag University, 16059 Bursa, Türkiye
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14
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He Q, Wei Y, Zhu H, Liang Q, Chen P, Li S, Song Y, Liu L, Wang B, Xu X, Dong Y. The combined effect of MTHFR C677T and A1298C polymorphisms on the risk of digestive system cancer among a hypertensive population. Discov Oncol 2024; 15:97. [PMID: 38565713 PMCID: PMC10987447 DOI: 10.1007/s12672-024-00960-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 03/29/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND AND PURPOSE The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in directing folate species towards nucleotide synthesis or DNA methylation. The MTHFR polymorphisms C677T and A1298C have been linked to cancer susceptibility, but the evidence supporting this association has been equivocal. To investigate the individual and joint associations between MTHFR C677T, A1298C, and digestive system cancer in a Chinese hypertensive population, we conducted a population-based case-control study involving 751 digestive system cancer cases and one-to-one matched controls from the China H-type Hypertension Registry Study (CHHRS). METHODS We utilized the conditional logistic regression model to evaluate multivariate odds ratios (ORs) and 95% confidence intervals (CIs) of digestive system cancer. RESULTS The analysis revealed a significantly lower risk of digestive system cancer in individuals with the CT genotype (adjusted OR: 0.71; 95% CI 0.52, 0.97; P = 0.034) and TT genotype (adjusted OR: 0.57; 95% CI 0.40, 0.82; P = 0.003; P for trend = 0.003) compared to those with the 677CC genotype. Although A1298C did not show a measurable association with digestive system cancer risk, further stratification of 677CT genotype carriers by A1298C homozygotes (AA) and heterozygotes (AC) revealed a distinct trend within these subgroups. CONCLUSION These findings indicate a potential protective effect against digestive system cancer associated with the T allele of MTHFR C677T. Moreover, we observed that the presence of different combinations of MTHFR polymorphisms may contribute to varying susceptibilities to digestive system cancer.
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Affiliation(s)
- Qiangqiang He
- Shenzhen International Graduate School, Tsinghua University, University Town of Shenzhen, No. 2279, Lishui Road. Nanshan District, Shenzhen, 518055, Guangdong, China
- Shenzhen Evergreen Medical Institute, Shenzhen, 518057, Guangdong, China
| | - Yaping Wei
- College of Public Health, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
| | - Hehao Zhu
- School of Science, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China
| | - Qiongyue Liang
- State Key Laboratory of Natural Medicines, Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China
| | - Ping Chen
- College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, China
- Inspection and Testing Center, Key Laboratory of Cancer FSMP for State Market Regulation, Shenzhen, 518057, China
| | - Shuqun Li
- Department of Gastrointestinal Surgery/Clinical Nutrition, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, 100038, China
| | - Yun Song
- Shenzhen Evergreen Medical Institute, Shenzhen, 518057, Guangdong, China
| | - Lishun Liu
- Shenzhen International Graduate School, Tsinghua University, University Town of Shenzhen, No. 2279, Lishui Road. Nanshan District, Shenzhen, 518055, Guangdong, China
- Shenzhen Evergreen Medical Institute, Shenzhen, 518057, Guangdong, China
- Guangdong Key Laboratory of H-Type Hypertension and Stroke Precision Prevention Research and Development Enterprise, Shenzhen, 518057, China
| | - Binyan Wang
- Shenzhen Evergreen Medical Institute, Shenzhen, 518057, Guangdong, China
- Institute of Biomedicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Xiping Xu
- National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health, Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yuhan Dong
- Shenzhen International Graduate School, Tsinghua University, University Town of Shenzhen, No. 2279, Lishui Road. Nanshan District, Shenzhen, 518055, Guangdong, China.
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15
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Leclerc D, Christensen KE, Reagan AM, Keser V, Luan Y, Malysheva OV, Wasek B, Bottiglieri T, Caudill MA, Howell GR, Rozen R. Folate Deficiency and/or the Genetic Variant Mthfr 677C >T Can Drive Hepatic Fibrosis or Steatosis in Mice, in a Sex-Specific Manner. Mol Nutr Food Res 2024; 68:e2300355. [PMID: 38327171 DOI: 10.1002/mnfr.202300355] [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: 05/31/2023] [Revised: 11/24/2023] [Indexed: 02/09/2024]
Abstract
SCOPE Disturbances in one-carbon metabolism contribute to nonalcoholic fatty liver disease (NAFLD) which encompasses steatosis, steatohepatitis, fibrosis, and cirrhosis. The goal is to examine impact of folate deficiency and the Mthfr677C >T variant on NAFLD. METHODS AND RESULTS This study uses the new Mthfr677C >T mouse model for the human MTHFR677C >T variant. Mthfr677CC and Mthfr677TT mice were fed control diet (CD) or folate-deficient (FD) diets for 4 months. FD and Mthfr677TT alter choline/methyl metabolites in liver and/or plasma (decreased S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio, methyltetrahydrofolate, and betaine; increased homocysteine [Hcy]). FD, with contribution from Mthfr677TT, provokes fibrosis in males. Studies of normal livers reveal alterations in plasma markers and gene expression that suggest an underlying predisposition to fibrosis induced by FD and/or Mthfr677TT in males. These changes are absent or reverse in females, consistent with the sex disparity of fibrosis. Sex-based differences in methylation potential, betaine, sphingomyelin, and trimethylamine-N-oxide (TMAO) levels may prevent fibrogenesis in females. In contrast, Mthfr677TT alters choline metabolism, dysregulates expression of lipid metabolism genes, and promotes steatosis in females. CONCLUSION This study suggests that folate deficiency predisposes males to fibrosis, which is exacerbated by Mthfr677TT, whereas Mthfr677TT predisposes females to steatosis, and reveal novel contributory mechanisms for these NAFLD-related disorders.
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Affiliation(s)
- Daniel Leclerc
- Departments of Human Genetics and Pediatrics, McGill University, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
| | - Karen E Christensen
- Departments of Human Genetics and Pediatrics, McGill University, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
| | | | - Vafa Keser
- Departments of Human Genetics and Pediatrics, McGill University, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
| | - Yan Luan
- Departments of Human Genetics and Pediatrics, McGill University, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
| | - Olga V Malysheva
- Division of Nutritional Sciences and Genomics, Cornell University, Ithaca, NY, USA
| | - Brandi Wasek
- Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA
| | - Teodoro Bottiglieri
- Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA
| | - Marie A Caudill
- Division of Nutritional Sciences and Genomics, Cornell University, Ithaca, NY, USA
| | | | - Rima Rozen
- Departments of Human Genetics and Pediatrics, McGill University, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
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Diaz-Garcia H, Vilchis-Gil J, Castro-Cerritos KV, Rivera-Susunaga LE, Klünder-Klünder M, Granados-Riveron JT, Gómez-López J, López-Torres A, Sánchez-Urbina R. Association between maternal diet, smoking, and the placenta MTHFR 677C/T genotype and global placental DNA methylation. Placenta 2024; 146:17-24. [PMID: 38160599 DOI: 10.1016/j.placenta.2023.12.017] [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: 07/19/2023] [Revised: 12/11/2023] [Accepted: 12/13/2023] [Indexed: 01/03/2024]
Abstract
INTRODUCTION The placenta provides nutrients to the fetus, and it has protective effects against harmful substances. Unhealthy maternal diets and toxic agents might increase free radical (FR) production. Elevated FR levels are associated with a high risk of oxidative stress, which may cause DNA damage. DNA might be oxidized in the placenta, occasionally affecting its methylation profile due to 8-hidroxy-2'-deoxyguanosine formation. METHODS This study assessed 130 mothers and their children. The maternal's nutritional patterns were determined using the Food Frequency Questionnaire. Information on smoking and alcohol consumption was collected during the medical examination. Data on placental DNA were obtained to determine the MTHFR 677C/T genotype and the proportion of placental DNA methylation (pDNAm). RESULTS Consumption of vitamins and folic acid was above 85%. The pDNAm was found to be correlated with gestational age and coffee intake. Mothers with a smoking history had a low pDNAm. Placentas with the TT genotype had a higher but not significant pDNAm. In the placentas with the CC/CT genotype, the pDNAm was positively associated with carbohydrate and biotin intake. However, the TT genotype was negatively associated with folate and vegetable intake. DISCUSSION The pDNAm was positively associated with coffee intake, but not with macro-, and micronutrient intake. However, it was negatively associated with cigarette smoking. The placentas with the CC/CT genotype had a lower pDNAm than those with the TT genotype. In the placentas with the CC/CT or TT genotype, methylation was positively, and negatively associated with micro- or macronutrients, respectively.
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Affiliation(s)
- Hector Diaz-Garcia
- Centro de Investigación en Malformaciones Congénitas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; Escuela Superior de Enfermería y Obstetricia, Instituto Politécnico Nacional, Mexico City 07738, Mexico
| | - Jenny Vilchis-Gil
- Unidad de Investigación Epidemiológica en Endocrinología y Nutrición, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | | | - Luis E Rivera-Susunaga
- Centro de Investigación en Malformaciones Congénitas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; Escuela Superior de Medicina del Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Miguel Klünder-Klünder
- Subdirección de la Gestión de la Investigación, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico
| | - Javier T Granados-Riveron
- Centro de Investigación en Malformaciones Congénitas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico
| | - Jaqueline Gómez-López
- Hospital Militar de Especialidades de la Mujer y Neonatología, Secretaria de la Defensa Nacional, Mexico City 11200, Mexico
| | - Adolfo López-Torres
- Instituto de Química Aplicada, Universidad del Papaloapan, Tuxtepec, Oaxaca 68301, Mexico
| | - Rocío Sánchez-Urbina
- Centro de Investigación en Malformaciones Congénitas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; Escuela Superior de Medicina del Instituto Politécnico Nacional, Mexico City 11340, Mexico.
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Paus T. Population Neuroscience: Principles and Advances. Curr Top Behav Neurosci 2024; 68:3-34. [PMID: 38589637 DOI: 10.1007/7854_2024_474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2024]
Abstract
In population neuroscience, three disciplines come together to advance our knowledge of factors that shape the human brain: neuroscience, genetics, and epidemiology (Paus, Human Brain Mapping 31:891-903, 2010). Here, I will come back to some of the background material reviewed in more detail in our previous book (Paus, Population Neuroscience, 2013), followed by a brief overview of current advances and challenges faced by this integrative approach.
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Affiliation(s)
- Tomáš Paus
- Department of Psychiatry and Neuroscience, Faculty of Medicine, University of Montreal, Montreal, QC, Canada
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18
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Cirstoveanu C, Calin N, Heriseanu C, Filip C, Vasile CM, Margarint I, Marcu V, Dimitriu M, Ples L, Tarnoveanu S, Bizubac M. Consistent Correlation between MTHFR and Vascular Thrombosis in Neonates-Case Series and Clinical Considerations. J Clin Med 2023; 12:4856. [PMID: 37510971 PMCID: PMC10381825 DOI: 10.3390/jcm12144856] [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: 05/14/2023] [Revised: 07/20/2023] [Accepted: 07/22/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND MTHFR polymorphism has been inconsistently linked to thrombotic events-some studies have shown its contribution to venous thrombosis, arterial thrombosis, and ischemic stroke, whereas others have found no statistically significant correlation between them. METHODS A descriptive case series study was performed in the Neonatal Intensive Care Unit of "Marie Sklodowska Curie" Emergency Clinical Hospital for Children in Bucharest, Romania. RESULTS All patients had positive results for MTHFR variants; 14 patients were positive for compound heterozygosity, 13 patients for MTHFR C677T (seven of which were homozygous), and 13 patients for MTHFR A1298C (three of which were homozygous). Eighteen patients received anticoagulants (heparin, enoxaparin, or bivalirudin), and thrombolytics (alteplase) were administered in six cases. In one case, a thrombectomy was performed; in another, vascular plasty was undertaken. Only in six cases was complete revascularization possible. Incomplete revascularization occurred for one patient with a negative outcome. CONCLUSION The particularity of this case series is that every patient in our unit who developed thrombi had a positive genetic result for MTHFR mutations. MTHFR mutations should be regarded as a thrombotic risk factor for critically ill patients, and screening for MTHFR mutations should be performed in every admitted patient to intensive care units, thus achieving the prevention of thrombi.
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Affiliation(s)
- Catalin Cirstoveanu
- Department of Neonatal Intensive Care, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Neonatal Intensive Care Unit, "M.S. Curie" Children's Hospital, Constantin Brâncoveanu Boulevard, No. 20, 4th District, 041451 Bucharest, Romania
| | - Nicoleta Calin
- Neonatal Intensive Care Unit, "M.S. Curie" Children's Hospital, Constantin Brâncoveanu Boulevard, No. 20, 4th District, 041451 Bucharest, Romania
| | - Carmen Heriseanu
- Neonatal Intensive Care Unit, "M.S. Curie" Children's Hospital, Constantin Brâncoveanu Boulevard, No. 20, 4th District, 041451 Bucharest, Romania
- Ph.D. School Department, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Cristina Filip
- Department of Pediatrics, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Pediatric Cardiology, "M.S. Curie" Children's Hospital, Constantin Brâncoveanu Boulevard, No. 20, 4th District, 041451 Bucharest, Romania
| | - Corina Maria Vasile
- Pediatric Cardiology, "M.S. Curie" Children's Hospital, Constantin Brâncoveanu Boulevard, No. 20, 4th District, 041451 Bucharest, Romania
- Department of Pediatric and Adult Congenital Cardiology, University Hospital of Bordeaux, 33600 Pessac, France
| | - Irina Margarint
- Ph.D. School Department, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Pediatric Cardiovascular Surgery, "M.S. Curie" Children's Hospital, Constantin Brâncoveanu Boulevard, No. 20, 4th District, 041451 Bucharest, Romania
| | - Veronica Marcu
- Department of Radiology, "M.S. Curie" Children's Hospital, Constantin Brâncoveanu Boulevard, No. 20, 4th District, 041451 Bucharest, Romania
| | - Mihai Dimitriu
- Ph.D. School Department, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- "Sf. Pantelimon" Emergency Clinical Hospital, 340-342 Pantelimon Road, 021661 Bucharest, Romania
| | - Liliana Ples
- Ph.D. School Department, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- "Bucur" Maternity, "Saint John" Hospital, Intre Garle Street, 040294 Bucharest, Romania
| | - Sorin Tarnoveanu
- Department of Neurosurgery, "M.S. Curie" Children's Hospital, Constantin Brâncoveanu Boulevard, No. 20, 4th District, 041451 Bucharest, Romania
| | - Mihaela Bizubac
- Department of Neonatal Intensive Care, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Neonatal Intensive Care Unit, "M.S. Curie" Children's Hospital, Constantin Brâncoveanu Boulevard, No. 20, 4th District, 041451 Bucharest, Romania
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Hassan MH, Raslan MA, Tharwat M, Sakhr HM, El-Khateeb EES, Sakr SF, Ameen HH, Hamdan AR. Metabolic Analysis of Methylenetetrahydrofolate Reductase Single Nucleotide Polymorphisms (MTHFR 677C<T and MTHFR 1298A<C), Serum Folate and Vitamin B12 in Neural Tube Defects. Indian J Clin Biochem 2023; 38:305-315. [PMID: 37234187 PMCID: PMC10205924 DOI: 10.1007/s12291-022-01049-5] [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: 03/04/2022] [Accepted: 04/17/2022] [Indexed: 10/18/2022]
Abstract
Neural tube defects (NTDs) are among the most prevalent and debilitating birth defects with their causes are still unknown, despite mounting evidence that genetic and/or environmental factors may play a role. We aimed to analyze two single nucleotide polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene, serum folate and vitamin B12 status among a cohort of Egyptian children with NTDs and their mothers. A case-control study has been conducted on 50 Egyptian children with various types of NTDs and their mothers. They were comparable with 50 unrelated healthy, age and sex matched children and their mothers (50) selected as controls. Pediatric and neurosurgical assessments were performed to the included cases. Serum folate and vitamin B12 were measured using ELISA kits. MTHFR 677C
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Affiliation(s)
- Mohammed H. Hassan
- Department of Medical Biochemistry, Faculty of Medicine, South Valley University, Qena, 83523 Egypt
| | - Mohamed A. Raslan
- Department of Chemistry, Faculty of Science, Aswan University, Aswan, 81528 Egypt
| | - Mena Tharwat
- Department of Chemistry, Faculty of Science, Aswan University, Aswan, 81528 Egypt
| | - Hala M. Sakhr
- Department of Pediatrics, Faculty of Medicine, South Valley University, Qena, 83523 Egypt
| | | | - Shimaa Fathy Sakr
- Molecular Biology Unit, Medical Technology Center, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Hesham H. Ameen
- Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University (Assiut Branch), Assiut, Egypt
| | - Ali R. Hamdan
- Department of Neurosurgery, Faculty of Medicine, South Valley University, Qena, 83523 Egypt
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20
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Wang X, Wang Y, Ma X, Zhou S, Xu J, Guo Y, Liu L, Liu Y, Gao L, Yuan L. Gender-specific association of SLC19A1 and MTHFR genetic polymorphism with oxidative stress biomarkers and plasma folate levels in older adults. Exp Gerontol 2023; 178:112208. [PMID: 37201763 DOI: 10.1016/j.exger.2023.112208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/05/2023] [Accepted: 05/15/2023] [Indexed: 05/20/2023]
Abstract
BACKGROUND Plasma folate levels are closely related to antioxidant capacity and are regulated by folate pathway gene polymorphism. However, few studies have explored the gender-specific association of folate pathway gene polymorphism with oxidative stress biomarkers. The present study was designed to explore the gender-specific independent and combined impacts of solute carrier family 19 member 1 (SLC19A1) and methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms on oxidative stress biomarkers in older adults. METHODS A total of 401 subjects were recruited, including 145 males and 256 females. Demographic characteristics of the participants were collected by using a self-administered questionnaire. Fasting venous blood samples were taken for folate pathway gene genotyping, circulating lipids parameters and erythrocyte oxidative stress biomarkers measurement. The difference of genotype distribution and the Hardy-Weinberg equilibrium was calculated by the Chi-square test. The general linear model was applied to compare the plasma folate levels and erythrocyte oxidative stress biomarkers. Multiple linear regression was used to explore the correlation between genetic risk scores and oxidative stress biomarkers. Logistic regression was used to explore the association of genetic risk scores of folate pathway gene with folate deficiency. RESULTS The male subjects have lower plasma folate and HDL-C levels than the female ones, and the male carrying MTHFR rs1801133 (CC) or MTHFR rs2274976 (GA) genotypes have higher erythrocyte SOD activity. The plasma folate levels, erythrocyte SOD and GSH-PX activities were negatively correlated with genetic risk scores in the male subjects. A positive correlation between the genetic risk scores and folate deficiency was observed in the male subjects. CONCLUSIONS There was association between folate pathway gene polymorphism of Solute Carrier Family 19 Member 1 (SLC19A1) and Methylenetetrahydrofolate Reductase (MTHFR) with erythrocyte SOD and GSH-PX activities, and folate levels in male but not in female aging subjects. Genetic variant of genes involved in folate metabolism has strong impact on plasma folate levels in the male aging subjects. Our data demonstrated that there was a potential interaction of gender and its genetic background in affecting the body's antioxidant capacity and the risk of folate deficiency in aging subjects.
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Affiliation(s)
- Xixiang Wang
- School of Public Health, Capital Medical University, Beijing, PR China
| | - Ying Wang
- Suzhou Science & Technology Town Hospital, Suzhou, Jiangsu, PR China
| | - Xiaojun Ma
- School of Public Health, Capital Medical University, Beijing, PR China
| | - Shaobo Zhou
- School of Science, Faculty of Engineering and Science, University of Greenwich, Central Avenue, Chatham ME4 4TB, UK
| | - Jingjing Xu
- School of Public Health, Capital Medical University, Beijing, PR China
| | - Yujie Guo
- School of Public Health, Capital Medical University, Beijing, PR China
| | - Lu Liu
- School of Public Health, Capital Medical University, Beijing, PR China
| | - Yu Liu
- School of Public Health, Capital Medical University, Beijing, PR China
| | - Lifang Gao
- School of Public Health, Capital Medical University, Beijing, PR China
| | - Linhong Yuan
- School of Public Health, Capital Medical University, Beijing, PR China.
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21
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McCaddon A, Miller JW. Homocysteine-a retrospective and prospective appraisal. Front Nutr 2023; 10:1179807. [PMID: 37384104 PMCID: PMC10294675 DOI: 10.3389/fnut.2023.1179807] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 05/22/2023] [Indexed: 06/30/2023] Open
Abstract
The biologically important amino acid homocysteine links sulfur, methionine, and one-carbon metabolism. This review describes its initial discovery, the identification of the clinical condition of "homocystinuria" and the recognition of its close relationship to folate and vitamin B12 metabolism. It discusses the history behind its current association with diverse diseases including neural tube defects, cardio- and cerebrovascular disease and, more recently, dementia and Alzheimer's Disease. It also explores current controversies and considers potential future research directions. It is intended to give a general overview of homocysteine in relation to health and disease.
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Affiliation(s)
- Andrew McCaddon
- Faculty of Social and Life Sciences, Wrexham Glyndwr University, Wrexham, United Kingdom
| | - Joshua W. Miller
- Department of Nutritional Sciences, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ, United States
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22
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Ledowsky CJ, Schloss J, Steel A. Variations in folate prescriptions for patients with the MTHFR genetic polymorphisms: A case series study. EXPLORATORY RESEARCH IN CLINICAL AND SOCIAL PHARMACY 2023; 10:100277. [PMID: 37228355 PMCID: PMC10205484 DOI: 10.1016/j.rcsop.2023.100277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 03/16/2023] [Accepted: 04/30/2023] [Indexed: 05/27/2023] Open
Abstract
Background Over 48.5 million couples are reported with infertility worldwide. Health policy recommends folic acid in women of childbearing age, particularly in preconception and pregnancy which results in women purchasing over-the-counter prenatal multivitamins containing folic acid through pharmacies and other retail outlets. Emerging studies are investigating whether other forms of supplemental folate are more suitable, particularly for those with methylenetetrahydrofolate reductase (MTHFR) polymorphisms. This case series aimed to document variations in forms and dosage of folate prescribed by Australian practitioners to patients with diagnosed infertility and MTHFR polymorphisms. Methods Australian practitioners were invited to complete a retrospective case report form for patients that presented with unexplained infertility. This case report form documented the form and dose of folate that practitioners were prescribing to their infertility patient with MTHFR polymorphisms, together with their fertility history. Results Six practitioners submitted case information for 12 patients with diagnosed infertility and MTHFR polymorphisms. All patients had been advised by their practitioner to remove folic acid in supplemental form and were prescribed 5-methyltetrahydrofolate (5-MTHF) or a combination of 5-MTHF and folinic acid, at higher doses than the Australian recommended dose (mean daily maximum prescribed dose: 2325μg). Eleven patients conceived within the treatment period (average treatment of one year) and ten were reported as having a live birth. Conclusion This case series has highlighted clinical practices that vary from the recommendations by Australian policy. Further research is required to verify the clinical importance of variations in folate prescriptions for women with MTHFR polymorphisms and how folate recommendations may need to change depending on these polymorphisms. This has direct relevance to those prescribing at the pharmacy and retail level, specifically pharmacists and pharmacy assistants.
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Affiliation(s)
- Carolyn Jane Ledowsky
- Endeavour College of Natural Health, now at University of Technology Sydney, Faculty of Health, Australia
| | - Janet Schloss
- Southern Cross University, Natural Centre for Naturopathic Medicine, Lismore, NSW, Australia
| | - Amie Steel
- University of Technology Sydney, Faculty of Health, Australia
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23
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Ovrom EA, Mostert KA, Khakhkhar S, McKee DP, Yang P, Her YF. A Comprehensive Review of the Genetic and Epigenetic Contributions to the Development of Fibromyalgia. Biomedicines 2023; 11:1119. [PMID: 37189737 PMCID: PMC10135661 DOI: 10.3390/biomedicines11041119] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 03/23/2023] [Accepted: 03/28/2023] [Indexed: 05/17/2023] Open
Abstract
This narrative review summarizes the current knowledge of the genetic and epigenetic contributions to the development of fibromyalgia (FM). Although there is no single gene that results in the development of FM, this study reveals that certain polymorphisms in genes involved in the catecholaminergic pathway, the serotonergic pathway, pain processing, oxidative stress, and inflammation may influence susceptibility to FM and the severity of its symptoms. Furthermore, epigenetic changes at the DNA level may lead to the development of FM. Likewise, microRNAs may impact the expression of certain proteins that lead to the worsening of FM-associated symptoms.
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Affiliation(s)
- Erik A. Ovrom
- Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA;
| | - Karson A. Mostert
- Department of Physical Medicine and Rehabilitation, Mayo Clinic Hospital, Rochester, MN 55905, USA
| | - Shivani Khakhkhar
- Department of Orthopedics and Rehabilitation, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Daniel P. McKee
- Department of Orthopedics and Rehabilitation, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Padao Yang
- Department of Psychiatry and Psychology, Mayo Clinic Hospital, Rochester, MN 55905, USA
| | - Yeng F. Her
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic Hospital, Rochester, MN 55905, USA
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24
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Courseault J, Kingry C, Morrison V, Edstrom C, Morrell K, Jaubert L, Elia V, Bix G. Folate-dependent hypermobility syndrome: A proposed mechanism and diagnosis. Heliyon 2023; 9:e15387. [PMID: 37095957 PMCID: PMC10122021 DOI: 10.1016/j.heliyon.2023.e15387] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 04/04/2023] [Accepted: 04/05/2023] [Indexed: 04/26/2023] Open
Abstract
Hypermobility involves excessive flexibility and systemic manifestations of connective tissue fragility. We propose a folate-dependent hypermobility syndrome model based on clinical observations, and through a review of existing literature, we raise the possibility that hypermobility presentation may be dependent on folate status. In our model, decreased methylenetetrahydrofolate reductase (MTHFR) activity disrupts the regulation of the ECM-specific proteinase matrix metalloproteinase 2 (MMP-2), leading to high levels of MMP-2 and elevated MMP-2-mediated cleavage of the proteoglycan decorin. Cleavage of decorin leads ultimately to extracellular matrix (ECM) disorganization and increased fibrosis. This review aims to describe relationships between folate metabolism and key proteins in the ECM that can further explain the signs and symptoms associated with hypermobility, along with possible treatment with 5-methyltetrahydrofolate supplementation.
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Affiliation(s)
- Jacques Courseault
- Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA
- Corresponding
| | - Catherine Kingry
- Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA
| | - Vivianne Morrison
- Tulane University School of Medicine, Departments of Neurosurgery and Neurology, Clinical Neuroscience Research Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
| | - Christiania Edstrom
- Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA
| | - Kelli Morrell
- Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA
| | - Lisa Jaubert
- Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA
| | - Victoria Elia
- Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA
| | - Gregory Bix
- Tulane University School of Medicine, Departments of Neurosurgery and Neurology, Clinical Neuroscience Research Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
- Corresponding
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25
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Jiang H, Liu Z, Townsend JH, Wang J. Effects of Methylenetetrahydrofolate Reductase ( MTHFR) Polymorphisms on Retinal Tissue Perfusion in Mild Diabetic Retinopathy Patients Receiving the Medical Food, Ocufolin ®. Clin Ophthalmol 2023; 17:1121-1127. [PMID: 37077224 PMCID: PMC10106310 DOI: 10.2147/opth.s401743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/27/2023] [Indexed: 04/21/2023] Open
Abstract
Purpose We evaluate the effects of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on retinal tissue perfusion in patients with mild diabetic retinopathy (DR + PM) taking the medical food, Ocufolin®, for 6 months. Methods Prospective, case-controlled study. Eight early diabetic retinopathy patients with common reduced function MTHFR polymorphisms (DR+PM) and 15 normal controls (NC) were recruited. MTHFR polymorphisms were subtyped as normal, C677T, or A1298C. Best corrected visual acuity (BCVA) was evaluated. Retinal blood flow velocity (BFV) was measured using Retinal Function Imager. Retinal tissue perfusion (RTP, blood flow rate per inner retinal volume) was calculated within a 2.5 mm diameter circle centered on the fovea. The medical food is intended to address ocular ischemia with high doses of vitamin B-complexes and antioxidants, including L-methylfolate, methylcobalamin, zinc, copper, lutein, vitamins C, D, E, and n-acetylcysteine. The subjects were provided with a medical food for a period of 6 months. Results BCVA and vascular indices of DR + PM patients at baseline were initially below those of NC and improved after medical food. Compared to baseline, DR + PM patients after the medical food had significantly improved BCVA during the follow-up period (P < 0.05). In comparison, overall RTP and arteriolar BFV were significantly increased at 6 months (P < 0.05). The changes varied with MTHFR subtypes. In patients with the C677T and the C677T/A1298C compound mutations, RTP was increased at 6 months as compared to that at baseline and 4 months (P < 0.05). In patients with only the A1298C mutation, all microcirculation metrics were increased from baseline at 4 and 6 months, but with less improvement at 6 months than at 4 months (P < 0.05). Conclusion Medical food was effective in improving both visual acuity and retinal tissue perfusion in DR + PM patients. The degree of improvement of retinal microcirculation varied among MTHFR subtypes.
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Affiliation(s)
- Hong Jiang
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Zhiping Liu
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Justin H Townsend
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jianhua Wang
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Correspondence: Jianhua Wang, Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, 1638 NW 10th Avenue, McKnight Building - Room 202A, Miami, FL, 33136, USA, Tel +1 305 482-5010, Fax +1 305 482-5012, Email
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26
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Bernsen EC, Hanff LM, Haveman LM, Tops BBJ, van der Lee M, Swen JJ, Huitema ADR, Diekstra MHM. Genetic variants found in paediatric oncology patients with severe chemotherapy-induced toxicity: A case series. J Oncol Pharm Pract 2022:10781552221137302. [DOI: 10.1177/10781552221137302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Paediatric oncology patients who develop severe chemotherapy-induced toxicity that requires dose reduction, delay or termination of treatment are at risk of decreased treatment efficacy. Previous research has provided evidence that genetic variants in TPMT, NUDT15, UGT1A1 and DPYD are associated with toxicity of anticancer drugs. This led to pharmacogenetic guidelines that are integrated into clinical practice in paediatric oncology. Recently, novel genetic variants have been associated with a higher risk of developing chemotherapy-induced toxicity. In this case series, we selected 21 novel variants and genotyped these in nine patients with excessive chemotherapy-induced toxicity using whole exome sequencing or micro-array data. We observed that six out of nine patients carried at least one variant that, according to recent studies, potentially increased the risk of developing methotrexate- or vincristine-induced toxicity. As patient-derived genetic data are becoming widely accessible in paediatric oncology, these variants could potentially enter clinical practice to mitigate chemotherapy-induced toxicity.
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Affiliation(s)
- EC Bernsen
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Pharmacology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek, Amsterdam, The Netherlands
| | - LM Hanff
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Pharmacology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek, Amsterdam, The Netherlands
| | - LM Haveman
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - BBJ Tops
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Diagnostic Laboratory
| | - M van der Lee
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - JJ Swen
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - ADR Huitema
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Pharmacology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek, Amsterdam, The Netherlands
- Department Pharmacy & Pharmacology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek, Amsterdam, The Netherlands
- Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands
| | - MHM Diekstra
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Pharmacology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek, Amsterdam, The Netherlands
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27
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Reagan AM, Christensen KE, Graham LC, Bedwell AA, Eldridge K, Speedy R, Figueiredo LL, Persohn SC, Bottiglieri T, Nho K, Sasner M, Territo PR, Rozen R, Howell GR. The 677C > T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice. J Cereb Blood Flow Metab 2022; 42:2333-2350. [PMID: 36050860 PMCID: PMC9670012 DOI: 10.1177/0271678x221122644] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 06/30/2022] [Accepted: 07/12/2022] [Indexed: 02/03/2023]
Abstract
Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimer's disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants in MTHFR, notably 677 C > T, are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR677C > T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr677C > T allele on the C57BL/6J background (Mthfr677C > T) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr677C > T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity is also reduced in the Mthfr677C > T brain. Mice showed reduced tissue perfusion in numerous brain regions by PET/CT as well as significantly reduced vascular density, pericyte number and increased GFAP-expressing astrocytes in frontal cortex. Electron microscopy revealed cerebrovascular damage including endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment. Collectively, these data support a mechanism by which variations in MTHFR perturb cerebrovascular health laying the foundation to incorporate our new Mthfr677C > T mouse model in studies examining genetic susceptibility for cerebrovascular dysfunction in ADRDs.
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Affiliation(s)
| | - Karen E Christensen
- Departments of Human Genetics and Pediatrics, McGill University,
Research Institute of the Health Center, Montreal, QC, Canada
| | | | - Amanda A Bedwell
- Department of Medicine, Division of Clinical Pharmacology,
Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kierra Eldridge
- Department of Medicine, Division of Clinical Pharmacology,
Indiana University School of Medicine, Indianapolis, IN, USA
| | - Rachael Speedy
- Department of Medicine, Division of Clinical Pharmacology,
Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lucas L Figueiredo
- Department of Medicine, Division of Clinical Pharmacology,
Indiana University School of Medicine, Indianapolis, IN, USA
| | - Scott C Persohn
- Department of Medicine, Division of Clinical Pharmacology,
Indiana University School of Medicine, Indianapolis, IN, USA
| | - Teodoro Bottiglieri
- Center of Metabolomics, Institute of Metabolic Disease, Baylor
Scott & White Research Institute, Dallas, TX, USA
| | - Kwangsik Nho
- Center for Neuroimaging, Indiana Alzheimer’s Disease Research
Center, Department of Radiology and Imaging Sciences, Indiana University School
of Medicine, Indianapolis, IN, USA
| | | | - Paul R Territo
- Department of Medicine, Division of Clinical Pharmacology,
Indiana University School of Medicine, Indianapolis, IN, USA
| | - Rima Rozen
- Departments of Human Genetics and Pediatrics, McGill University,
Research Institute of the Health Center, Montreal, QC, Canada
| | - Gareth R Howell
- The Jackson Laboratory, Bar Harbor, ME, USA
- Graduate School of Biomedical Sciences, Tufts University School
of Medicine, Boston, MA, USA
- Graduate School of Biomedical Sciences and Engineering,
University of Maine, Orono, ME, USA
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Kumari R, Kumar S, Thakur VK, Singh K, Kumar U. MTHFR C677T and MTR A2756G Gene Polymorphism in Neural Tube Defect Patients and Its Association with Red Blood Cell Folate Level in Eastern Indian Population. J Indian Assoc Pediatr Surg 2022; 27:699-706. [PMID: 36714485 PMCID: PMC9878516 DOI: 10.4103/jiaps.jiaps_29_22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 05/14/2022] [Accepted: 06/27/2022] [Indexed: 11/12/2022] Open
Abstract
Introduction Single-nucleotide polymorphism (SNP) is a single-nucleotide change in a deoxyribose nucleic acid (DNA) sequence that occurs in >1% of population. Methylene tetra hydro folate reductase (MTHFR) C677T (rs1801133) and methionine synthase enzyme (MTR) A2756G (rs1805087) are two such SNPs occurring in coding sequence of the respective genes, which are frequently seen with neural tube defects (NTDs). MTHFR and MTR genes are involved in folate metabolism. The folate level in the course of pregnancy is treated as vital in the etiopathogenesis of NTDs. This study aims to explore the association of SNPs of both genes and red blood cell (RBC) folate levels in the predisposition to NTDs. Aims and Objective The purpose of this investigation was to determine the relationship of NTDs with polymorphisms in MTHFR and MTR genotype and to estimate and compare the RBC folate levels in NTD patients and controls. Materials and Methods A total of 397 individuals were enrolled (163 patients and 234 controls) for this observational study. Genotyping to find out MTHFR C677T and MTR A2756G was performed by polymerase chain reaction-restriction fragment length polymorphism technique from DNA extracted from the subject's blood. RBC folate level was estimated by chemiluminescence immunoassay method with the same blood sample. Results The total RBC folate levels were significantly less among cases compared to controls (P = 0.020). A significant difference for RBC folate was observed between case and control groups of various genotypes of MTHFR C677T, except heterozygote CT (P = 0.459). Among MTR A2756G, genotypes with only homozygous AA have significant difference (P = 0.003) for RBC folate levels. Among different types of NTDs, there were no significant differences for RBC folate levels. Among MTHFR C677T, T allele possessed 1.9 times risk compared to C allele for the occurrence of NTDs. In MTR A2756G polymorphism, the odds of developing NTDs were 1.6 times in heterozygous AG compared to homozygous AA. Similarly, the risk for NTDs was three times higher in subjects with both heterozygous AG and CT genotypes compared to wild-type homozygous AA and CC genotypes. Conclusion The total RBC folate levels were significantly less among cases compared to controls, and the genotypes had no such effect in decrease in RBC folate levels. The presence of mutant allele in homozygous or heterozygous condition for both SNPs had increased risk associated with NTDs.
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Affiliation(s)
- Rekha Kumari
- Department of Biochemistry, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
| | - Santosh Kumar
- Department of Biochemistry, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
| | - Vinit Kumar Thakur
- Department of Pediatric Surgery, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
| | - Kalpana Singh
- Department of Reproductive Medicine, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
| | - Uday Kumar
- Department of Biochemistry, Netaji Subhas Medical College and Hospital, Dayalpur Daulatpur, Bihar, India
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Wu X, Liu K, Zhao X, Zhang X, Guo H, Jiang H, Chang J, Lv X, Gao X, Zhi X, Ren C, Chen Q, Liang Y, Li Y. Correlation Between the MTHFR C677T Genotype and Coronary Heart Disease in Populations from Gansu, China. DNA Cell Biol 2022; 41:981-986. [DOI: 10.1089/dna.2022.0329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Xue Wu
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Department of Cardiology, The Second Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Prevention and Treatment for Chronic Diseases by Traditional Chinese Medicine, University Hospital of Gansu Traditional Chinese Medicine, Lanzhou, China
- Second Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Kai Liu
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Key Laboratory of Prevention and Treatment for Chronic Diseases by Traditional Chinese Medicine, University Hospital of Gansu Traditional Chinese Medicine, Lanzhou, China
- Department of Cardiology, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, China
| | - Xinke Zhao
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Key Laboratory of Prevention and Treatment for Chronic Diseases by Traditional Chinese Medicine, University Hospital of Gansu Traditional Chinese Medicine, Lanzhou, China
- Department of Cardiology, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, China
| | - Xiaowei Zhang
- Department of Cardiology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Huan Guo
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Hugang Jiang
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Juan Chang
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Xinfang Lv
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Department of Cardiology, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, China
| | - Xiang Gao
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Department of Cardiology, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, China
| | - Xiaodong Zhi
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Department of Cardiology, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, China
| | - Chunzhen Ren
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Qilin Chen
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yufang Liang
- Department of Cardiology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Yingdong Li
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Key Laboratory of Prevention and Treatment for Chronic Diseases by Traditional Chinese Medicine, University Hospital of Gansu Traditional Chinese Medicine, Lanzhou, China
- Department of Cardiology, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, China
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The Impact of Maternal Folates on Brain Development and Function after Birth. Metabolites 2022; 12:metabo12090876. [PMID: 36144280 PMCID: PMC9503684 DOI: 10.3390/metabo12090876] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/28/2022] [Accepted: 09/13/2022] [Indexed: 11/29/2022] Open
Abstract
Folate is vital for biological processes within the body, including DNA synthesis, DNA repair, and methylation reactions that metabolize homocysteine. The role of folate is particularly important in pregnancy, where there is rapid cellular and tissue growth. Maternal folate deficiencies secondary to inadequate dietary supplementation are known to produce defects in the neural tube and spinal cord, yet the exact mechanism of folate in neurodevelopment is unknown. The consequences of maternal folate deficiency on offspring brain development and function beyond gestation are not well defined. The objective of this review is to investigate the role of folate deficiency in offspring neurodevelopment, and the complications that arise post-gestation. This was accomplished through a comprehensive review of the data presented in both clinical and preclinical studies. Evidence supports that folate deficiency is associated with altered offspring neurodevelopment, including smaller total brain volume, altered cortical thickness and cerebral white matter, altered neurogenesis, and neuronal apoptosis. Some of these changes have been associated with altered brain function in offspring with memory, motor function, language skills, and psychological issues. This review of literature also presents potential mechanisms of folate deficiency in neurodevelopment with altered metabolism, neuroinflammation, epigenetic modification through DNA methylation, and a genetic deficiency in one-carbon metabolism.
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Women Taking a Folic Acid Supplement in Countries with Mandatory Food Fortification Programs May Be Exceeding the Upper Tolerable Limit of Folic Acid: A Systematic Review. Nutrients 2022; 14:nu14132715. [PMID: 35807899 PMCID: PMC9268323 DOI: 10.3390/nu14132715] [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: 06/04/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 12/24/2022] Open
Abstract
Background: In preconception and pregnancy, women are encouraged to take folic acid-based supplements over and above food intake. The upper tolerable limit of folic acid is 1000 mcg per day; however, this level was determined to avoid masking a vitamin B12 deficiency and not based on folic acid bioavailability and metabolism. This review’s aim is to assess the total all-source intake of folate in women of childbearing age and in pregnancy in high-income countries with folate food fortification programs. Methods: A systematic search was conducted in five databases to find studies published since 1998 that reported folate and folic acid intake in countries with a mandatory fortification policy. Results: Women of childbearing age do not receive sufficient folate intake from food sources alone even when consuming fortified food products; however, almost all women taking a folic acid-based supplement exceed the upper tolerable limit of folic acid intake. Conclusions: Folic acid supplement recommendations and the upper tolerable limit of 1000 mcg set by policy makers warrant careful review in light of potential adverse effects of exceeding the upper tolerable limit on folic acid absorption and metabolism, and subsequent impacts on women’s health during their childbearing years.
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Genes Predisposing to Erectile Dysfunction and Management: A Review. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2022. [DOI: 10.2478/sjecr-2021-0080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
Background: The burden of erectile dysfunction (ED) is rising worldwide due to unresponsiveness of some affected individuals to existing drugs and treatment strategies. Fortunately, improvement in biological techniques has led to the understanding that some cases of the disorder may have a genetic etiology, which, when fully understood, may lead to improved treatment.
Objective: This review articulated established ED candidate genes and pathophysiology to assist researchers and medical practitioners to formulate effective drugs and treatment procedures.
Methods: The Google search engine was used to retrieve relevant information on the topic from reputable academic databases, including PubMed, Medline, Google Scholar, Scopus, and SpringerLink.
Results: The search discovered 10 ED candidate genes, which are SIM1, SLC6A4, 5-HTTLPR, TGFB1, DAT1, MC4R, NOS3, GNB3, AR, and MTHFR. Polymorphisms or mutations in these genes may disrupt erectile activities of the hypothalamus, neurotransmitters such as dopamine, serotonin, and nitric oxide as well as relaxation of penile tissues. Clinical presentations of ED include loss of erection, weak vaginal penetration, premature ejaculation, and anejaculation. Each gene has a distinct mechanism, which, if targeted in the affected may reverse the disorder or reduce the effects.
Conclusion: Some cases of ED are genetic, which, when fully understood, may give an insight into new treatment procedures or improve on the current ones. Medical practitioners are advised to formulate treatment procedures that target the affected gene (s) in individuals.
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Li J, Feng D, He S, Yang H, Su Z, Ye H. Association of MTHFR 677C > T gene polymorphism with neonatal defects: a meta-analysis of 81444 subjects. J OBSTET GYNAECOL 2022; 42:1811-1822. [PMID: 35282788 DOI: 10.1080/01443615.2022.2039908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Juan Li
- Department of Clinical Laboratory, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Danqin Feng
- Department of Clinical Laboratory, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Shiwei He
- School of Public Health, Xiamen University, Xiamen, China
| | - Hua Yang
- Department of Obstetrics, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Zhiying Su
- Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Huiming Ye
- Department of Clinical Laboratory, Women and Children’s Hospital, School of Medicine, and Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, China
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Gubina MA, Babenko VN, Batsevich VA, Leibova NA, Zabiyako AP. Polymorphism of Mitochondrial DNA and Six Nuclear Genes in the Amur Evenk Population. RUSS J GENET+ 2022. [DOI: 10.1134/s1022795422010033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles. Biomolecules 2022; 12:biom12020197. [PMID: 35204698 PMCID: PMC8961567 DOI: 10.3390/biom12020197] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued embryo development. The methylation of DNA and histones drives cell division and regulation of gene expression through epigenesis and imprinting. Brain development and its maturation also depend on correct lipid methylation, and continued neuronal function depends on biogenic amines that require methylation for their synthesis. All methylation processes are carried out via a methyltransferase enzyme and its unique co-factor S-adenosylmethionine (SAM); the transfer of a methyl group to a target molecule results in the release of SAH (SA homocysteine), and then homocysteine (Hcy). Both of these molecules are toxic, inhibiting methylation in a variety of ways, and Hcy recycling to methionine is imperative; this is achieved via the one carbon cycle, supported by the folates cycle. Folate deficiency causes hyperhomocysteinaemia, with several associated diseases; during early pregnancy, deficiency interferes with closure of the neural tube at the fourth week of gestation, and nutraceutical supplementation has been routinely prescribed to prevent neural tube defects, mainly involving B vitamins, Zn and folates. The two metabolic pathways are subject to single nucleotide polymorphisms that alter their activity/capacity, often severely, impairing specific physiological functions including fertility, brain and cardiac function. The impact of three types of nutraceutical supplements, folic acid (FA), folinic acid (FLA) and 5 Methyl THF (MTHF), will be discussed here, with their positive effects alongside potentially hazardous secondary effects. The issue surrounding FA and its association with UMFA (unmetabolized folic acid) syndrome is now a matter of concern, as UMFA is currently found in the umbilical cord of the fetus, and even in infants’ blood. We will discuss its putative role in influencing the acquisition of epigenetic marks in the germline, acquired during embryogenesis, as well as the role of FA in the management of cancerous disease.
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Rai V, Kumar P. Relation Between Methylenetetrahydrofolate Reductase Polymorphisms (C677T and A1298C) and Migraine Susceptibility. Indian J Clin Biochem 2022; 37:3-17. [PMID: 35125689 PMCID: PMC8799834 DOI: 10.1007/s12291-021-01000-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 08/17/2021] [Indexed: 01/03/2023]
Abstract
Migraine is a neurological disorder which impairs the patient's quality of life. Several association studies investigating the association between MTHFR gene C677T and A1298C polymorphisms and susceptibility to migraine were published. But the results were conflicting, so authors performed a meta-analysis of published case control studies to find out the exact association between MTHFR polymorphism and migraine susceptibility. Four databases were searched for suitable studies up to December, 2018. Odds ratios (OR) with 95% confidence intervals (CI) was calculated adopting additive, homozygote, co-dominant, dominant, and recessive genetic models. Results of MTHFR C677T polymorphism studies meta-analysis showed significant association with migraine risk using allele contrast, homozygote, dominant and recessive genetic models (T vs. C: OR = 1.18, 95% CI = 1.00-1.26, p = 0.05; TT vs. CC: OR = 1.24, 95% CI = 1.0-1.5, p = 0.04; CT vs. CC: OR = 1.08, 95% CI = 0.97-1.07, p = 0.25; TT + CT vs. CC: OR = 1.15, 95% CI = 1.0-1.29, p = 0.04; TT vs. CT + CC: OR = 1.97, 95% CI = 1.28-3.42, p = 0.002). However, results of MTHFR A1298 polymorphism studies meta-analysis did not show any association with migraine. Subgroup analysis based on ethnicity and migraine types i.e. migraine with aura (MA) and without aura (MO) were also performed. Results of present meta-analysis indicate overall association between MTHFR C677T polymorphism with migraine in total 24 studies, in Asian population and in MA cases but did not show any association with Caucasian population and MO cases.
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Affiliation(s)
- Vandana Rai
- Human Molecular Genetics Laboratory, Department of Biotechnology, VBS Purvanchal University, Jaunpur, UP 222 003 India
| | - Pradeep Kumar
- Human Molecular Genetics Laboratory, Department of Biotechnology, VBS Purvanchal University, Jaunpur, UP 222 003 India
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Raghubeer S, Matsha TE. Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks. Nutrients 2021; 13:nu13124562. [PMID: 34960114 PMCID: PMC8703276 DOI: 10.3390/nu13124562] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/07/2021] [Accepted: 12/15/2021] [Indexed: 02/06/2023] Open
Abstract
The 5-10-methylenetetrahydrofolate reductase (MTHFR) enzyme is vital for cellular homeostasis due to its key functions in the one-carbon cycle, which include methionine and folate metabolism and protein, DNA, and RNA synthesis. The enzyme is responsible for maintaining methionine and homocysteine (Hcy) balance to prevent cellular dysfunction. Polymorphisms in the MTHFR gene, especially C677T, have been associated with various diseases, including cardiovascular diseases (CVDs), cancer, inflammatory conditions, diabetes, and vascular disorders. The C677T MTHFR polymorphism is thought to be the most common cause of elevated Hcy levels, which is considered an independent risk factor for CVD. This polymorphism results in an amino acid change from alanine to valine, which prevents optimal functioning of the enzyme at temperatures above 37 °C. Many studies have been conducted to determine whether there is an association between the C677T polymorphism and increased risk for CVD. There is much evidence in favour of this association, while several studies have concluded that the polymorphism cannot be used to predict CVD development or progression. This review discusses current research regarding the C677T polymorphism and its relationship with CVD, inflammation, diabetes, and epigenetic regulation and compares the evidence provided for and against the association with CVD.
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Ravi KS, Divasha, Hassan SB, Pasi R, Mittra S, Kumar R. Neural tube defects: Different types and brief review of neurulation process and its clinical implication. J Family Med Prim Care 2021; 10:4383-4390. [PMID: 35280642 PMCID: PMC8884297 DOI: 10.4103/jfmpc.jfmpc_904_21] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 09/12/2021] [Accepted: 09/29/2021] [Indexed: 11/13/2022] Open
Abstract
UNLABELLED Neural Tube Defects are the most typical congenital malformations, with almost 300,000 cases annually worldwide. The incidence varies amongst geographical ranges from 0.2 to up to 11 per 1000 live births. In India, incidence is reportedly higher in north than south and can be attributable to diet and genetic variances. Etiology is multifactorial. Severe forms of whitethorn are allied with syndromes. Primary neurulation and secondary neurulation are the most crucial steps in the formation and closure of the neural tube; any interruption can lead to mild to severe NTDs depending on the level of insult during embryogenesis. Various molecular and cellular events take place simultaneously for neural tube bending and closure of the neural tube. Neurological deficit in the newborn is contingent on the level of defect and severity of the structures affected. Survival of the newborn also depends on the severity of the lesion. Folic acid supplementation in all prospective mothers, preferably 4 weeks before conception and at least 12 weeks after conception, can prevent NTDs in folic responsive groups. But there is a significant number of other causes leading to neural tube defects apart from folic acid. Hydrocephalus is the commonest abnormality allied with NTDs in syndromic cases. CONCLUSION NTDs are a frequent cause of stillbirths, infant mortality, and palsies in children. There are various reasons for NTDs, but the process of neurulation points towards some factors of NTC, which can be taken care of to lessen the burden of NTDs.
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Affiliation(s)
- Kumar S. Ravi
- Departments of Anatomy, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Divasha
- Departments of Anatomy, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Sameeullah B. Hassan
- Departments of Anatomy, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Rachna Pasi
- Department of Pediatrics, All India Institute of Medical Sciences, Mangalagiri, Andhra Pradesh, India
| | - Sangh Mittra
- Department of Obstetrics and Gynaecology Avanti Bai Hospital, Balram Pur, Lucknow, Uttar Pradesh, India
| | - Raj Kumar
- Department of Neurosurgery, Uttar Pradesh University of Medical Sciences, Saifai, Uttar Pradesh, India
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Goyal A, Kumawat M, Vashisth M, Gill PS, Sing I, Dhaulakhandi DB. Study of C677T Methylene Tetrahydrofolate Reductase Gene Polymorphism as a Risk Factor for Neural Tube Defects. Asian J Neurosurg 2021; 16:554-561. [PMID: 34660368 PMCID: PMC8477844 DOI: 10.4103/ajns.ajns_372_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 10/08/2020] [Accepted: 03/26/2021] [Indexed: 11/04/2022] Open
Abstract
Introduction Various genetic and environmental factors contribute to the development of neural tube defects (NTDs) which are a group of neurulation defects resulting from failure of closure of embryonic neural tube. Among genetic factors is polymorphism in methylene tetrahydrofolate reductase (MTHFR) gene, giving rise to a gene variant or mutant. However, in most studies directed at finding an association between MTHFR variants and NTD, there is no clear evidence of a cause-and-effect relationship. Materials and Methods Forty diagnosed cases of NTDs and forty healthy individuals were investigated in a case-control study for presence of C677T MTHFR gene polymorphism. Serum folate and Vitamin B12 levels were estimated and MTHFR gene polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism. Results It was found that 32 cases were homozygous with CC genotype and eight were heterozygous with CT genotype, whereas 35 controls had CC genotype and five had CT genotype. TT genotype was absent in both the groups. There was no statistically significant difference between both the groups. No evidence of association between MTHFR C677T polymorphism and NTDs was found. Conclusion Although there was no evidence of association between MTHFR C677T polymorphism and NTDs, our study does not rule out the impact of MTHFR gene mutation on folate metabolism. The reason for absence of TT genotype and no association could be a small sample size. Larger, comprehensive, and well-designed multicentric but feasible studies involving proper subjects and appropriate and adequate controls from several hospitals may provide more meaningful data.
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Affiliation(s)
- Anjalika Goyal
- Department of Biochemistry, PGIMS, Pandit Bhagwat Dayal Sharma University of Health Sciences, Rohtak, Haryana, India
| | - Manjulata Kumawat
- Department of Biochemistry, PGIMS, Pandit Bhagwat Dayal Sharma University of Health Sciences, Rohtak, Haryana, India
| | - Minakshi Vashisth
- Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Paramjit Singh Gill
- Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Ishwar Sing
- Department of Neurosurgery, PGIMS, Pandit Bhagwat Dayal Sharma University of Health Sciences, Rohtak, Haryana, India
| | - Dhara B Dhaulakhandi
- Department of Biotechnology and Molecular Medicine, PGIMS, Pandit Bhagwat Dayal Sharma University of Health Sciences, Rohtak, Haryana, India
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Ledowsky C, Steel A, Schloss J. Methylenetetrahydrofolate Reductase (MTHFR) genetic polymorphisms and the risk of infertility in couples accessing Assisted Reproductive technologies: a systematic review. ADVANCES IN INTEGRATIVE MEDICINE 2021. [DOI: 10.1016/j.aimed.2021.05.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Cassinadane AV, Ramasamy R, Lenin M, Velu K, Hussain SA. Association of MTHFR (rs 1801133) gene polymorphism with biochemical markers of B12 deficiency in type 2 diabetes mellitus patients on metformin therapy. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Tseng FC, Huang TC. Using data mining technology to explore homocysteine at low levels. Medicine (Baltimore) 2021; 100:e26893. [PMID: 34414944 PMCID: PMC8376364 DOI: 10.1097/md.0000000000026893] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 07/19/2021] [Indexed: 01/04/2023] Open
Abstract
A high homocysteine level is known to be an independent risk factor for cardiovascular diseases; however, whether or not low homocysteine level contributes to any damage to the body has not been extensively studied. Furthermore, acquiring healthy subject databases from domestic studies on homocysteine is not trivial. Therefore, we aimed to investigate the causality between serum homocysteine levels and health status and lifestyle factors, particularly with a focus on low serum homocysteine levels. Additionally, we discussed a systematic methodical platform for data collection and statistical analysis, using the descriptive analysis of the chi-square test, t test, multivariate analysis of variance, and logistic regression.This study was a cross-sectional analysis of 5864 subjects (i.e., clients of a health examination clinic) in Taipei, Taiwan during a general health check-up in 2017. The patients' personal information and associated links were excluded. A sample group was selected as per the health criteria defined for this research whose data were processed using SPSS for descriptive statistical analysis using chi-square test, t test, multivariate analysis of variance, and logistic regression analysis.Those working for >12 hours/day had a higher homocysteine level than those working for <12 hours/day (P < .001). The average serum homocysteine level was 7.9 and 8.6 mol/L for people with poor sleep quality and good sleep quality, respectively (P = .003). The homocysteine value of people known to have cancer was analyzed using the logistic regression analysis, revealing a Δodds value of 0.898. The percentage of subjects with a homocysteine value of ≤6.3 μmol/L, who perceived their health status as "not very good" or "very bad," was higher than those with a higher homocysteine level. The number of subjects who perceived their health as poor was higher than expected.The results suggest that the homocysteine level could be an effective health management indicator. We conclude that normal homocysteine level should not be ≤6.3 μmol/L. Moreover, homocysteine should not be considered as harmful and its fluctuations from the normal range could be utilized to infer a person's physical status for health management.
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Affiliation(s)
- Fei-Ching Tseng
- The Lianan Wellness Center of the Lianan Preventative Medicine Institution, Songshan District, Taipei City
| | - Tin-Chung Huang
- Ching-Kuo Institute of Management and Health – Graduate School of Health Industry, Zhongshan District, Keelung City, Taiwan
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Xiao W, Ye P, Wang F, Cao R, Bai Y, Wang X. Plasma Homocysteine Is a Predictive Factor for Accelerated Renal Function Decline and Chronic Kidney Disease in a Community-Dwelling Population. Kidney Blood Press Res 2021; 46:541-549. [PMID: 34365457 DOI: 10.1159/000514360] [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] [Received: 10/12/2020] [Accepted: 01/12/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Whether elevated plasma total homocysteine (tHcy) is a risk factor for the progression of kidney disease in general population has not been well established. The purpose of this study was to investigate the prognostic properties of plasma tHcy for renal function decrement and early chronic kidney disease (CKD) in community-dwelling populations with normal renal function at baseline. METHODS A total of 1,426 participants were enrolled and followed for a median of 4.8 years (interquartile range, 4.5-5.2), and estimated glomerular filtration rate (eGFR) was evaluated. One main outcome was the rapid eGFR decline defined as a decline in eGFR of >3 mL/min per 1.73 m2 per year; the other was the new incidence of CKD. RESULTS At the end of follow-up, the incidence of rapid eGFR decline and new-onset CKD was 20.7 and 5.6%, respectively. In multivariate linear regression analysis, age, central pulse pressure, fasting blood glucose, and concentration of tHcy were independent determinants of the change in eGFR. There was a graded association between tHcy quartiles and eGFR decline. Compared with participants with the lowest quartile of tHcy levels, those with the highest quartile had significantly increased risk for rapid eGFR decline (adjusted odds ratio [aOR] = 1.81; 95% confidence interval [CI]: 1.25-2.94) and new onset of CKD (adjusted hazard ratio = 4.29; 95% CI: 1.42-12.99) after adjusting for various confounders. Similarly, significant associations were also found when baseline tHcy was classified as hyperhomocysteinemia (>15 μmol/L) versus normal tHcy level (≤15 μmol/L). However, there was only association between the change in tHcy levels and new occurrence of CKD but not with rapid eGFR decline (aOR = 0.99, p = 0.613). CONCLUSIONS In this prospective cohort of individuals from community-based population, elevated plasma tHcy emerged as an independent predictor of renal function decline and incident CKD, which might support selection of at-risk individuals.
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Affiliation(s)
- Wenkai Xiao
- Department of Geriatric Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Ping Ye
- Department of Geriatric Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Fan Wang
- Department of Geriatric Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Ruihua Cao
- Department of Geriatric Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yongyi Bai
- Department of Geriatric Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiaona Wang
- Department of Geriatric Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China
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Rallidis LS, Kosmas N, Stathopoulou E, Rallidi M, Gialeraki A. Homozygosity of the TT methylenetetrahydrofolate reductase C677T genotype is an independent long-term predictor of cardiac death in patients with premature myocardial infarction. Curr Med Res Opin 2021; 37:1079-1084. [PMID: 33813997 DOI: 10.1080/03007995.2021.1912720] [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] [Indexed: 10/21/2022]
Abstract
BACKGROUND Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is the main genetic modulator of homocysteine. Data suggest a potential association of homozygosity for the TT MTHFR genotype with premature myocardial infarction (MI). We explored whether TT homozygosity is associated with long-term prognosis in patients with premature ST-segment elevation MI (STEMI). METHODS A total of 265 consecutive patients who had survived their first STEMI ≤35 years of age were followed for a median of 8 years (5-12). Primary endpoints were cardiac death and secondary endpoints were hospitalizations for acute coronary syndrome, myocardial revascularization, arrhythmic event or ischemic stroke. Serum lipids, homocysteine, folate levels were measured at baseline and all patients were also tested for the MTHFR C677T polymorphism. RESULTS During follow-up 14 patients died (cardiac death) [5.3%] while 84 (31.7%) met the secondary endpoints. In univariate Cox regression analysis TT homozygosity predicted the occurrence of cardiac death (Hazard ratio (HR): 4.071; 95% confidence interval (CI): 1.404-11.809, p = .010) but not the occurrence of secondary endpoints (HR: 0.877; 95% CI: 0.479-1.605, p = .669). TT homozygosity remained an independent predictor of cardiac death after adjustment for conventional risk factors (i.e., sex, diabetes mellitus, hypertension, family history of premature coronary artery disease [CAD]) [HR: 4.350; 95% CI: 1.472-12.856, p = .008]. The association also remained after adjustment for left ventricular ejection fraction or the presence of significant CAD. CONCLUSIONS Homozygosity for the TT MTHFR is an independent long-term predictor of cardiac death in patients with premature STEMI.
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Affiliation(s)
- Loukianos S Rallidis
- Second Department of Cardiology, National & Kapodistrian University of Athens School of Medicine, University General Hospital Attikon, Athens, Greece
| | - Nikolaos Kosmas
- Second Department of Cardiology, National & Kapodistrian University of Athens School of Medicine, University General Hospital Attikon, Athens, Greece
| | - Eleni Stathopoulou
- Department of Clinical Biochemistry, National & Kapodistrian University of Athens School of Medicine, University General Hospital Attikon, Athens, Greece
| | - Maria Rallidi
- Harokopio University, Department of Nutrition and Dietetics, Athens, Greece
| | - Argyri Gialeraki
- Laboratory of Haematology and Blood Transfusion Unit, National & Kapodistrian University of Athens School of Medicine, University General Hospital Attikon, Athens, Greece
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Singh BK, Maria A, Bandyopadhyay T, Choudhary SK. Clinico-epidemiological profile and outcomes of babies with neural tube defects in a tertiary care center in Northern India. J Matern Fetal Neonatal Med 2021; 35:7052-7057. [PMID: 34121591 DOI: 10.1080/14767058.2021.1937102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Neural tube defects constitute a major source of disability among children. Proper management requires accurate diagnosis, an assessment of the severity of the lesion, a decision whether intervention is warranted, the nature of the intervention, and educating the family of the need for lifelong medical care. But to do so, reliable data regarding presentation and outcome is very crucial. AIM OF THE STUDY To discuss the clinical epidemiological profile and outcome of babies admitted with neural tube defects (NTDs). MATERIAL AND METHODS Retrospective observational study was done by extracting data from case notes and follow-up files in Department of Neonatology, PGIMER and Dr. RML Hospital, New Delhi over a period from March 2015 to July 2020. RESULTS A total of 25 babies were included in the study. Majority of babies were born to mother at a median age group of 24 (19-36) yrs and nearly one-third of them were illiterate. The history of maternal periconceptional folic acid intake was seen in only five babies (21%). Two third of babies were male (64%) and the median age at admission was at 9 (1-27) days of life. Majority of the cases were open types of NTDs with most common type being meningomyelocele (88%) followed by occipital encephalocele (12%) and there was one case of closed type of neural tube defect having lipomeningomyelocele (4%). The most common associated anomaly was hydrocephalus (76%) followed by Arnold chiari malformation (56%). Motor weakness in form of paraparesis or paraplegia was present in 21 (84%) babies and sensory deficit was present in 44% babies. Bowel and bladder dysfuntion was present in 48% of cases. Ventriculitis was the most common associated morbidity (38%). Meningomyelocele (MMC) repair was the most commonly performed primary surgery (33%) followed by Ventriculo-peritoneal (VP) shunt repair (24%). Twelve babies (48%) were discharged while 2 (8%) expired and 11 (44%) babies left against medical advice. CONCLUSION Neural tube defect is a congenital disorder with significant morbidity. The clinical severity of the NTDs and the uncertainty in their cause makes this a priority for further research. National policies for prevention, in utero diagnosis, and early surgical intervention are required for a better prognosis.
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Affiliation(s)
- Bhawana Komal Singh
- Department of Neonatology, Dr Ram Manohar Lohia Hospital and Post Graduate Institute of Medical Education and Research, New Delhi, India, Atal Bihari Vajpayi Institute of Medical Sciences (ABVIMS) and Dr Ram Manohar Lohia Hospital, New Delhi, India
| | - Arti Maria
- Department of Neonatology, Dr Ram Manohar Lohia Hospital and Post Graduate Institute of Medical Education and Research, New Delhi, India, Atal Bihari Vajpayi Institute of Medical Sciences (ABVIMS) and Dr Ram Manohar Lohia Hospital, New Delhi, India
| | - Tapas Bandyopadhyay
- Department of Neonatology, Dr Ram Manohar Lohia Hospital and Post Graduate Institute of Medical Education and Research, New Delhi, India, Atal Bihari Vajpayi Institute of Medical Sciences (ABVIMS) and Dr Ram Manohar Lohia Hospital, New Delhi, India
| | - Sushil Kumar Choudhary
- Department of Neonatology, Dr Ram Manohar Lohia Hospital and Post Graduate Institute of Medical Education and Research, New Delhi, India, Atal Bihari Vajpayi Institute of Medical Sciences (ABVIMS) and Dr Ram Manohar Lohia Hospital, New Delhi, India
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Liu M, Yu J, Su Z, Sun Y, Liu Y, Xie Q, Li Z, Wang L, Zhang J, Jin L, Ren A. Associations between prenatal exposure to cadmium and lead with neural tube defect risks are modified by single-nucleotide polymorphisms of fetal MTHFR and SOD2: a case-control study. Environ Health 2021; 20:66. [PMID: 34090432 PMCID: PMC8180011 DOI: 10.1186/s12940-021-00752-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 05/24/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND Prenatal exposure to heavy metals is implicated in the etiology of birth defects. We investigated whether concentrations of cadmium (Cd) and lead (Pb) in umbilical cord tissue are associated with risk for neural tube defects (NTDs) and whether selected genetic variants of the fetus modify their associations. METHODS This study included 166 cases of NTD fetuses/newborns and 166 newborns without congenital malformations. Umbilical cord tissue was collected at birth or elective pregnancy termination. Cd and Pb concentrations were assessed by inductively coupled plasma-mass spectrometry, and 20 single-nucleotide polymorphisms (SNPs) in 9 genes were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the risk for NTDs in association with metal concentrations or genotype using logistic regression. Multiplicative-scale interactions between the metals and genotypes on NTD risk were assessed with logistic regression, and additive-scale interactions were estimated with a non-linear mixed effects model. RESULTS Higher concentrations of Cd were observed in the NTD group than in the control group, but no difference was found for Pb. Concentrations of Cd above the median level showed a risk effect, while the association between Pb and NTD risk was not significant in univariate analyses. The association of Cd was attenuated after adjusting for periconceptional folic acid supplementation. Fetuses with the AG and GG genotypes of rs4880 in SOD2 (superoxide dismutase 2) tended to have a lower risk, but fetuses with the CT and TT genotypes of rs1801133 in MTHFR (5,10-methylenetetrahydrofolatereductase) have a higher risk for NTDs when compared to their respective wild-type. rs4880 and Cd exhibited a multiplicative-scale interaction on NTD risk: the association between higher Cd and the risk for NTDs was increased by over fourfold in fetuses carrying the G allele [OR 4.43 (1.30-15.07)] compared to fetuses with the wild-type genotype. rs1801133 and Cd exposure showed an additive interaction, with a significant relative excess risk of interaction [RERI 0.64 (0.02-1.25)]. CONCLUSIONS Prenatal exposure to Cd may be a risk factor for NTDs, and the risk effect may be enhanced in fetuses who carry the G allele of rs4880 in SOD2 and T allele of rs1801133 in MTHFR.
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Affiliation(s)
- Mengyuan Liu
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Jinhui Yu
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Zaiming Su
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Ying Sun
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Yaqiong Liu
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Qing Xie
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Zhiwen Li
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Linlin Wang
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Jie Zhang
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Lei Jin
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Aiguo Ren
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
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Ponti G, Pastorino L, Manfredini M, Ozben T, Oliva G, Kaleci S, Iannella R, Tomasi A. COVID-19 spreading across world correlates with C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene prevalence. J Clin Lab Anal 2021; 35:e23798. [PMID: 34061414 PMCID: PMC8209953 DOI: 10.1002/jcla.23798] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/15/2021] [Accepted: 03/31/2021] [Indexed: 11/30/2022] Open
Abstract
Background Homocysteine assessment has been proposed as a potential predictive biomarker for the severity of COVID‐19 infection. The purpose of this review was to analyze the correlation between the prevalence of MTHFR C677 T gene polymorphism and COVID‐19 incidence and mortality worldwide. Methods Data regarding MTHFR C677 T gene mutation were obtained from the interrogation of the Genome Aggregation Database (genomAD), which is publicly available from the web“https://gnomad.broadinstitute.org.” COVID‐19 cases, including prevalence and mortality, were obtained from“https://www.worldometers.info/coronavirus” 27 August 2020. Results There is a clear trend toward the worldwide prevalence of MTHFR 677 T and COVID‐19 incidence and mortality. The prevalence of MTHFR677 T allele in the Latino population, and the incidence and mortality for COVID‐19 was higher for this ethnic group than that reported for most other populations globally. Statistical analysis showed a relatively strong correlation between C677 T and death from coronavirus. Conclusions Genetic polymorphism of MTHFR C677 T may modulate the incidence and severity of COVID‐19 pandemic infection.
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Affiliation(s)
- Giovanni Ponti
- Division of Clinical Pathology, Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | | | - Marco Manfredini
- Dermatology Unit, Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Tomris Ozben
- Department of Clinical Biochemistry, Medical Faculty, Akdeniz University, Antalya, Turkey
| | - Gabriella Oliva
- Internal Medicine, Ospedale del Mare, Asl Napoli1, Naples, Italy
| | - Shaniko Kaleci
- Clinical and experimental medicine (CEM), Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Raffaele Iannella
- Division of Clinical Pathology, Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Aldo Tomasi
- Division of Clinical Pathology, Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
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Fedota O, Sadovnychenko I, Chorna L, Roshcheniuk L, Vorontsov V, Ryzhko P, Haybonyuk I, Belyaev S, Belozorov I, Makukh H. The Effects of Polymorphisms in One-carbon Metabolism Genes on Manifestation of Ichthyosis Vulgaris. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.6004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Ichthyosis vulgaris is the most common type of Mendelian disorders of cornification, caused by loss-of-function mutations in the gene encoding epidermal protein filaggrin (FLG), namely R501X and 2282del4. FLG 2282del4 mutation in heterozygotes is incompletely penetrant. Polymorphisms in one-carbon metabolism genes could be associated with clinical manifestation of ichthyosis vulgaris.
AIM: The purpose of the present study was to analyze the effects of MTHFR, MTR and MTRR polymorphisms in patients with ichthyosis vulgaris.
METHODS: 31 patients with ichthyosis vulgaris, 7 their FLG heterozygous relatives without symptoms of disorder, and 150 healthy controls were enrolled in study. FLG null mutations —R501X (rs61816761) and 2282del4 (rs558269137) — and one-carbon metabolism gene polymorphisms — MTHFR C677T (rs1801133), MTHFR A1298C (rs1801131), MTR A2756G (rs1805087) and MTRR A66G (rs1801394) — were analyzed by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay.
RESULTS: Among patients with ichthyosis, heterozygous for FLG 2282del4 mutation, the distributions of genotypes for folate metabolism genes were: MTHFR C677T CC:CT:TT —29.4%:70.6%:0.0%; MTHFR A1298C AA:AC:CC — 52.9%:47.1%:0.0%; MTR A2756G AA:AG:GG — 70.3%:23.5%:5.9%; MTRR A66G AA:AG:GG — 23.4%:52.9%:23.5%. The frequencies of MTR 2756AA and MTRR 66GG genotypes were 1.4–1.6 times higher in affected individuals heterozygous for 2282del4 than in patients with other FLG genotypes. In affected 2282del4 heterozygotes, the frequency of MTR 2756AA genotype was 1.6 times greater than in healthy controls (p<0.01). The strongest association was found between MTHFR 677CT/MTHFR 1298AA/MTR 2756AA/MTRR 66AG genotype and ichthyosis — OR=11.23 (95% CI 2.51−50.21, p=0.002).
CONCLUSIONS: Various genotypes of one-carbon metabolism genes increase the risk of ichthyosis in heterozygotes for the FLG 2282del4 mutation (OR 2.799‑11.231). The most probable predisposing genotype is 677CT/1298AA/2756AA+AG/66AG.
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Ho P, Quigley MA, Tatwavedi D, Britto C, Kurinczuk JJ. Neonatal and infant mortality associated with spina bifida: A systematic review and meta-analysis. PLoS One 2021; 16:e0250098. [PMID: 33979363 PMCID: PMC8115829 DOI: 10.1371/journal.pone.0250098] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/30/2021] [Indexed: 11/24/2022] Open
Abstract
Objectives A systematic review was conducted in high-income country settings to analyse: (i) spina bifida neonatal and IMRs over time, and (ii) clinical and socio-demographic factors associated with mortality in the first year after birth in infants affected by spina bifida. Data sources PubMed, Embase, Ovid, Web of Science, CINAHL, Scopus and the Cochrane Library were searched from 1st January, 1990 to 31st August, 2020 to review evidence. Study selection Population-based studies that provided data for spina bifida infant mortality and case fatality according to clinical and socio-demographical characteristics were included. Studies were excluded if they were conducted solely in tertiary centres. Spina bifida occulta or syndromal spina bifida were excluded where possible. Data extraction and synthesis Independent reviewers extracted data and assessed their quality using MOOSE guideline. Pooled mortality estimates were calculated using random-effects (+/- fixed effects) models meta-analyses. Heterogeneity between studies was assessed using the Cochrane Q test and I2 statistics. Meta-regression was performed to examine the impact of year of birth cohort on spina bifida infant mortality. Results Twenty studies met the full inclusion criteria with a total study population of over 30 million liveborn infants and approximately 12,000 spina bifida-affected infants. Significant declines in spina bifida associated infant and neonatal mortality rates (e.g. 4.76% decrease in IMR per 100, 000 live births per year) and case fatality (e.g. 2.70% decrease in infant case fatality per year) were consistently observed over time. Preterm birth (RR 4.45; 2.30–8.60) and low birthweight (RR 4.77; 2.67–8.55) are the strongest risk factors associated with increased spina bifida infant case fatality. Significance Significant declines in spina bifida associated infant/neonatal mortality and case fatality were consistently observed, advances in treatment and mandatory folic acid food fortification both likely play an important role. Particular attention is warranted from clinicians caring for preterm and low birthweight babies affected by spina bifida.
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Affiliation(s)
- Peter Ho
- National Perinatal Epidemiology Unit (NPEU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Maria A Quigley
- National Perinatal Epidemiology Unit (NPEU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | | | - Carl Britto
- Oxford Vaccine Group, University of Oxford, Oxford, United Kingdom
| | - Jennifer J Kurinczuk
- National Perinatal Epidemiology Unit (NPEU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
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Chen L, Chen H, Wang X, Wei B, Wu Z, Chen S, Wang B, Huang H, Jin L. Association of homocysteine with IVF/ICSI outcomes stratified by MTHFR C677T polymorphisms: a prospective cohort study. Reprod Biomed Online 2021; 43:52-61. [PMID: 34016520 DOI: 10.1016/j.rbmo.2021.04.009] [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] [Received: 12/13/2020] [Revised: 04/08/2021] [Accepted: 04/11/2021] [Indexed: 10/21/2022]
Abstract
RESEARCH QUESTION What is the association between homocysteine (Hcy) and IVF/intracytoplasmic sperm injection (ICSI) outcomes, stratified by methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms? DESIGN This prospective cohort study recruited 1011 infertile women undergoing IVF/ICSI treatment for the first time at the International Peace Maternity and Child Health Hospital between June 2015 and March 2018. RESULTS The concentration of total serum Hcy was significantly negatively associated with clinical pregnancy and implantation rate. When adjusted for maternal and paternal age and educational level, maternal body mass index, and FSH and oestradiol concentrations, logistic regression analysis showed that women with higher Hcy had a higher risk of unsuccessful pregnancy. After stratification by MTHFR C677T polymorphisms and adjustment for confounding factors, a higher risk of unsuccessful pregnancy and a significantly lower implantation rate only existed in women with higher Hcy concentration in the MTHFR C677T TT genotype. There was no significant association between Hcy concentrations and other ovarian stimulation outcomes (oocytes retrieved, metaphase II stage oocytes, fertilization rate, cleavage rate, high-quality embryo rate) or neonatal outcomes (preterm birth, gestational age at delivery, Caesarean section, birthweight, small for gestational age, large for gestational age or birth defects). CONCLUSIONS Hcy is highly negatively associated with clinical pregnancy and implantation rate during the first IVF/ICSI cycle, especially in women carrying the MTHFR C677T TT genotype. Other factors with impacts on reproductive outcomes, such as stage of embryo transferred, other factors involved in folate metabolism, preimplantation genetic testing, etc., should be taken into account in further research.
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Affiliation(s)
- Luting Chen
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China
| | - Huixi Chen
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China
| | - Xiaojin Wang
- Department of Biostatistics, Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Bing Wei
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Zhengmu Wu
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Songchang Chen
- Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China
| | - Bingshun Wang
- Department of Biostatistics, Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hefeng Huang
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China; Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China.
| | - Li Jin
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China.
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