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Marcuzzi A, Caceres-Matos R, Åsvold BO, Gil-Garcia E, Nilsen TIL, Mork PJ. Interplay between chronic widespread pain and lifestyle factors on the risk of type 2 diabetes: longitudinal data from the Norwegian HUNT Study. BMJ Open Diabetes Res Care 2023; 11:e003249. [PMID: 37739420 PMCID: PMC10533697 DOI: 10.1136/bmjdrc-2022-003249] [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: 11/28/2022] [Accepted: 09/05/2023] [Indexed: 09/24/2023] Open
Abstract
INTRODUCTION Chronic widespread pain (CWP) and diabetes commonly co-occur; however, it is unclear whether CWP infers an additional risk for diabetes among those with known risk factors for type 2 diabetes. We aimed to examine if CWP magnifies the effect of adverse lifestyle factors on the risk of diabetes. RESEARCH DESIGN AND METHODS The study comprised data on 25 528 adults in the Norwegian HUNT Study without diabetes at baseline (2006-2008). We calculated adjusted risk ratios (RRs) with 95% CIs for diabetes at follow-up (2017-2019), associated with CWP and body mass index (BMI), physical activity, and insomnia symptoms. The relative excess risk due to interaction (RERI) was calculated to investigate the synergistic effect between CWP and adverse lifestyle factors. RESULTS Compared with the reference group without chronic pain and no adverse lifestyle factors, those with BMI ≥30 kg/m2 with and without CWP had RRs for diabetes of 10.85 (95% CI 7.83 to 15.05) and 8.87 (95% CI 6.49 to 12.12), respectively; those with physical activity <2 hours/week with and without CWP had RRs for diabetes of 2.26 (95% CI 1.78 to 2.88) and 1.54 (95% CI 1.24 to 1.93), respectively; and those with insomnia symptoms with and without CWP had RRs for diabetes of 1.31 (95% CI 1.07 to 1.60) and 1.27 (95% CI 1.04 to 1.56), respectively. There was little evidence of synergistic effect between CWP and BMI ≥30 kg/m2 (RERI=1.66, 95% CI -0.44 to 3.76), low physical activity (RERI=0.37, 95% CI -0.29 to 1.03) or insomnia symptoms (RERI=-0.09, 95% CI -0.51 to 0.34) on the risk of diabetes. CONCLUSIONS These findings show no clear interaction between CWP and adverse lifestyle factors on the risk of diabetes.
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Affiliation(s)
- Anna Marcuzzi
- Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Physical Medicine and Rehabilitation, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Rocio Caceres-Matos
- Department of Nursing, Faculty of Nursing, Physiotherapy and Podiatry, University of Seville, Seville, Spain
| | - Bjørn Olav Åsvold
- Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
- K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway
- HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway
| | - Eugenia Gil-Garcia
- Department of Nursing, Faculty of Nursing, Physiotherapy and Podiatry, University of Seville, Seville, Spain
| | - Tom I L Nilsen
- Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway
- Clinic of Anesthesia and Intensive Care, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Paul Jarle Mork
- Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway
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Sardarzadeh N, Khojasteh-Leylakoohi F, Damavandi S, Khalili-Tanha G, Dashtiahangar M, Khalili-Tanha N, Avan A, Amoueian S, Hassanian SM, Esmaily H, Khazaei M, Ferns G, Khooei A, Aliakbarian M. Association of a Genetic Variant in the Cyclin-Dependent Kinase Inhibitor 2B with Risk of Pancreatic Cancer. Rep Biochem Mol Biol 2022; 11:336-343. [PMID: 36164638 PMCID: PMC9455181 DOI: 10.52547/rbmb.11.2.336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 03/27/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Pancreatic cancer (PC) is among the most aggressive tumors with a poor prognosis, indicating the need for the identification of a novel prognostic biomarker for risk stratifications. Recent genome-wide association studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of different malignancies. METHODS In the present study, we explore the possible relationship between genetic variant, rs10811661, and gene expression of CDKN2B in 75 pancreatic cancer patients, and 188 healthy individuals. DNAs were extracted and genotyping and gene expression were performed by TaqMan real-time PCR and RT-PCR, respectively. Logistic regression was used to assess the association between risk and genotypes, while the significant prognostic variables in the univariate analysis were included in multivariate analyses. RESULTS The patients with PDAC had a higher frequency of a TT genotype for rs10811661 than the control group. Also, PDAC patients with dominant genetic model, (TT + TC), was associated with increased risk of developing PDAC (OR= 14.71, 95% CI [1.96-110.35], p= 0.009). Moreover, patients with CC genotype had a higher expression of CDKN2B, in comparison with TT genotype. CONCLUSION Our findings demonstrated that CDKN2A/B was associated with the risk of developing PDAC, supporting further investigations in the larger and multicenter setting to validate the potential value of this gene as an emerging marker for PDAC.
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Affiliation(s)
- Newsha Sardarzadeh
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Fatemeh Khojasteh-Leylakoohi
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Sedigheh Damavandi
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Ghazaleh Khalili-Tanha
- Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Medical Genetics Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mohammad Dashtiahangar
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Nima Khalili-Tanha
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Medical Genetics Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Sakineh Amoueian
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Habibollah Esmaily
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Majid Khazaei
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Gordon Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK.
| | - Alireza Khooei
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mohsen Aliakbarian
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Nurun Nabi A, Ebihara A. Diabetes and Renin-Angiotensin-Aldosterone System: Pathophysiology and Genetics. RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM 2021. [DOI: 10.5772/intechopen.97518] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Diabetes mellitus (DM) is a metabolic disorder and characterized by hyperglycemia. Being a concern of both the developed and developing world, diabetes is a global health burden and is a major cause of mortality world-wide. The most common is the type 2 diabetes mellitus (T2DM), which is mainly caused by resistance to insulin. Long-term complications of diabetes cause microvascular related problems (eg. nephropathy, neuropathy and retinopathy) along with macrovascular complications (eg. cardiovascular diseases, ischemic heart disease, peripheral vascular disease). Renin-angiotensin-aldosterone system (RAAS) regulates homeostasis of body fluid that in turn, maintains blood pressure. Thus, RAAS plays pivotal role in the pathogenesis of long-term DM complications like cardiovascular diseases and chronic kidney diseases. T2DM is a polygenic disease, and the roles of RAAS components in insulin signaling pathway and insulin resistance have been well documented. Hyperglycemia has been found to be associated with the increased plasma renin activity, arterial pressure and renal vascular resistance. Several studies have reported involvement of single variants within particular genes in initiation and development of T2D using different approaches. This chapter aims to investigate and discuss potential genetic polymorphisms underlying T2D identified through candidate gene studies, genetic linkage studies, genome wide association studies.
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Cao J, Yan W, Ma X, Huang H, Yan H. Insulin-like Growth Factor 2 mRNA-Binding Protein 2-a Potential Link Between Type 2 Diabetes Mellitus and Cancer. J Clin Endocrinol Metab 2021; 106:2807-2818. [PMID: 34061963 PMCID: PMC8475209 DOI: 10.1210/clinem/dgab391] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Indexed: 12/12/2022]
Abstract
CONTEXT Type 2 diabetes mellitus (T2DM) and cancer share a variety of risk factors and pathophysiological features. It is becoming increasingly accepted that the 2 diseases are related, and that T2DM increases the risk of certain malignancies. OBJECTIVE This review summarizes recent advancements in the elucidation of functions of insulin-like growth factor 2 (IGF-2) messenger RNA (mRNA)-binding protein 2 (IGF2BP2) in T2DM and cancer. METHODS A PubMed review of the literature was conducted, and search terms included IGF2BP2, IMP2, or p62 in combination with cancer or T2DM. Additional sources were identified through manual searches of reference lists. The increased risk of multiple malignancies and cancer-associated mortality in patients with T2DM is believed to be driven by insulin resistance, hyperinsulinemia, hyperglycemia, chronic inflammation, and dysregulation of adipokines and sex hormones. Furthermore, IGF-2 is oncogenic, and its loss-of-function splice variant is protective against T2DM, which highlights the pivotal role of this growth factor in the pathogenesis of these 2 diseases. IGF-2 mRNA-binding proteins, particularly IGF2BP2, are also involved in T2DM and cancer, and single-nucleotide variations (formerly single-nucleotide polymorphisms) of IGF2BP2 are associated with both diseases. Deletion of the IGF2BP2 gene in mice improves their glucose tolerance and insulin sensitivity, and mice with transgenic p62, a splice variant of IGF2BP2, are prone to diet-induced fatty liver disease and hepatocellular carcinoma, suggesting the biological significance of IGF2BP2 in T2DM and cancer. CONCLUSION Accumulating evidence has revealed that IGF2BP2 mediates the pathogenesis of T2DM and cancer by regulating glucose metabolism, insulin sensitivity, and tumorigenesis. This review provides insight into the potential involvement of this RNA binding protein in the link between T2DM and cancer.
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Affiliation(s)
- Junguo Cao
- Shaanxi Eye Hospital (Xi’an People’s Hospital), Affiliated Guangren Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an 71004, Shaanxi Province, China
- Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg 69120, Germany
| | - Weijia Yan
- Shaanxi Eye Hospital (Xi’an People’s Hospital), Affiliated Guangren Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an 71004, Shaanxi Province, China
- Department of Ophthalmology, University of Heidelberg, Heidelberg 69120, Germany
| | - Xiujian Ma
- Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | - Haiyan Huang
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130000, China
| | - Hong Yan
- Shaanxi Eye Hospital (Xi’an People’s Hospital), Affiliated Guangren Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an 71004, Shaanxi Province, China
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Arikoglu H, Erkoc-Kaya D, Ipekci SH, Gokturk F, Iscioglu F, Korez MK, Baldane S, Gonen MS. Type 2 diabetes is associated with the MTNR1B gene, a genetic bridge between circadian rhythm and glucose metabolism, in a Turkish population. Mol Biol Rep 2021; 48:4181-4189. [PMID: 34117605 DOI: 10.1007/s11033-021-06431-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/21/2021] [Indexed: 01/06/2023]
Abstract
Type 2 diabetes (T2D) is a complicated public health problem in Turkey as well as worldwide. Genome-wide approaches have been guiding in very challenging situations, such as the elucidation of genetic variations underlying complex diseases such as T2D. Despite intensive studies worldwide, few studies have determined the genetic susceptibility to T2D in Turkish populations. In this study, we investigated the effect of genes that are strongly associated with T2D in genome-wide association (GWA) studies, including MTNR1B, CDKAL1, THADA, ADAMTS9 and ENPP1, on T2D and its characteristic traits in a Turkish population. In 824 nonobese individuals (454 T2D patients and 370 healthy individuals), prominent variants of these GWA genes were genotyped by real-time PCR using the LightSNiP Genotyping Assay System. The SNP rs1387153 C/T, which is located 28 kb upstream of the MTNR1B gene, was significantly associated with T2D and fasting blood glucose levels (P < 0.05). The intronic SNP rs10830963 C/G in the MTNR1B gene was not associated with T2D, but it was associated with fasting blood glucose, HbA1C and LDL levels (P < 0.05). The other important GWA loci investigated in our study were not found to be associated with T2D or its traits. Only the SNP rs1044498 (A/C variation) in the ENPP1 gene was determined to be related to fasting blood glucose (P < 0.05). Our study suggests, consistent with the literature, that the MTNR1B locus, which has a prominent role in glucose regulation, is associated with T2D development by affecting blood glucose levels in our population.
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Affiliation(s)
- Hilal Arikoglu
- Department of Medical Biology, Faculty of Medicine, Selcuk University, Konya, Turkey.
| | - Dudu Erkoc-Kaya
- Department of Medical Biology, Faculty of Medicine, Selcuk University, Konya, Turkey
| | - Suleyman Hilmi Ipekci
- Department of Endocrinology and Metabolic Diseases, Hisar Hospital Intercontinental, Istanbul, Turkey
| | - Fatma Gokturk
- Department of Medical Biology, Faculty of Medicine, Selcuk University, Konya, Turkey
| | - Funda Iscioglu
- Department of Statistics, Faculty of Science, Ege University, Izmir, Turkey
| | - Muslu Kazim Korez
- Department of Biostatistics, Faculty of Medicine, Selcuk University, Konya, Turkey
| | - Suleyman Baldane
- Department of Endocrinology and Metabolic Diseases, Faculty of Medicine, Selcuk University, Konya, Turkey
| | - Mustafa Sait Gonen
- Department of Endocrinology and Metabolic Diseases, Faculty of Cerrahpasa Medicine, Istanbul University, Istanbul, Turkey
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Boughanem H, Yubero-Serrano EM, López-Miranda J, Tinahones FJ, Macias-Gonzalez M. Potential Role of Insulin Growth-Factor-Binding Protein 2 as Therapeutic Target for Obesity-Related Insulin Resistance. Int J Mol Sci 2021; 22:ijms22031133. [PMID: 33498859 PMCID: PMC7865532 DOI: 10.3390/ijms22031133] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/13/2021] [Accepted: 01/21/2021] [Indexed: 12/26/2022] Open
Abstract
Evidence from observational and in vitro studies suggests that insulin growth-factor-binding protein type 2 (IGFBP2) is a promising protein in non-communicable diseases, such as obesity, insulin resistance, metabolic syndrome, or type 2 diabetes. Accordingly, great efforts have been carried out to explore the role of IGFBP2 in obesity state and insulin-related diseases, which it is typically found decreased. However, the physiological pathways have not been explored yet, and the relevance of IGFBP2 as an important pathway integrator of metabolic disorders is still unknown. Here, we review and discuss the molecular structure of IGFBP2 as the first element of regulating the expression of IGFBP2. We highlight an update of the association between low serum IGFBP2 and an increased risk of obesity, type 2 diabetes, metabolic syndrome, and low insulin sensitivity. We hypothesize mechanisms of IGFBP2 on the development of obesity and insulin resistance in an insulin-independent manner, which meant that could be evaluated as a therapeutic target. Finally, we cover the most interesting lifestyle modifications that regulate IGFBP2, since lifestyle factors (diet and/or physical activity) are associated with important variations in serum IGFBP2.
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Affiliation(s)
- Hatim Boughanem
- Department of Endocrinology and Nutrition, Institute of Biomedical Research Institute in Malaga (IBIMA), Virgen de la Victoria University Hospital, 29010 Málaga, Spain;
| | - Elena M. Yubero-Serrano
- Lipids and Atherosclerosis Unit, Maimonides Institute for Biomedical Research in Cordoba (IMIBIC), Reina Sofia University Hospital, University of Córdoba, 14004 Córdoba, Spain; (E.M.Y.-S.); (J.L.-M.)
- CIBEROBN (CIBER in Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - José López-Miranda
- Lipids and Atherosclerosis Unit, Maimonides Institute for Biomedical Research in Cordoba (IMIBIC), Reina Sofia University Hospital, University of Córdoba, 14004 Córdoba, Spain; (E.M.Y.-S.); (J.L.-M.)
- CIBEROBN (CIBER in Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Francisco J. Tinahones
- Department of Endocrinology and Nutrition, Institute of Biomedical Research Institute in Malaga (IBIMA), Virgen de la Victoria University Hospital, 29010 Málaga, Spain;
- CIBEROBN (CIBER in Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (F.J.T.); (M.M.-G.); Tel.: +34-951-036-2647 (F.J.T. & M.M.-G.); Fax: +34-951-924-651 (F.J.T. & M.M.-G.)
| | - Manuel Macias-Gonzalez
- Department of Endocrinology and Nutrition, Institute of Biomedical Research Institute in Malaga (IBIMA), Virgen de la Victoria University Hospital, 29010 Málaga, Spain;
- CIBEROBN (CIBER in Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (F.J.T.); (M.M.-G.); Tel.: +34-951-036-2647 (F.J.T. & M.M.-G.); Fax: +34-951-924-651 (F.J.T. & M.M.-G.)
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Sargazi S, Heidari Nia M, Sargazi FM, Sheervalilou R, Saravani R, Mirinejad S. SNPs in the 3'-untranslated region of SLC30A8 confer risk of type 2 diabetes mellitus in a south-east Iranian population: Evidences from case-control and bioinformatics studies. J Diabetes Metab Disord 2020; 19:979-988. [PMID: 33553018 PMCID: PMC7843856 DOI: 10.1007/s40200-020-00590-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/26/2020] [Accepted: 07/15/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is a heterogenic disease with increasing incidence. The SLC30A8 gene encodes an islet zinc transporter (ZnT8), and its variants have been associated with glucose and pro-insulin levels. This study was aimed to examine the effects of a missense variant (rs13266634 C/T), and two 3'UTR variants (rs2466294 C/G and rs2466293 T/C) in SLC30A8 gene on T2DM risk in a south-east Iranian population. METHODS In this experiment, 450 patients diagnosed with T2DM and 453 healthy subjects from the same geographic area were enrolled. Genotypes were amplified using the ARMS-PCR method. In silico analyses were performed to determine the effects of the variants on the local structure of mRNA, splicing patterns, and potential miRNA-gene interactions as well. RESULTS Significant differences were noticed between cases and controls regarding the genotypic and allelic distribution of the studied variants. As regards rs2466293 and rs2466294 variants, enhanced risk of T2DM was found under allelic, dominant, recessive, and codominant models (OR > 1). Besides, different genetic models of rs13266634 were associated with decreased risk of T2DM (OR < 1). Bioinformatics analyses indicated that the rs2466293 variant might influence the binding of some miRNAs, while the G-allele of rs2466294 decreased the stability of SLC30A8-mRNA. CONCLUSIONS In our population, both SNPs in the 3'-untranslated region of SLC30A8 increased the risk of T2DM, while the rs13266634 variant showed a protective association against T2DM susceptibility. Investigating the effects of other variants in this gene or other ZnTs can further indicate such associations in subjects from the same ethnicity.
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Affiliation(s)
- Saman Sargazi
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Milad Heidari Nia
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Fariba Mirani Sargazi
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Roghayeh Sheervalilou
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Ramin Saravani
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Shekoufeh Mirinejad
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran
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Mashal S, Khanfar M, Al-Khalayfa S, Srour L, Mustafa L, Hakooz NM, Zayed AA, Khader YS, Azab B. SLC30A8 gene polymorphism rs13266634 associated with increased risk for developing type 2 diabetes mellitus in Jordanian population. Gene 2020; 768:145279. [PMID: 33161057 DOI: 10.1016/j.gene.2020.145279] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/08/2020] [Accepted: 10/23/2020] [Indexed: 01/15/2023]
Abstract
BACKGROUND Several genome-wide association studies (GWAS) have identified the single nucleotide polymorphism (SNP) rs13266634 in the Solute carrier family 30 member 8 (SLC30A8) gene as a risk factor to type 2 diabetes mellitus (T2DM). Nevertheless, other studies reported controversial findings of no significant association between the rs13266634 with T2DM. In this study, we aimed to investigate the association of this SNP with T2DM among Jordanian population in addition to define its corresponding allelic and genotypic frequencies. METHOD This case-control study enrolled 358 T2DM patients and 326 healthy controls who fulfilled the inclusion criteria. Blood samples were collected from all participants and were used for the rs13266634 SNP genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS We demonstrated a significant association between the C/T rs13266634 SNP and T2DM among Jordanian population. A significant difference was found between the cases and controls regarding the allelic (P = 0.003) distribution. Compared to people having T allele, those with C allele had higher risk of T2DM (OR = 1.47 ; 95% CI: 1.14 - 1.89; P = 0.003). Having a CC genotype versus TT genotype was significantly associated with increased risk to T2DM (OR = 2.44; 95% CI: 1.16 - 5.12; P = 0.019) after adjusting for age, gender, and BMI. Under the recessive model, subjects with CC genotype were more likely to have T2DM compared to those with CT or TT genotypes, (OR = 1.64; 95% CI: 1.18 - 2.26; P = 0.003) after adjusting for age, gender and BMI. CONCLUSION The rs13266634 SNP is significantly associated with T2DM susceptibility among Jordanian Population.
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Affiliation(s)
- Safaa Mashal
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, PO Box: 13617, Queen Rania St., Amman 11942, Jordan
| | - Mariam Khanfar
- Department of Medical Laboratory Sciences, Jordan University of Science and Technology, P.O.Box 3030, Irbid 22110, Jordan
| | - Sawsan Al-Khalayfa
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, PO Box: 13617, Queen Rania St., Amman 11942, Jordan
| | - Luma Srour
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, PO Box: 13617, Queen Rania St., Amman 11942, Jordan
| | - Lina Mustafa
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, PO Box: 13617, Queen Rania St., Amman 11942, Jordan
| | - Nancy M Hakooz
- Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, University of Jordan, PO Box: 13617, Queen Rania St., Amman 11942, Jordan
| | - Ayman A Zayed
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, School of Medicine, The University of Jordan, Jordan University Hospital, PO Box: 13617, Queen Rania St., Amman 11942, Jordan
| | - Yousef S Khader
- Department of Community Medicine, Public Health and Family Medicine, Faculty of Medicine, Jordan University of Science and Technology, P.O.Box 3030, Irbid 22110, Jordan
| | - Bilal Azab
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, PO Box: 13617, Queen Rania St., Amman 11942, Jordan; Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, United States.
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Kahoul Y, Oger F, Montaigne J, Froguel P, Breton C, Annicotte JS. Emerging Roles for the INK4a/ARF ( CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes. Biomolecules 2020; 10:biom10091350. [PMID: 32971832 PMCID: PMC7563355 DOI: 10.3390/biom10091350] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/16/2020] [Accepted: 09/16/2020] [Indexed: 12/25/2022] Open
Abstract
Besides its role as a cell cycle and proliferation regulator, the INK4a/ARF (CDKN2A) locus and its associated pathways are thought to play additional functions in the control of energy homeostasis. Genome-wide association studies in humans and rodents have revealed that single nucleotide polymorphisms in this locus are risk factors for obesity and related metabolic diseases including cardiovascular complications and type-2 diabetes (T2D). Recent studies showed that both p16INK4a-CDK4-E2F1/pRB and p19ARF-P53 (p14ARF in humans) related pathways regulate adipose tissue (AT) physiology and adipocyte functions such as lipid storage, inflammation, oxidative activity, and cellular plasticity (browning). Targeting these metabolic pathways in AT emerged as a new putative therapy to alleviate the effects of obesity and prevent T2D. This review aims to provide an overview of the literature linking the INK4a/ARF locus with AT functions, focusing on its mechanisms of action in the regulation of energy homeostasis.
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Hubáček JA, Šedová L, Olišarová V, Adámková V, Tóthová V. Different prevalence of T2DM risk alleles in Roma population in comparison with the majority Czech population. Mol Genet Genomic Med 2020; 8:e1361. [PMID: 32578971 PMCID: PMC7507457 DOI: 10.1002/mgg3.1361] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/11/2020] [Accepted: 05/19/2020] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND The Czech governmental study suggests up to a 25% higher prevalence of type 2 diabetes mellitus (T2DM) in the Roma population than within the majority population. It is not known whether and to what extent these differences have a genetic background. METHODS To analyze whether the frequencies of the alleles/genotypes of the FTO, TCF7L2, CDKN2A/2B, MAEA, TLE4, IGF2BP2, ARAP1, and KCNJ11 genes differ between the two major ethnic groups in the Czech Republic, we examined them in DNA samples from 302 Roma individuals and 298 Czech individuals. RESULTS Compared to the majority population, Roma are more likely to carry risk alleles in the FTO (26% vs. 16% GG homozygotes, p < .01), IGF2BP2 (22% vs. 10% TT homozygotes, p < .0001), ARAP1 (98% vs. 95% of A allele carriers, p < .005), and CDKN2A/2B (81% vs. 66% of TT homozygotes, p < .001) genes; however, less frequently they are carriers of the TCF7L2 risk allele (34% vs. 48% of the T allele p < .0005). Finally, we found significant accumulation of T2DM-associated alleles between the Roma population in comparison with the majority population (25.4% vs. 15.2% of the carriers of at least 12 risk alleles; p < .0001). CONCLUSION The increased prevalence of T2DM in the Roma population may have a background in different frequencies of the risk alleles of genes associated with T2DM development.
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Affiliation(s)
- Jaroslav A. Hubáček
- Centre for Experimental MedicineInstitute for Clinical and Experimental MedicinePragueCzech Republic
| | - Lenka Šedová
- Faculty of Health and Social SciencesUniversity of South BohemiaČeské BudějoviceCzech Republic
| | - Věra Olišarová
- Faculty of Health and Social SciencesUniversity of South BohemiaČeské BudějoviceCzech Republic
| | - Věra Adámková
- Department of Preventive CardiologyInstitute for Clinical and Experimental MedicinePragueCzech Republic
| | - Valérie Tóthová
- Faculty of Health and Social SciencesUniversity of South BohemiaČeské BudějoviceCzech Republic
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11
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Chuang LY, Yang CS, Yang HS, Yang CH. Identification of High-Order Single-Nucleotide Polymorphism Barcodes in Breast Cancer Using a Hybrid Taguchi-Genetic Algorithm: Case-Control Study. JMIR Med Inform 2020; 8:e16886. [PMID: 32554381 PMCID: PMC7351259 DOI: 10.2196/16886] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/09/2020] [Accepted: 04/08/2020] [Indexed: 12/24/2022] Open
Abstract
Background Breast cancer has a major disease burden in the female population, and it is a highly genome-associated human disease. However, in genetic studies of complex diseases, modern geneticists face challenges in detecting interactions among loci. Objective This study aimed to investigate whether variations of single-nucleotide polymorphisms (SNPs) are associated with histopathological tumor characteristics in breast cancer patients. Methods A hybrid Taguchi-genetic algorithm (HTGA) was proposed to identify the high-order SNP barcodes in a breast cancer case-control study. A Taguchi method was used to enhance a genetic algorithm (GA) for identifying high-order SNP barcodes. The Taguchi method was integrated into the GA after the crossover operations in order to optimize the generated offspring systematically for enhancing the GA search ability. Results The proposed HTGA effectively converged to a promising region within the problem space and provided excellent SNP barcode identification. Regression analysis was used to validate the association between breast cancer and the identified high-order SNP barcodes. The maximum OR was less than 1 (range 0.870-0.755) for two- to seven-order SNP barcodes. Conclusions We systematically evaluated the interaction effects of 26 SNPs within growth factor–related genes for breast carcinogenesis pathways. The HTGA could successfully identify relevant high-order SNP barcodes by evaluating the differences between cases and controls. The validation results showed that the HTGA can provide better fitness values as compared with other methods for the identification of high-order SNP barcodes using breast cancer case-control data sets.
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Affiliation(s)
| | - Cheng-San Yang
- Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City, Taiwan
| | - Huai-Shuo Yang
- Department of Electronic Engineering, National Kaohsiung University of Science and Technology, Kaohsiung City, Taiwan
| | - Cheng-Hong Yang
- Department of Electronic Engineering, National Kaohsiung University of Science and Technology, Kaohsiung City, Taiwan.,Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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12
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Hsieh FI, Chiou HY, Hu CJ, Jeng JS, Lin HJ, Lee JT, Lien LM. Combined Effects of MMP-7, MMP-8 and MMP-26 on the Risk of Ischemic Stroke. J Clin Med 2019; 8:jcm8112011. [PMID: 31752174 PMCID: PMC6912324 DOI: 10.3390/jcm8112011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 10/31/2019] [Accepted: 11/11/2019] [Indexed: 12/16/2022] Open
Abstract
Ischemic stroke (IS) is multifactorial causation combining with traditional cardiovascular disease (CVD) and genetic risk factors. Combined effects of MMP-7, MMP-8 and MMP-26 on the risk of IS remain incompletely understood. We aimed to assess individual and joint effects for IS risk by weighted genetic risk score (wGRS) from these three genes and traditional CVD risk factors. A case-control study including 500 cases with IS and 500 stroke-free healthy controls frequency-matched with cases by age and sex was conducted. The wGRS was a weighted average of the number of risk genotype across selected SNPs from MMP-7, MMP-8 and MMP-26. Multivariate logistic regression models were used to analyze the relationship between wGRS and risk of IS. A wGRS in the second tertile was associated with a 1.5-fold increased risk of IS compared with the lowest tertile after adjusting for traditional CVD risk factors. Compared to subjects with low genetic and low modifiable CVD risk, those with high genetic and high modifiable CVD risk had the highest risk of IS (adjusted-OR = 5.75). In conclusion, higher wGRS was significantly associated with an increased risk for IS. A significant interaction between genetic and traditional CVD risk factors was also found on the risk of IS.
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Affiliation(s)
- Fang-I Hsieh
- School of Public Health, College of Public Health, Taipei Medical University, Taipei 110, Taiwan; (F.-I.H.); (H.-Y.C.)
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
| | - Hung-Yi Chiou
- School of Public Health, College of Public Health, Taipei Medical University, Taipei 110, Taiwan; (F.-I.H.); (H.-Y.C.)
| | - Chaur-Jong Hu
- Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan;
| | - Jiann-Shing Jeng
- Stroke Center and Department of Neurology, National Taiwan University Hospital, Taipei 100, Taiwan;
| | - Huey-Juan Lin
- Department of Neurology, Chi-Mei Medical Center, Tainan 710, Taiwan;
| | - Jiunn-Tay Lee
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan;
| | - Li-Ming Lien
- School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
- Correspondence:
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13
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Abuhendi N, Qush A, Naji F, Abunada H, Al Buainain R, Shi Z, Zayed H. Genetic polymorphisms associated with type 2 diabetes in the Arab world: A systematic review and meta-analysis. Diabetes Res Clin Pract 2019; 151:198-208. [PMID: 30954515 DOI: 10.1016/j.diabres.2019.03.037] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 03/27/2019] [Indexed: 02/07/2023]
Abstract
AIMS T2DM reach epidemic levels in the Arab countries. In this study, we aimed to perform a systematic review and meta-analysis to underline the susceptibility genetic profile of Arab patients with T2DM that result from SNPs. METHODS We searched four literature databases (PubMed, Scopus, Science Direct and Web of Science) through January 2019. We included all SNPs in candidate genes with an OR > 1 that were associated with T2DM among Arab patients with T2DM. Statistical programs such as software Review Manager (Version 5.02) and STATA (Version 15.1) were used. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with a random effects model or a fixed effect model depending on the heterogeneity among studies. I2 statistics and Egger's tests were performed to assess heterogeneity and publication bias. RESULTS Out of 2245 studies, 47 were used for meta-analysis. We captured 31,307 cases and 26,464 controls in which we collected 71 SNPs in 32 genes. A pooled meta-analysis demonstrated 24-69% increase in T2DM risk. Among the 57 SNPs (in 32 genes) that were not included in the meta-analysis, the OR for diabetes ranged from 1.02 to 5.10, with a median of 1.38 (interquartile range 1.33-2.09). Ten studies examined the association between the TCF7L2 polymorphism rs7903146 and T2DM, leading to an aggregated OR of 1.34 (95%CI 1.27-1.41). CONCLUSION The genetic profile that confer susceptibility to T2DM in Arab patients is diverse. This study may serve as a platform for designing a gene panel for testing the susceptibility to T2DM.
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Affiliation(s)
- Najat Abuhendi
- Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar
| | - Abeer Qush
- Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar
| | - Fozieh Naji
- Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar
| | - Hanan Abunada
- Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar
| | - Reeham Al Buainain
- Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar
| | - Zumin Shi
- Department of Nutrition, College of Health Sciences, Qatar University, Doha, Qatar
| | - Hatem Zayed
- Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar.
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14
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Zhang X, Gu HF, Frystyk J, Efendic S, Brismar K, Thorell A. Analyses of IGFBP2 DNA methylation and mRNA expression in visceral and subcutaneous adipose tissues of obese subjects. Growth Horm IGF Res 2019; 45:31-36. [PMID: 30921666 DOI: 10.1016/j.ghir.2019.03.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 03/18/2019] [Accepted: 03/19/2019] [Indexed: 12/13/2022]
Abstract
Insulin-like growth factor binding-protein 2 (IGFBP-2) is secreted by differentiating white adipocytes. Clinical studies demonstrate that circulating IGFBP-2 levels associated inversely with body mass index (BMI) and insulin resistance. To explore possible epigenetic changes of the IGFBP2 gene in obesity, we analyzed DNA methylation and mRNA expression in adipocytes from different depots. Healthy lean controls (BMI = 24.5 ± 0.3 kg/m2, n = 19) and obese subjects (BMI > 35 kg/m2, n = 24) were recruited. All subjects were Swedish Caucasian. Visceral abdominal adipose tissue (VAT) and subcutaneous adipose tissue (SAT) fragments were homogenized. Genomic DNA and total RNAs were extracted. Four CpG sites in the IGFBP2 gene promoter region were analyzed with bisulfite pyrosequencing. IGFBP2 gene expression at mRNA levels was determined with TaqMan real time RT-PCR. Serum samples were used for measurement of circulating IGFBP-2 and leptin levels. IGFBP2 DNA methylation levels in VAT were increased in obese subjects compared with controls (P < .05). By contrast, IGFBP2 mRNA expression levels in VAT were lower in obesity subjects than in controls (P < .05). In SAT, IGFBP2 DNA methylation and RNA expression levels were lower than in VAT, irrespective of obesity. Obese subjects demonstrated increased serum leptin levels (P < .001) and reduced serum IGFBP-2 levels compared to controls (P < .05). In conclusion, the current study demonstrates that IGFBP2 DNA methylation levels are increased in VAT from obese subjects. This suggests that IGFBP-2 is epigenetically regulated in abdominal obesity.
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Affiliation(s)
- Xiuli Zhang
- Department of Nephrology, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Guangdong 518000, China
| | - Harvest F Gu
- Center for Pathophysiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Jan Frystyk
- Department of Endocrinology, Odense University Hospital & Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense DK-5000, Denmark; Department of Clinical Medicine Health, Aarhus University, Aarhus C DK-8000, Denmark.
| | - Suad Efendic
- Rolf Luft Center for Diabetes Research and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17176, Sweden.
| | - Kerstin Brismar
- Rolf Luft Center for Diabetes Research and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17176, Sweden; Department of Endocrinology, Diabetes and Metabolism, Karolinska University Hospital, Stockholm, Sweden.
| | - Anders Thorell
- Department of Clinical Science, Danderyds Hospital, Karolinska Institutet, Danderyd, Stockholm 18288, Sweden; Department of Surgery, Ersta Hospital, Karolinska Institutet, Stockholm 11691, Sweden.
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15
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Witka BZ, Oktaviani DJ, Marcellino M, Barliana MI, Abdulah R. Type 2 Diabetes-Associated Genetic Polymorphisms as Potential Disease Predictors. Diabetes Metab Syndr Obes 2019; 12:2689-2706. [PMID: 31908510 PMCID: PMC6927489 DOI: 10.2147/dmso.s230061] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 11/19/2019] [Indexed: 12/18/2022] Open
Abstract
Diabetes is a major cause of mortality worldwide. There are several types of diabetes, with type 2 diabetes mellitus (T2DM) being the most common. Many factors, including environmental and genetic factors, are involved in the etiology of the disease. Numerous studies have reported the role of genetic polymorphisms in the initiation and development of T2DM. While genome-wide association studies have identified around more than 200 susceptibility loci, it remains unclear whether these loci are correlated with the pathophysiology of the disease. The present review aimed to elucidate the potential genetic mechanisms underlying T2DM. We found that some genetic polymorphisms were related to T2DM, either in the form of single-nucleotide polymorphisms or direct amino acid changes in proteins. These polymorphisms are potential predictors for the management of T2DM.
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Affiliation(s)
- Beska Z Witka
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Dede J Oktaviani
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Marcellino Marcellino
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Melisa I Barliana
- Departement of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
- Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Jatinangor, Indonesia
- Correspondence: Melisa I Barliana Department of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung Sumedang KM. 21, Jatinangor45363, Indonesia Email
| | - Rizky Abdulah
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
- Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Jatinangor, Indonesia
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16
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Xie F, Chan JCN, Ma RCW. Precision medicine in diabetes prevention, classification and management. J Diabetes Investig 2018; 9:998-1015. [PMID: 29499103 PMCID: PMC6123056 DOI: 10.1111/jdi.12830] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 02/12/2018] [Indexed: 12/18/2022] Open
Abstract
Diabetes has become a major burden of healthcare expenditure. Diabetes management following a uniform treatment algorithm is often associated with progressive treatment failure and development of diabetic complications. Recent advances in our understanding of the genomic architecture of diabetes and its complications have provided the framework for development of precision medicine to personalize diabetes prevention and management. In the present review, we summarized recent advances in the understanding of the genetic basis of diabetes and its complications. From a clinician's perspective, we attempted to provide a balanced perspective on the utility of genomic medicine in the field of diabetes. Using genetic information to guide management of monogenic forms of diabetes represents the best-known examples of genomic medicine for diabetes. Although major strides have been made in genetic research for diabetes, its complications and pharmacogenetics, ongoing efforts are required to translate these findings into practice by incorporating genetic information into a risk prediction model for prioritization of treatment strategies, as well as using multi-omic analyses to discover novel drug targets with companion diagnostics. Further research is also required to ensure the appropriate use of this information to empower individuals and healthcare professionals to make personalized decisions for achieving the optimal outcome.
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Affiliation(s)
- Fangying Xie
- Department of Medicine and TherapeuticsPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
| | - Juliana CN Chan
- Department of Medicine and TherapeuticsPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
- Hong Kong Institute of Diabetes and ObesityPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
- Li Ka Shing Institute of Health SciencesPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
- CUHK‐SJTU Joint Research Centre in Diabetes Genomics and Precision MedicinePrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
| | - Ronald CW Ma
- Department of Medicine and TherapeuticsPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
- Hong Kong Institute of Diabetes and ObesityPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
- Li Ka Shing Institute of Health SciencesPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
- CUHK‐SJTU Joint Research Centre in Diabetes Genomics and Precision MedicinePrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
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17
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Szabo M, Máté B, Csép K, Benedek T. Genetic Approaches to the Study of Gene Variants and Their Impact on the Pathophysiology of Type 2 Diabetes. Biochem Genet 2017; 56:22-55. [DOI: 10.1007/s10528-017-9827-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 10/06/2017] [Indexed: 12/18/2022]
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18
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Kodama S, Fujihara K, Ishiguro H, Horikawa C, Ohara N, Yachi Y, Tanaka S, Shimano H, Kato K, Hanyu O, Sone H. Quantitative Relationship Between Cumulative Risk Alleles Based on Genome-Wide Association Studies and Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis. J Epidemiol 2017; 28:3-18. [PMID: 29093303 PMCID: PMC5742374 DOI: 10.2188/jea.je20160151] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Many epidemiological studies have assessed the genetic risk of having undiagnosed or of developing type 2 diabetes mellitus (T2DM) using several single nucleotide polymorphisms (SNPs) based on findings of genome-wide association studies (GWAS). However, the quantitative association of cumulative risk alleles (RAs) of such SNPs with T2DM risk has been unclear. The aim of this meta-analysis is to review the strength of the association between cumulative RAs and T2DM risk. Systematic literature searches were conducted for cross-sectional or longitudinal studies that examined odds ratios (ORs) for T2DM in relation to genetic profiles. Logarithm of the estimated OR (log OR) of T2DM for 1 increment in RAs carried (1-ΔRA) in each study was pooled using a random-effects model. There were 46 eligible studies that included 74,880 cases among 249,365 participants. In 32 studies with a cross-sectional design, the pooled OR for T2DM morbidity for 1-ΔRA was 1.16 (95% confidence interval [CI], 1.13–1.19). In 15 studies that had a longitudinal design, the OR for incident T2DM was 1.10 (95% CI, 1.08–1.13). There was large heterogeneity in the magnitude of log OR (P < 0.001 for both cross-sectional studies and longitudinal studies). The top 10 commonly used genes significantly explained the variance in the log OR (P = 0.04 for cross-sectional studies; P = 0.006 for longitudinal studies). The current meta-analysis indicated that carrying 1-ΔRA in T2DM-associated SNPs was associated with a modest risk of prevalent or incident T2DM, although the heterogeneity in the used genes among studies requires us to interpret the results with caution.
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Affiliation(s)
- Satoru Kodama
- Department of Laboratory Medicine and Clinical Epidemiology for Prevention of Noncommunicable Niigata University Graduate School of Medical and Dental Sciences
| | - Kazuya Fujihara
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine
| | - Hajime Ishiguro
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine
| | - Chika Horikawa
- Department of Health and Nutrition, Faculty of Human Life Studies, University of Niigata Prefecture
| | - Nobumasa Ohara
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine
| | - Yoko Yachi
- Department of Administrative Dietetics, Faculty of Health and Nutrition, Yamanashi Gakuin University
| | - Shiro Tanaka
- Department of Clinical Trial, Design & Management, Translational Research Center, Kyoto University Hospital
| | - Hitoshi Shimano
- Department of Internal Medicine, University of Tsukuba Institute of Clinical Medicine
| | - Kiminori Kato
- Department of Laboratory Medicine and Clinical Epidemiology for Prevention of Noncommunicable Niigata University Graduate School of Medical and Dental Sciences
| | - Osamu Hanyu
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine
| | - Hirohito Sone
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine
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Nikitin AG, Potapov VY, Brovkina OI, Koksharova EO, Khodyrev DS, Philippov YI, Michurova MS, Shamkhalova MS, Vikulova OK, Smetanina SA, Suplotova LA, Kononenko IV, Kalashnikov VY, Smirnova OM, Mayorov AY, Nosikov VV, Averyanov AV, Shestakova MV. Association of polymorphic markers of genes FTO, KCNJ11, CDKAL1, SLC30A8, and CDKN2B with type 2 diabetes mellitus in the Russian population. PeerJ 2017; 5:e3414. [PMID: 28717589 PMCID: PMC5511504 DOI: 10.7717/peerj.3414] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 05/14/2017] [Indexed: 01/11/2023] Open
Abstract
Background The association of type 2 diabetes mellitus (T2DM) with the KCNJ11, CDKAL1, SLC30A8, CDKN2B, and FTO genes in the Russian population has not been well studied. In this study, we analysed the population frequencies of polymorphic markers of these genes. Methods The study included 862 patients with T2DM and 443 control subjects of Russian origin. All subjects were genotyped for 10 single nucleotide polymorphisms (SNPs) of the genes using real-time PCR (TaqMan assays). HOMA-IR and HOMA-β were used to measure insulin resistance and β-cell secretory function, respectively. Results The analysis of the frequency distribution of polymorphic markers for genes KCNJ11, CDKAL1, SLC30A8 and CDKN2B showed statistically significant associations with T2DM in the Russian population. The association between the FTO gene and T2DM was not statistically significant. The polymorphic markers rs5219 of the KCNJ11 gene, rs13266634 of the SLC30A8 gene, rs10811661 of the CDKN2B gene and rs9465871, rs7756992 and rs10946398 of the CDKAL1 gene showed a significant association with impaired glucose metabolism or impaired β-cell function. Conclusion In the Russian population, genes, which affect insulin synthesis and secretion in the β-cells of the pancreas, play a central role in the development of T2DM.
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Affiliation(s)
- Aleksey G Nikitin
- Federal Research Clinical Center for Specialized Types of Health Care and Medical Technologies of Federal Medical and Biology Agency, Moscow, Russian Federation
| | - Viktor Y Potapov
- Clinic of New Medical Technologies "Archimedes", Moscow, Russian Federation
| | - Olga I Brovkina
- Federal Research Clinical Center for Specialized Types of Health Care and Medical Technologies of Federal Medical and Biology Agency, Moscow, Russian Federation
| | | | - Dmitry S Khodyrev
- Federal Research Clinical Center for Specialized Types of Health Care and Medical Technologies of Federal Medical and Biology Agency, Moscow, Russian Federation
| | | | | | | | - Olga K Vikulova
- Endocrinology Research Centre, Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | | | | | - Irina V Kononenko
- Endocrinology Research Centre, Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | | | - Olga M Smirnova
- Endocrinology Research Centre, Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Alexander Y Mayorov
- Endocrinology Research Centre, Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Valery V Nosikov
- State Research Institute of Genetics and Selection of Industrial Microorganisms, Moscow, Russian Federation
| | - Alexander V Averyanov
- Federal Research Clinical Center for Specialized Types of Health Care and Medical Technologies of Federal Medical and Biology Agency, Moscow, Russian Federation
| | - Marina V Shestakova
- Endocrinology Research Centre, Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
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20
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El-Husseiny AA, Gamal El-Din AM, Mariee AD, Mohamed RR, Ibrahiem AH. Association of CDKAL1 gene rs7756992 A/G polymorphism with type 2 diabetes mellitus and diabetic nephropathy in the Egyptian population. GENE REPORTS 2017. [DOI: 10.1016/j.genrep.2017.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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21
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El-Lebedy D, Ashmawy I. Common variants in TCF7L2 and CDKAL1 genes and risk of type 2 diabetes mellitus in Egyptians. J Genet Eng Biotechnol 2016; 14:247-251. [PMID: 30647622 PMCID: PMC6299909 DOI: 10.1016/j.jgeb.2016.10.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 09/21/2016] [Accepted: 10/17/2016] [Indexed: 12/19/2022]
Abstract
In this work we studied association of common variants in transcription factor 7-like 2 (TCF7L2) and cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) genes with type 2 diabetes mellitus (T2DM) in Egyptians. SUBJECTS AND METHODS This is a case-control study; 180 T2DM patients and 210 control subjects were genotyped for TCF7L2 rs7903146 and rs12255372 and CDKAL1 rs7756992 single nucleotide polymorphisms (SNPs) by TaqMan method on real time polymerase chain reaction system (real time-PCR). RESULTS TCF7L2 rs12255372 and rs7903146 associated with T2DM (p = 0.0001 and 0.003; respectively). The rs12255372 variant T allele associated with 2-fold increased risk for T2DM and TT genotype carriers were at 3.58-folds higher risk to develop T2DM than wild genotype (GG) carriers. Meanwhile, rs7903146 variant T allele associated with 1.6-fold increased risk for T2DM and TT genotype carriers were at 2.3-folds higher risk than wild genotype (CC) carriers. Both TCF7L2 SNPs significantly associated with T2DM under additive and dominant models and after adjustment for other covariates. On the other hand, CDKAL1 rs7756992 showed no significant association with T2DM under any genetic model. Both TCF7L2 SNPs were in strong LD (P = 0.02; D' = 0.85). Taking common TCF7L2 rs12255372/rs7903146 GC haplotype as reference, multivariate analysis confirmed the association of rs12255372 T allele-containing haplotypes (TC and TT) with T2DM. Haplotype TC associated with 6.32 times-higher risk for T2DM (95%CI = 0.55-76.17, Pc = 0.04) followed by haplotype TT which associated with 3.88 times-higher risk for the disease (95%CI = 1.09-13.76, Pc = 0.03). CONCLUSION TCF7L2 rs12255372 and rs7903146 common variants associate with T2DM risk in Egyptians.
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Affiliation(s)
- Dalia El-Lebedy
- Department of Clinical and Chemical Pathology, Medical Research Division, National Research Centre, Cairo, Egypt
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Khodyrev DS, Nikitin AG, Brovkin AN, Lavrikova EY, Lebedeva NO, Vikulova OK, Shamhalova MS, Shestakova MV, Mayorov MY, Potapov VA, Nosikov VV, Averyanov AV. The analysis of association between type 2 diabetes and polymorphic markers in the CDKAL1 gene and in the HHEX/IDE locus. RUSS J GENET+ 2016. [DOI: 10.1134/s1022795416110065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Quantitative assessment of genetic testing for type 2 diabetes mellitus based on findings of genome-wide association studies. Ann Epidemiol 2016; 26:816-818.e6. [PMID: 27751632 DOI: 10.1016/j.annepidem.2016.09.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 08/26/2016] [Accepted: 09/16/2016] [Indexed: 12/29/2022]
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Fan M, Li W, Wang L, Gu S, Dong S, Chen M, Yin H, Zheng J, Wu X, Jin J, Jiang X, Cai J, Liu P, Zheng C. Association of SLC30A8 gene polymorphism with type 2 diabetes, evidence from 46 studies: a meta-analysis. Endocrine 2016; 53:381-94. [PMID: 26832344 DOI: 10.1007/s12020-016-0870-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 01/13/2016] [Indexed: 11/30/2022]
Abstract
The solute carrier family 30 member 8 (SLC30A8) gene may be involved in the development of type 2 diabetes mellitus (T2DM) through disrupting β-cell function. The aim of this study was to assess the association between SLC30A8 rs13266634 polymorphism and susceptibility to T2DM. We searched all reports regarding the association between SLC30A8 rs13266634 polymorphism and T2DM risk through Pubmed, Embase, and the Cochrane Library for English language reports and Chongqing VIP database, Wanfang data, CBMDisc, and CNKI for Chinese language studies. Allelic and genotype comparisons between cases and controls were evaluated, and odds ratios with 95 % confidence intervals were used to assess the strength of their association. A random effects model was selected. Publication bias was estimated using Begg's test. Forty-six studies were included in the analysis with a total of 71,890 cases and 96,753 controls. This meta-analysis suggests that SLC30A8 (rs13266634) polymorphism was associated with T2DM risk. Although previous meta-analyses have shown that this association was only found in Asian and European groups, and not in African populations, our analysis revealed the deleterious effect of SLC30A8 rs13266634 on T2DM in an African population when stratified by ethnicity under additive model even with a small number of studies.
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Affiliation(s)
- Mengdi Fan
- Department of Pathology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Weimin Li
- Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Lian Wang
- Diabetes Center and Department of Endocrinology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Suping Gu
- Diabetes Center and Department of Endocrinology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Sisi Dong
- Diabetes Center and Department of Endocrinology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Mengdie Chen
- Diabetes Center and Department of Endocrinology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Haimin Yin
- Diabetes Center and Department of Endocrinology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Jinjue Zheng
- Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Xiaoying Wu
- Diabetes Center and Department of Endocrinology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Jian Jin
- Diabetes Center and Department of Endocrinology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Xuchao Jiang
- Department of Pathophysiology, Obesity and Diabetes Center, Second Military Medical University, Shanghai, 200433, China
| | - Jiao Cai
- Department of Pathophysiology, Obesity and Diabetes Center, Second Military Medical University, Shanghai, 200433, China
| | - Peining Liu
- Department of Child Health, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
| | - Chao Zheng
- Diabetes Center and Department of Endocrinology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
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Phani NM, Adhikari P, Nagri SK, D’Souza SC, Satyamoorthy K, Rai PS. Replication and Relevance of Multiple Susceptibility Loci Discovered from Genome Wide Association Studies for Type 2 Diabetes in an Indian Population. PLoS One 2016; 11:e0157364. [PMID: 27310578 PMCID: PMC4911058 DOI: 10.1371/journal.pone.0157364] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 05/27/2016] [Indexed: 12/13/2022] Open
Abstract
Aim Several genetic variants for type 2 diabetes (T2D) have been identified through genome wide association studies (GWAS) from Caucasian population; however replication studies were not consistent across various ethnicities. Objective of the current study is to examine the possible correlation of 9 most significant GWAS single nucleotide polymorphisms (SNPs) for T2D susceptibility as well as the interactive effect of these variants on the risk of T2D in an Indian population. Methods Case-control cohorts of 1156 individuals were genotyped for 9 SNPs from an Indian population. Association analyses were performed using logistic regression after adjusting for covariates. Multifactor dimensionality reduction (MDR) analysis was adopted to determine gene–gene interactions and discriminatory power of combined SNP effect was assessed by grouping individuals based on the number of risk alleles and by calculating area under the receiver-operator characteristic curve (AUC). Results We confirm the association of TCF7L2 (rs7903146) and SLC30A8 (rs13266634) with T2D. MDR analysis showed statistically significant interactions among four SNPs of SLC30A8 (rs13266634), IGF2BP2 (rs4402960), HHEX (rs1111875) and CDKN2A (rs10811661) genes. Cumulative analysis showed an increase in odds ratio against the baseline group of individuals carrying 5 to 6 risk alleles and discriminatory power of genetic test based on 9 variants showed higher AUC value when analyzed along with body mass index (BMI). Conclusion These results provide a strong evidence for independent association between T2D and SNPs for in TCF7L2 and SLC30A8. MDR analysis demonstrates that independently non-significant variants may interact with one another resulting in increased disease susceptibility in the population tested.
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Affiliation(s)
- Nagaraja M. Phani
- Department of Biotechnology, School of Life Sciences, Manipal University, Manipal-576104, Karnataka, India
| | - Prabha Adhikari
- Department of Medicine, Kasturba Medical College, Manipal University, Mangalore-575001, Karnataka, India
| | - Shivashankara K. Nagri
- Department of Medicine, Kasturba Medical College, Manipal University, Manipal-576104, Karnataka, India
| | - Sydney C. D’Souza
- Department of Medicine, Kasturba Medical College, Manipal University, Mangalore-575001, Karnataka, India
| | - Kapaettu Satyamoorthy
- Department of Biotechnology, School of Life Sciences, Manipal University, Manipal-576104, Karnataka, India
| | - Padmalatha S. Rai
- Department of Biotechnology, School of Life Sciences, Manipal University, Manipal-576104, Karnataka, India
- * E-mail:
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Yako YY, Guewo-Fokeng M, Balti EV, Bouatia-Naji N, Matsha TE, Sobngwi E, Erasmus RT, Echouffo-Tcheugui JB, Kengne AP. Genetic risk of type 2 diabetes in populations of the African continent: A systematic review and meta-analyses. Diabetes Res Clin Pract 2016; 114:136-50. [PMID: 26830076 DOI: 10.1016/j.diabres.2016.01.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 11/27/2015] [Accepted: 01/03/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Type 2 diabetes (T2D) is growing faster in Africa than anywhere else, driven by the dual effects of genetic and environmental factors. We conducted a systematic review and meta-analyses of published studies on genetic markers of T2D in populations within Africa. METHODS Multiple databases were searched for studies of genetic variants associated with T2D in populations living in Africa. Studies reporting on the association of a genetic marker with T2D or indicators of glycaemia were included. Data were extracted on study design and characteristics, genetic determinants, effect estimates of associations with T2D. FINDINGS Overall, 100 polymorphisms in 57 genes have been investigated in relation with T2D in populations within Africa, in 60 studies. Almost all studies used the candidate gene approach, with >88% published during 2006-2014 and 70% (42/60) originating from Tunisia and Egypt. Polymorphisms in ACE, AGRP, eNOS, GSTP1, HSP70-2, MC4R, MTHFR, PHLPP, POL1, TCF7L2, and TNF-α gene were found to be associated with T2D, with overlapping effect on various cardiometabolic traits. The polymorphisms investigated in multiple studies mostly had consistent effects across studies, with only modest or no statistical heterogeneity. Effect sizes were modestly significant [e.g., odd ratio 1.49 (95%CI 1.33-1.66) for TCF7L2 (rs7903146)]. Underpowered genome-wide studies revealed no diabetes risk loci specific to African populations. INTERPRETATION Current evidence on the genetic markers of T2D in African populations mostly originate from North African countries, is overall scanty and largely insufficient to reliably inform the genetic architecture of T2D across Africa.
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Affiliation(s)
- Yandiswa Y Yako
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa; Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Cape Town, South Africa
| | - Magellan Guewo-Fokeng
- Department of Biochemistry, Faculty of Science, University of Yaounde I, Yaounde, Cameroon
| | - Eric V Balti
- Diabetes Research Center, Faculty of Medicine and Pharmacy, Brussels Free University, Brussels, Belgium
| | - Nabila Bouatia-Naji
- INSERM UMR970 Paris Cardiovascular Research Center, 56 rue Leblanc F-75015 Paris, France; Paris Descartes University, PRES Paris Sorbonne, 12 rue de l'école de medecine F75006 Paris, France
| | - Tandi E Matsha
- Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Cape Town, South Africa
| | - Eugene Sobngwi
- Department of Internal Medicine, Faculty of Medicine and Biomedical Sciences, University of Yaounde I, Yaounde, Cameroon
| | - Rajiv T Erasmus
- Division of Chemical Pathology, Faculty of Medicine and Health Sciences, National Health Laboratory Service (NHLS), University of Stellenbosch, Cape Town, South Africa
| | - Justin B Echouffo-Tcheugui
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA; Department of Medicine, MedStar Health System, Baltimore, MD, USA
| | - Andre P Kengne
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa; Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa; The George Institute for Global Health, The University of Sydney, Sydney, NSW, Australia.
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Intronic Polymorphisms in the CDKN2B-AS1 Gene Are Strongly Associated with the Risk of Myocardial Infarction and Coronary Artery Disease in the Saudi Population. Int J Mol Sci 2016; 17:395. [PMID: 26999117 PMCID: PMC4813250 DOI: 10.3390/ijms17030395] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Revised: 03/02/2016] [Accepted: 03/11/2016] [Indexed: 01/01/2023] Open
Abstract
Recent genome-wide association studies identified single nucleotide polymorphisms (SNPs) on the chromosome 9p21.3 conferring the risk for CAD (coronary artery disease) in individuals of Caucasian ancestry. We performed a genetic association study to investigate the effect of 12 candidate SNPs within 9p21.3 locus on the risk of CAD in the Saudi population of the Eastern Province of Saudi Arabia. A total of 250 Saudi CAD patients who had experienced an myocardial infarction (MI) and 252 Saudi age-matched healthy controls were genotyped using TaqMan assay. Controls with evidenced lack of CAD provided 90% of statistical power at the type I error rate of 0.05. Five percent of the results were rechecked for quality control using Sanger sequencing, the results of which concurred with the TaqMan genotyping results. Association analysis of 12 SNPs indicated a significant difference in the genotype distribution for four SNPs between cases and controls (rs564398 p = 0.0315, χ2 = 4.6, odds ratio (OD) = 1.5; rs4977574 p = 0.0336, χ2 = 4.5, OD = 1.4; rs2891168 p = 1.85 × 10 − 10, χ2 = 40.6, OD = 2.1 and rs1333042 p = 5.14 × 10 − 9, χ2 = 34.1, OD = 2.2). The study identified three protective haplotypes (TAAG p = 1.00 × 10 − 4; AGTA p = 0.022 and GGGCC p = 0.0175) and a risk haplotype (TGGA p = 2.86 × 10 − 10) for the development of CAD. This study is in line with others that indicated that the SNPs located in the intronic region of the CDKN2B-AS1 gene are associated with CAD.
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Xiao S, Zeng X, Fan Y, Su Y, Ma Q, Zhu J, Yao H. Gene Polymorphism Association with Type 2 Diabetes and Related Gene-Gene and Gene-Environment Interactions in a Uyghur Population. Med Sci Monit 2016; 22:474-87. [PMID: 26873362 PMCID: PMC4755665 DOI: 10.12659/msm.895347] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 10/12/2015] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND We investigated the association between 8 single-nucleotide polymorphisms (SNPs) at 3 genetic loci (CDKAL1, CDKN2A/2B and FTO) with type 2 diabetes (T2D) in a Uyghur population. MATERIAL AND METHODS A case-control study of 879 Uyghur patients with T2D and 895 non-diabetic Uyghur controls was conducted at the Hospital of Xinjiang Medical University between 2010 and 2013. Eight SNPs in CDKAL1, CDKN2A/2B and FTO were analyzed using Sequenom MassARRAY®SNP genotyping. Factors associated with T2D were assessed by logistic regression analyses. Gene-gene and gene-environment interactions were analyzed by generalized multifactor dimensionality reduction. RESULTS Genotype distributions of rs10811661 (CDKN2A/2B), rs7195539, rs8050136, and rs9939609 (FTO) and allele frequencies of rs8050136 and rs9939609 differed significantly between diabetes and control groups (all P<0.05). While rs10811661, rs8050136, and rs9939609 were eliminated after adjusting for covariates (P>0.05), rs7195539 distribution differed significantly in co-dominant and dominant models (P<0.05). In gene-gene interaction analysis, after adjusting for covariates the two-locus rs10811661-rs7195539 interaction model had a cross-validation consistency of 10/10 and the highest balanced accuracy of 0.5483 (P=0.014). In gene-environment interaction analysis, the 3-locus interaction model TG-HDL-family history of diabetes had a cross-validation consistency of 10/10 and the highest balanced accuracy of 0.7072 (P<0.001). The 4-locus interaction model, rs7195539-TG-HDL-family history of diabetes had a cross-validation consistency of 8/10 (P<0.001). CONCLUSIONS Polymorphisms in CDKN2A/2B and FTO, but not CDKAL1, may be associated with T2D, and alleles rs8050136 and rs9939609 are likely risk alleles for T2D in this population. There were potential interactions among CDKN2A/2B (rs10811661) - FTO (rs7195539) or FTO (rs7195539)-TG-HDL-family history of diabetes in the pathogenesis of T2D in a Uyghur population.
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Affiliation(s)
- Shan Xiao
- Center of Prevention, Diagnosis, and Treatment of Diabetes, Department of Endocrinology, The First Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang, P.R. China
| | - Xiaoyun Zeng
- Center of Prevention, Diagnosis, and Treatment of Diabetes, Department of Endocrinology, The First Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang, P.R. China
| | - Yong Fan
- Center of Prevention, Diagnosis, and Treatment of Diabetes, Department of Endocrinology, The First Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang, P.R. China
| | - Yinxia Su
- Center of Prevention, Diagnosis, and Treatment of Diabetes, Key Laboratory of Metabolic Disease in Xinjiang, The First Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang, P.R. China
| | - Qi Ma
- Center of Prevention, Diagnosis, and Treatment of Diabetes, Key Laboratory of Metabolic Disease in Xinjiang, The First Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang, P.R. China
| | - Jun Zhu
- Center of Prevention, Diagnosis, and Treatment of Diabetes, Department of Endocrinology, The First Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang, P.R. China
| | - Hua Yao
- Center of Prevention, Diagnosis, and Treatment of Diabetes, Key Laboratory of Metabolic Disease in Xinjiang, The First Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang, P.R. China
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Kodama S, Fujihara K, Ishiguro H, Horikawa C, Ohara N, Yachi Y, Tanaka S, Shimano H, Kato K, Hanyu O, Sone H. Meta-analytic research on the relationship between cumulative risk alleles and risk of type 2 diabetes mellitus. Diabetes Metab Res Rev 2016; 32:178-86. [PMID: 26265102 DOI: 10.1002/dmrr.2680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 07/01/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND Our aim is to examine the dose-response association between cumulative genetic risk and actual risk of type 2 diabetes mellitus (T2DM) and the influence of adjustment for covariates on T2DM risk through a comprehensive meta-analysis of observational studies. METHODS Electronic literature search using EMBASE and MEDLINE (from 2003 to 2014) was conducted for cross-sectional or longitudinal studies that presented the odds ratio (OR) for T2DM in each group with categories based on the total number of risk alleles (RAs) carried (RAtotal ) using at least two single-nucleotide polymorphisms. Spline regression model was used to determine the shape of the relationship between the difference from the referent group of each study in RAtotal (ΔRAtotal ) and the natural logarithms of ORs (log OR) for T2DM. RESULTS Sixty-five eligible studies that included 68 267 cases among 182 603 participants were analysed. In both crude and adjusted ORs, defined by adjusting the risk for at least two confounders among age, gender and body mass index, the slope of the log OR for T2DM became less steep as the ΔRAtotal increased. In the analysis limited to 14 cross-sectional and four longitudinal studies presenting both crude and adjusted ORs, regression curves of both ORs in relation to ΔRAtotal were almost identical. CONCLUSION Using only single-nucleotide polymorphisms for T2DM screening was of limited value. However, when genotypic T2DM risk was considered independently from risk in relation to covariates, it was suggested that genetic profiles might have a supplementary role related to conventional T2DM risk factors in identifying individuals at high risk of T2DM. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- Satoru Kodama
- Department of Laboratory Medicine and Clinical Epidemiology for Prevention of Noncommunicable Diseases, Niigata University Faculty of Medicine, Niigata, Japan
| | - Kazuya Fujihara
- Department of Internal Medicine, University of Tsukuba Institute of Clinical Medicine, Ibaraki, Japan
| | - Hajime Ishiguro
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Japan
| | - Chika Horikawa
- Department of Health and Nutrition, Faculty of Human Life Studies, University of Niigata Prefecture, Niigata, Japan
| | - Nobumasa Ohara
- Department of Laboratory Medicine and Clinical Epidemiology for Prevention of Noncommunicable Diseases, Niigata University Faculty of Medicine, Niigata, Japan
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Japan
| | - Yoko Yachi
- Department of Administrative Dietetics, Faculty of Health and Nutrition, Yamanashi Gakuin University, Yamanashi, Japan
| | - Shiro Tanaka
- Department of Clinical Trial, Design and Management, Translational Research Center, Kyoto University Hospital, Kyoto, Japan
| | - Hitoshi Shimano
- Department of Internal Medicine, University of Tsukuba Institute of Clinical Medicine, Ibaraki, Japan
| | - Kiminori Kato
- Department of Laboratory Medicine and Clinical Epidemiology for Prevention of Noncommunicable Diseases, Niigata University Faculty of Medicine, Niigata, Japan
| | - Osamu Hanyu
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Japan
| | - Hirohito Sone
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Japan
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Wang X, Strizich G, Hu Y, Wang T, Kaplan RC, Qi Q. Genetic markers of type 2 diabetes: Progress in genome-wide association studies and clinical application for risk prediction. J Diabetes 2016; 8:24-35. [PMID: 26119161 DOI: 10.1111/1753-0407.12323] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 05/22/2015] [Accepted: 06/16/2015] [Indexed: 12/18/2022] Open
Abstract
Type 2 diabetes (T2D) has become a leading public health challenge worldwide. To date, a total of 83 susceptibility loci for T2D have been identified by genome-wide association studies (GWAS). Application of meta-analysis and modern genotype imputation approaches to GWAS data from diverse ethnic populations has been key in the effort to discover T2D loci. Genetic information is expected to play a vital role in the prediction of T2D, and many efforts have been made to develop T2D risk models that include both conventional and genetic risk factors. Yet, because most T2D genetic variants identified have small effect size individually (10%-20% increased risk of T2D per risk allele), their clinical utility remains unclear. Most studies report that a genetic risk score combining multiple T2D genetic variants does not substantially improve T2D risk prediction beyond conventional risk factors. In this article, we summarize the recent progress of T2D GWAS and further review the incremental predictive performance of genetic markers for T2D.
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Affiliation(s)
- Xueyin Wang
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
| | - Garrett Strizich
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Yonghua Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
| | - Tao Wang
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Robert C Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Qibin Qi
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA
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Khodaeian M, Enayati S, Tabatabaei-Malazy O, Amoli MM. Association between Genetic Variants and Diabetes Mellitus in Iranian Populations: A Systematic Review of Observational Studies. J Diabetes Res 2015; 2015:585917. [PMID: 26587547 PMCID: PMC4637497 DOI: 10.1155/2015/585917] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 01/15/2015] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Diabetes mellitus as the most prevalent metabolic disease is a multifactorial disease which is influenced by environmental and genetic factors. In this systematic review, we assessed the association between genetic variants and diabetes/its complications in studies with Iranian populations. METHODS Google Scholar, PubMed, Scopus, and Persian web databases were systematically searched up to January 2014. The search terms were "gene," "polymorphism," "diabetes," and "diabetic complications"; nephropathy, retinopathy, neuropathy, foot ulcer, and CAD (coronary artery diseases); and Persian equivalents. Animal studies, letters to editor, and in vitro studies were excluded. RESULTS Out of overall 3029 eligible articles, 88 articles were included. We found significant association between CTLA-4, IL-18, VDR, TAP2, IL-12, and CD4 genes and T1DM, HNFα and MODY, haptoglobin, paraoxonase, leptin, TCF7L2, calreticulin, ERα, PPAR-γ2, CXCL5, calpain-10, IRS-1 and 2, GSTM1, KCNJ11, eNOS, VDR, INSR, ACE, apoA-I, apo E, adiponectin, PTPN1, CETP, AT1R, resistin, MMP-3, BChE K, AT2R, SUMO4, IL-10, VEGF, MTHFR, and GSTM1 with T2DM or its complications. DISCUSSION We found some controversial results due to heterogeneity in ethnicity and genetic background. We thought genome wide association studies on large number of samples will be helpful in identifying diabetes susceptible genes as an alternative to studying individual candidate genes in Iranian populations.
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Affiliation(s)
- Mehrnoosh Khodaeian
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Samaneh Enayati
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ozra Tabatabaei-Malazy
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsa M. Amoli
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Uma Jyothi K, Reddy BM. Gene-gene and gene-environment interactions in the etiology of type 2 diabetes mellitus in the population of Hyderabad, India. Meta Gene 2015; 5:9-20. [PMID: 26042206 PMCID: PMC4443428 DOI: 10.1016/j.mgene.2015.05.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Revised: 04/17/2015] [Accepted: 05/04/2015] [Indexed: 12/13/2022] Open
Abstract
Fifteen SNPs from nine different genes were genotyped on 1379 individuals, 758 T2DM patients and 621 controls, from the city of Hyderabad, India, using Sequenom Massarray platform. These data were analyzed to examine the role of gene-gene and gene-environment interactions in the manifestation of T2DM. The multivariate analysis suggests that TCF7L2, CDKAL1, IGF2BP2, HHEX and PPARG genes are significantly associated with T2DM, albeit only the first two of the above 5 were associated in the univariate analysis. Significant gene-gene and gene-environment interactions were also observed with reference to TCF7L2, CAPN10 and CDKAL1 genes, highlighting their importance in the pathophysiology of T2DM. In the analysis for cumulative effect of risk alleles, SLC30A8 steps in as significant contributor to the disease by its presence in all combinations of risk alleles. A striking difference between risk allele categories, 1-4 and 5-6, was evident in showing protective and susceptible roles, respectively, while the latter was characterized by the presence of TCF7L2 and CDKAL1 variants. Overall, these two genes TCF7L2 and CDKAL1 showed strong association with T2DM, either individually or in interaction with the other genes. However, we need further studies on gene-gene and gene-environment interactions among heterogeneous Indian populations to obtain unequivocal conclusions that are applicable for the Indian population as a whole.
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Affiliation(s)
- Kommoju Uma Jyothi
- Biological Anthropology Unit (Molecular Anthropology Group), Indian Statistical Institute, Hyderabad, India
| | - Battini Mohan Reddy
- Biological Anthropology Unit (Molecular Anthropology Group), Indian Statistical Institute, Hyderabad, India
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Abstract
Type 2 diabetes (T2D) is a metabolic disorder characterized by high blood glucose levels and elevated risk of cardiovascular events. The progression of T2D can be delayed, or prevented, so early prediction is of high importance. More than 70 genetic loci are associated with T2D risk, raising the possibility of early identification of future cases. Results show that the benefits in discrimination by including genes in current risk models are uncertain. Improvements have been shown in reclassification but are too modest for clinical use. Given the current guidelines for T2D risk assessment and the increasing availability of genotyped individuals, we could soon be able to use genetics, not to quantify risk, but to inform clinicians on those requiring earlier observation.
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Affiliation(s)
- Fotios Drenos
- MRC Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, Bristol, UK
- Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK
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Cheng L, Zhang D, Zhou L, Zhao J, Chen B. Association between SLC30A8 rs13266634 Polymorphism and Type 2 Diabetes Risk: A Meta-Analysis. Med Sci Monit 2015. [PMID: 26214053 PMCID: PMC4527121 DOI: 10.12659/msm.894052] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Accumulating but inconsistent data about the role of rs13266634 variant of SLC30A8 in type 2 diabetes have been reported, partly due to small sample sizes and non-identical ethnicity. MATERIAL AND METHODS We searched PubMed and Cochrane Library to identify eligible studies and extract data of baseline characteristics, genotype count, odds ratio (OR), and 95% confidence interval (CI). Both adjusted OR with 95% CI and genotype counts were employed to assess the association. Genotype data were further pooled to provide estimates under different genetic models and the most appropriate model was determined. Sensitivity and cumulative analysis were conducted to assure the strength of results. RESULTS Fifty-five datasets of 39 studies (including 38 of 24 with genotype count) were included. Significant associations were found in allelic contrasts using adjusted ORs and raw genotype count, respectively, overall in Asian and European populations (overall: OR=1.147/1.157, 95% CI 1.114-1.181/1.135-1.180; Asian: OR=1.186/1.165, 95% CI 1.150-1.222/1.132-1.198; European: OR=1.100/1.151, 95% CI 1.049-1.153/1.120-1.183; All p=0.00), but not in African populations (African: OR=1.255/1.111, 95% CI 0.964-1.634/0.908-1.360, p=0.091/0.305). Further analysis with genotype count under different genetic models all showed that individuals with CC genotype had 33.0% and 16.5% higher risk of type 2 diabetes than those carrying TT and CT genotypes, respectively, under the most likely codominant model. Cumulative analysis indicated gradually improved precision of estimation after studies accumulated. CONCLUSIONS Our results suggest that rs13266634 may be an important genetic factor of type 2 diabetes risk among Asian and European but not African populations.
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Affiliation(s)
- Liqing Cheng
- Department of Endocrinology and Metabolism, Southwest Hospital, Third Military Medical University, Chongqing, China (mainland)
| | - Dongmei Zhang
- Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China (mainland)
| | - Lina Zhou
- Department of Endocrinology and Metabolism, Southwest Hospital, Third Military Medical University, Chongqing, China (mainland)
| | - Jie Zhao
- Department of Endocrinology and Metabolism, Southwest Hospital, Third Military Medical University, Chongqing, China (mainland)
| | - Bing Chen
- Department of Endocrinology and Metabolism, Southwest Hospital, Third Military Medical University, Chongqing, China (mainland)
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Davis JA, Burgoon LD. Can data science inform environmental justice and community risk screening for type 2 diabetes? PLoS One 2015; 10:e0121855. [PMID: 25875676 PMCID: PMC4396977 DOI: 10.1371/journal.pone.0121855] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 02/16/2015] [Indexed: 11/24/2022] Open
Abstract
Background Having the ability to scan the entire country for potential “hotspots” with increased risk of developing chronic diseases due to various environmental, demographic, and genetic susceptibility factors may inform risk management decisions and enable better environmental public health policies. Objectives Develop an approach for community-level risk screening focused on identifying potential genetic susceptibility hotpots. Methods Our approach combines analyses of phenotype-genotype data, genetic prevalence of single nucleotide polymorphisms, and census/geographic information to estimate census tract-level population attributable risks among various ethnicities and total population for the state of California. Results We estimate that the rs13266634 single nucleotide polymorphism, a type 2 diabetes susceptibility genotype, has a genetic prevalence of 56.3%, 47.4% and 37.0% in Mexican Mestizo, Caucasian, and Asian populations. Looking at the top quintile for total population attributable risk, 16 California counties have greater than 25% of their population living in hotspots of genetic susceptibility for developing type 2 diabetes due to this single genotypic susceptibility factor. Conclusions This study identified counties in California where large portions of the population may bear additional type 2 diabetes risk due to increased genetic prevalence of a susceptibility genotype. This type of screening can easily be extended to include information on environmental contaminants of interest and other related diseases, and potentially enables the rapid identification of potential environmental justice communities. Other potential uses of this approach include problem formulation in support of risk assessments, land use planning, and prioritization of site cleanup and remediation actions.
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Affiliation(s)
- J. Allen Davis
- National Center for Environmental Assessment, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America
- * E-mail:
| | - Lyle D. Burgoon
- National Center for Environmental Assessment, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America
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Al-Sinani S, Woodhouse N, Al-Mamari A, Al-Shafie O, Al-Shafaee M, Al-Yahyaee S, Hassan M, Jaju D, Al-Hashmi K, Al-Abri M, Al-Rassadi K, Rizvi S, Loic Y, Froguel P, Bayoumi R. Association of gene variants with susceptibility to type 2 diabetes among Omanis. World J Diabetes 2015; 6:358-366. [PMID: 25789119 PMCID: PMC4360431 DOI: 10.4239/wjd.v6.i2.358] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Revised: 10/01/2014] [Accepted: 02/09/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the association of 10 known common gene variants with susceptibility to type 2 diabetes mellitus (T2D) among Omanis.
METHODS: Using case-control design, a total of 992 diabetic patients and 294 normoglycemic Omani Arabs were genotyped, by an allelic discrimination assay-by-design TaqMan method on fast real time polymerase chain reaction system, for the following gene variants: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398), CDKN2A/B (rs10811661), FTO (rs9939609 and rs8050136), IGF2BP2 (rs4402960), SLC30A8 (rs13266634) CAPN10 (rs3792267) and HHEX (rs1111875). T2D patients were recruited from the Diabetes Clinic (n = 243) and inpatients (n = 749) at Sultan Qaboos Univesity Hospital (SQUH), Muscat, Oman. Adult control participants (n = 294) were volunteers from the community and from those visiting Family Medicine Clinic at SQU, for regular medical checkup. The difficulty in recruiting Omani participants with no family history of diabetes was the main reason behind the small number of control participants in this study. Almost all volunteers questioned had a relative with diabetes mellitus. Inspite of the small number of normoglycemic controls in this study, this sample was sufficient for detection of genes and loci for common alleles influencing T2D with an odds ratio of ≥ 1.3 reaching at least 80% power. Data was collected from June 2010 to February 2012.
RESULTS: Using binary logistic regression analysis, four gene variants showed significant association with T2D risk: KCNJ11 (rs5219, P = 5.8 × 10-6, OR = 1.74), TCF7L2 (rs7903146, P = 0.001, OR = 1.46), CDKAL1 (rs10946398, P = 0.002, OR = 1.44) and CDKN2A/B (rs10811661, P = 0.020, OR = 1.40). The fixation index analysis of these four gene variants indicated significant genetic differentiation between diabetics and controls {[KCNJ11 (rs5219), P < 0.001], [TCF7L2 (rs7903146), P < 0.001], [CDKAL1 (rs10946398), P < 0.05], [CDKN2A/B (rs10811661), P < 0.05]}. The highest genotype variation % between diabetics and controls was found at KCNJ11 (2.07%) and TCF7L2 (1.62%). This study was not able to detect an association of T2D risk with gene variants of IGF2BP2 (rs4402960), SLC30A8 (rs13266634), CAPN10 (rs3792267) and HHEX (rs1111875). Moreover, no association was found between FTO gene variants (rs9939609 and rs8050136) and T2D risk. However, T2D risk was found to be significantly associated with obesity (P = 0.002, OR = 2.22); and with the Waist-to-Hip ratio (n = 532, P = 1.9 ×10-7, OR = 2.4), [among males (n = 234, P = 1.2 × 10-4, OR = 2.0) and females (n = 298, P = 0.001, OR = 6.3)].
CONCLUSION: Results confirmed the association of KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661) gene variants with susceptibility to T2D among Omani Arabs.
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Nikitin AG, Potapov VA, Brovkin AN, Lavrikova EY, Khodyrev DS, Shamhalova MS, Smetanina SA, Suplotova LN, Shestakova MV, Nosikov VV, Averyanov AV. Association of FTO, KCNJ11, SLC30A8, and CDKN2B polymorphisms with type 2 diabetes mellitus. Mol Biol 2015. [DOI: 10.1134/s0026893315010112] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Mansoori Y, Daraei A, Naghizadeh MM, Salehi R. Significance of a common variant in the CDKAL1 gene with susceptibility to type 2 diabetes mellitus in Iranian population. Adv Biomed Res 2015; 4:45. [PMID: 25789271 PMCID: PMC4358034 DOI: 10.4103/2277-9175.151256] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 06/23/2014] [Indexed: 12/29/2022] Open
Abstract
Background: Type 2 diabetes mellitus (T2DM) is a worldwide problem that threatens the public health and economies of all countries. A multifactorial etiology and interaction between environmental factors and genetic components are responsible for triggering and progression of T2DM. Recently, rs7754840 single nucleotide polymorphism (SNP) in the CDKAL1 gene was reported to be associated with T2DM in various populations. However, due to inconsistent results in various populations about the association of rs7754840 with T2DM, and lack of information in the Iranian population, we have evaluated its association with T2DM in a subset of the Iranian population from Isfahan province, central part of Iran. Materials and Methods: The study included 140 patients and 140 controls selected based on the World Health Organization guidelines. Genomic DNA was extracted from blood samples and the rs7754840 SNP was genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay with specific primers and restriction enzyme (Ac1I). Results: The frequency of the C allele in the cases was higher than that in the controls (72.9% vs. 65%; P = 0.045). Using logistic regression analysis, we found a significant risk association of CC genotype with T2DM susceptibility (OR = 2.319, 95% CI = 1.436-3.744, P = 0.001). Furthermore, compared with the CC genotype, individuals with the GC genotype had a lower risk (protective association) of developing T2DM (OR = 0.332, 95% CI = 0.202-0.547, P < 0.001). Conclusions: We confirmed that there is a significant risk association between rs7754840 polymorphism and development of T2DM in a subset of the Iranian population from Isfahan province.
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Affiliation(s)
- Yaser Mansoori
- Department of Biochemistry, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Abdolreza Daraei
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Rasoul Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Cumulative effect and predictive value of genetic variants associated with type 2 diabetes in Han Chinese: a case-control study. PLoS One 2015; 10:e0116537. [PMID: 25587982 PMCID: PMC4294637 DOI: 10.1371/journal.pone.0116537] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 12/09/2014] [Indexed: 11/19/2022] Open
Abstract
Background Genome-wide association studies (GWAS) have identified dozens of single nucleotide polymorphisms (SNPs) associated with type 2 diabetes risk. We have previously confirmed the associations of genetic variants in HHEX, CDKAL1, VEGFA and FTO with type 2 diabetes in Han Chinese. However, the cumulative effect and predictive value of these GWAS identified SNPs on the risk of type 2 diabetes in Han Chinese are largely unknown. Methodology/Principal Findings We conducted a two-stage case-control study consisting of 2,925 cases and 3,281controls to examine the association of 30 SNPs identified by GWAS with type 2 diabetes in Han Chinese. Significant associations were found for proxy SNPs at KCNQ1 [odds ratio (OR) = 1.41, P = 9.91 × 10–16 for rs2237897], CDKN2A/CDKN2B (OR = 1.30, P = 1.34 × 10–10 for rs10811661), CENTD2 (OR = 1.28, P = 9.88 × 10-4 for rs1552224) and SLC30A8 (OR = 1.19, P = 1.43 × 10-5 for rs13266634). We further evaluated the cumulative effect on type 2 diabetes of these 4 SNPs, in combination with 5 SNPs at HHEX, CDKAL1, VEGFA and FTO reported previously. Individuals carrying 12 or more risk alleles had a nearly 4-fold increased risk for developing type 2 diabetes compared with those carrying less than 6 risk alleles [adjusted OR = 3.68, 95% confidence interval (CI): 2.76–4.91]. Adding the genetic factors to clinical factors slightly improved the prediction of type 2 diabetes, with the area under the receiver operating characteristic curve increasing from 0.76 to 0.78. However, the difference was statistically significant (P < 0.0001). Conclusions/Significance We confirmed associations of SNPs in KCNQ1, CDKN2A/CDKN2B, CENTD2 and SLC30A8 with type 2 diabetes in Han Chinese. The utilization of genetic information may improve the accuracy of risk prediction in combination with clinical characteristics for type 2 diabetes.
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Lasram K, Ben Halim N, Benrahma H, Mediene-Benchekor S, Arfa I, Hsouna S, Kefi R, Jamoussi H, Ben Ammar S, Bahri S, Abid A, Benhamamouch S, Barakat A, Abdelhak S. Contribution of CDKAL1 rs7756992 and IGF2BP2 rs4402960 polymorphisms in type 2 diabetes, diabetic complications, obesity risk and hypertension in the Tunisian population. J Diabetes 2015; 7:102-13. [PMID: 24636221 DOI: 10.1111/1753-0407.12147] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Revised: 02/26/2013] [Accepted: 03/11/2014] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND The insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and the cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) identified through genome-wide association (GWA) studies have been shown to be associated with Type 2 diabetes in various ethnic groups. In this study, we investigated the association of the rs7756992 of CDKAL1 and the rs4402960 of IGF2BP2 with Type 2 diabetes, diabetic complications (nephropathy, retinopathy and cardiovascular disease), obesity and hypertension in a Tunisian population. METHODS A case-control association study including 200 Type 2 diabetes Tunisian patients (World Health Organization criteria) and 208 controls (age ≥40; fasting plasma glucose <6.1 mmol/L; without first degree family history of diabetes) has been performed. Other parameters such as diabetic nephropathy, diabetic retinopathy, cardiovascular disease, overweight/obesity and hypertension have been also collected. Genotyping was performed using TaqMan technology. RESULTS A significant association between the rs4402960 and Type 2 diabetes (OR = 1.86, 95% CI = 1.34-2.58, P < 10(-4) ) has been found. Overweight/obese subjects bearing the T-allele have an increased risk to develop Type 2 diabetes (OR = 2.06, 95% CI = 1.40-3.03, P < 10(-4) ). Furthermore, the rs7756992 was found to be associated with the reduced risk of diabetic nephropathy in patients with diabetes (OR = 0.44, 95% CI = 0.27-0.73, P = 0.001). CONCLUSIONS The present study confirms that the rs4402960 of IGF2BP2 gene is a strong candidate for Type 2 diabetes susceptibility and overweight/obesity risk in the Tunisian population. Interestingly, our data suggest that the rs7756992 of CDKAL1 gene have a protective effect against diabetic nephropathy.
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Affiliation(s)
- Khaled Lasram
- Biomedical Genomics and Oncogenetics Laboratory (LR 11 IPT 05), Institut Pasteur de Tunis, Université El Manar de Tunis, Tunis, Tunisia
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Tang ZH, Wang L, Zeng F, Zhang K. Human genetics of diabetic retinopathy. J Endocrinol Invest 2014; 37:1165-74. [PMID: 25201002 DOI: 10.1007/s40618-014-0172-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 08/25/2014] [Indexed: 01/03/2023]
Abstract
There is evidence demonstrating that genetic factors contribute to the risk of diabetic retinopathy (DR). Genetics variants, structural variants (copy number variation, CNV) and epigenetic changes play important roles in the development of DR. Genetic linkage and association studies have uncovered a number of genetic loci and common genetic variants susceptibility to DR. CNV and interactions of gene by environment have also been detected by association analysis. Apart from nucleus genome, mitochondrial DNA plays critical roles in regulation of development of DR. Epigenetic studies have indicated epigenetic changes in chromatin affecting gene transcription in response to environmental stimuli, which provided a large body of evidence of regulating development of diabetes mellitus. Identification of genetic variants and epigenetic changes contributed to risk or protection of DR will benefit uncovering the complex mechanism underlying DR. This review focused on the current knowledge of the genetic and epigenetic basis of DR.
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Affiliation(s)
- Z-H Tang
- Department of Endocrinology and Metabolism, Shanghai Tongji Hospital, Tongji University School of Medicine, Room 517 Building 2nd, NO. 389 Xincun Road, Shanghai, 200063, China,
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Zhang LF, Pei Q, Yang GP, Zhao YC, Mu YF, Huang Q, Zhu YL. The effect of IGF2BP2 gene polymorphisms on pioglitazone response in Chinese type 2 diabetes patients. Pharmacology 2014; 94:115-22. [PMID: 25247335 DOI: 10.1159/000363414] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 05/06/2014] [Indexed: 11/19/2022]
Abstract
BACKGROUND Genome-wide association studies identified that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) genetic polymorphisms are related to type 2 diabetes mellitus (T2DM) in several populations. This study aimed to investigate whether the IGF2BP2 gene rs1470579 and rs4402960 polymorphisms were associated with T2DM and pioglitazone efficacy in Chinese T2DM patients. METHODS A total of 281 T2DM patients and 111 healthy volunteers were enrolled to identify the IGF2BP2 gene rs1470579 and rs4402960 polymorphisms; 86 patients were randomly selected and given a 12-week pioglitazone treatment (30 mg/day). Fasting plasma glucose, postprandial plasma glucose (PPG), glycated hemoglobin, serum triglycerides (TG), total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (HDL-C) were determined before and after pioglitazone treatment. RESULTS The results showed that the IGF2BP2 gene rs1470579 and rs4402960 polymorphisms were associated with T2DM in a Chinese population (OR = 2.002, 95% CI 1.170-3.426, p < 0.05; OR = 1.879, 95% CI 1.110-3.182, p < 0.05). The effect of pioglitazone on PPG (p < 0.05), TG (p < 0.01) and HDL-C (p < 0.05) was lower in patients with the rs1470579 AC+CC genotypes than in AA genotype carriers. Its effect on PPG level was also lower in patients with the GT+TT genotypes of rs4402960 than in patients with the GG genotype (p < 0.05). CONCLUSIONS The IGF2BP2 gene rs1470579 and rs4402960 polymorphisms were associated with T2DM and therapeutic efficacy of pioglitazone in this Chinese population.
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Affiliation(s)
- Liu-Fu Zhang
- Department of Neurology, Hefei Binhu Hospital, Hefei First People's Hospital, Hefei, PR China
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Cormier H, Vigneault J, Garneau V, Tchernof A, Vohl MC, Weisnagel SJ, Robitaille J. An explained variance-based genetic risk score associated with gestational diabetes antecedent and with progression to pre-diabetes and type 2 diabetes: a cohort study. BJOG 2014; 122:411-9. [PMID: 25041170 DOI: 10.1111/1471-0528.12937] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2014] [Indexed: 01/11/2023]
Abstract
OBJECTIVE To determine whether an explained-variance genetic risk score (GRS), with 36 single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes (T2D), is also associated with gestational diabetes mellitus (GDM), and with the progression to pre-diabetes and T2D among women with prior GDM. DESIGN A cohort study. SETTING Clinical investigation unit of Laval University, Quebec, Canada. POPULATION A cohort of 214 women with prior GDM and 82 controls recruited between 2009 and 2012. METHODS Associations between the GRS and GDM. MAIN OUTCOMES MEASURES GDM and prevalence of pre-diabetes and T2D. RESULTS Women with prior GDM had a higher GRS compared with controls (38.6 ± 3.9, 95% CI 38.1-39.1, versus 37.4 ± 3.2, 95% CI 36.7-38.1; P < 0.0001). In women with prior GDM, the explained-variance GRS was higher for pre-diabetic women compared with women who remained normoglucotolerant at testing (1.21 ± 0.18, 95% CI 1.18-1.23, versus 1.17 ± 0.15, 95% CI 1.13-1.20; P < 0.0001). Similarly, women with T2D had a higher explained-variance GRS compared with women with prior GDM who remained normoglucotolerant (1.20 ± 0.18, 95% CI 1.14-1.25, versus 1.17 ± 0.17, 95% CI 1.13-1.20; P < 0.0001). The predictive effects of the explained-variance GRS, age, and body mass index (BMI), or the additive effects of the three variables, were tested for pre-diabetes and T2D. We observed an area under the curve of 0.6269 (95% CI 0.5638-0.6901) for age and BMI, and adding the explained-variance GRS into the model increased the area to 0.6672 (95% CI 0.6064-0.7281) for the prediction of pre-diabetes. CONCLUSIONS An explained-variance GRS is associated with both GDM and progression to pre-diabetes and T2D in women with prior GDM.
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Affiliation(s)
- H Cormier
- Department of Food Sciences and Nutrition, Laval University, Quebec City, QC, Canada; Institute of Nutrition and Functional Foods (INAF), Laval University, Quebec City, QC, Canada
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Double-bottom chaotic map particle swarm optimization based on chi-square test to determine gene-gene interactions. BIOMED RESEARCH INTERNATIONAL 2014; 2014:172049. [PMID: 24895547 PMCID: PMC4033510 DOI: 10.1155/2014/172049] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Accepted: 04/16/2014] [Indexed: 11/19/2022]
Abstract
Gene-gene interaction studies focus on the investigation of the association between the single nucleotide polymorphisms (SNPs) of genes for disease susceptibility. Statistical methods are widely used to search for a good model of gene-gene interaction for disease analysis, and the previously determined models have successfully explained the effects between SNPs and diseases. However, the huge numbers of potential combinations of SNP genotypes limit the use of statistical methods for analysing high-order interaction, and finding an available high-order model of gene-gene interaction remains a challenge. In this study, an improved particle swarm optimization with double-bottom chaotic maps (DBM-PSO) was applied to assist statistical methods in the analysis of associated variations to disease susceptibility. A big data set was simulated using the published genotype frequencies of 26 SNPs amongst eight genes for breast cancer. Results showed that the proposed DBM-PSO successfully determined two- to six-order models of gene-gene interaction for the risk association with breast cancer (odds ratio > 1.0; P value <0.05). Analysis results supported that the proposed DBM-PSO can identify good models and provide higher chi-square values than conventional PSO. This study indicates that DBM-PSO is a robust and precise algorithm for determination of gene-gene interaction models for breast cancer.
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Benrahma H, Charoute H, Lasram K, Boulouiz R, Atig RKB, Fakiri M, Rouba H, Abdelhak S, Barakat A. Association analysis of IGF2BP2, KCNJ11, and CDKAL1 polymorphisms with type 2 diabetes mellitus in a Moroccan population: a case-control study and meta-analysis. Biochem Genet 2014; 52:430-42. [PMID: 24898818 DOI: 10.1007/s10528-014-9658-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 04/25/2014] [Indexed: 11/24/2022]
Abstract
Associations with type 2 diabetes mellitus have been identified for variants CDKAL1 rs7756992, KCNJ11 rs5219, and IGF2BP2 rs4402960 in different populations. In a case-control study of 250 unrelated Moroccan diabetic patients and 250 healthy controls, we used TaqMan allelic discrimination assays to genotype the three SNPs and meta-analysis to investigate the association between the polymorphisms and diabetes in Arab populations. The results showed a significant diabetes association only with the variant rs4402960 of the IGF2BP2 gene under additive 2 (GG vs. TT; p = 0.009) and recessive (TT vs. GG+GT; p = 0.003) models. Meta-analysis indicated significant association between the IGF2BP2 rs4402960 and CDKAL1 rs7756992 polymorphisms and increased risk of diabetes in Arab populations. According to our results, the case-control study and meta-analysis revealed a significant association between the IGF2BP2 rs4402960 variant and type 2 diabetes in Moroccan and Arab populations.
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Affiliation(s)
- Houda Benrahma
- Laboratoire de Génétique Moléculaire Humaine, Département de Recherche Scientifique, Institut Pasteur du Maroc, Place Louis Pasteur, 20100, Casablanca, Morocco
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Faghih H, Khatami SR, Azarpira N, Foroughmand AM. SLC30A8 gene polymorphism (rs13266634 C/T) and type 2 diabetes mellitus in south Iranian population. Mol Biol Rep 2014; 41:2709-15. [DOI: 10.1007/s11033-014-3158-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 01/13/2014] [Indexed: 10/25/2022]
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Min SK, Nakazato K, Ishigami H, Hiranuma K. Cartilage Intermediate Layer Protein and Asporin Polymorphisms Are Independent Risk Factors of Lumbar Disc Degeneration in Male Collegiate Athletes. Cartilage 2014; 5:37-42. [PMID: 26069683 PMCID: PMC4297097 DOI: 10.1177/1947603513500786] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
OBJECTIVE Lumbar disc degeneration (LDDG), recently reported to have strong genetic determinants, is a major cause of discopathy and lower back pain. However, most studies have only evaluated the effects of a single susceptibility polymorphism. Our purpose was to examine the effect of two susceptibility polymorphism for LDDG in Japanese collegiate athletes. DESIGN We investigated two susceptibility genes for LDDG-cartilage intermediate layer protein (CILP) and asporin (ASPN)-in 516 collegiate athletes and genotyped the risk allele of CILP (1184T/C) and ASPN (D14). LDDG was evaluated using T2-weighted magnetic resonance imaging. RESULTS By using logistic regression analysis, we found that the ASPN D14 allele and CILP genotype were associated with an increased risk of LDDG in male but not female athletes (CILP CT: odds ratios [OR] = 1.77, 95% confidence interval [CI] = 1.07-2.93; CILP CC: OR = 4.38, 95% CI = 1.42-13.54; ASPN D14: OR = 2.17, 95% CI = 1.10-4.28]. We also found that CILP C and ASPN D14 were independent variables. The ORs with more than two risk alleles were largely increased. CONCLUSIONS The CILP and ASPN polymorphisms are independent genetic risk factors for LDDG in male but not female Japanese collegiate athletes.
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Affiliation(s)
- Seok-Ki Min
- Department of Exercise Physiology, Nippon Sport Science University, Tokyo, Japan,Anti-Aging Research Institute, Dong-A University, Busan, Korea
| | - Koichi Nakazato
- Department of Exercise Physiology, Nippon Sport Science University, Tokyo, Japan
| | - Hideaki Ishigami
- Department of Social Science, Nippon Sport Science University, Tokyo, Japan
| | - Kenji Hiranuma
- Department of Sport Medicine, Nippon Sport Science University, Tokyo, Japan
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Ludwig B, Barthel A, Reichel A, Block NL, Ludwig S, Schally AV, Bornstein SR. Modulation of the pancreatic islet-stress axis as a novel potential therapeutic target in diabetes mellitus. VITAMINS AND HORMONES 2014; 95:195-222. [PMID: 24559919 DOI: 10.1016/b978-0-12-800174-5.00008-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Loss of pancreatic islet function and insulin-producing beta cell mass is a central hallmark in the pathogenesis of both type 1 and type 2 diabetes. While in type 1 diabetes this phenomenon is due to an extensive destruction of beta cells caused by an autoimmune process, the mechanisms resulting in beta cell failure in type 2 diabetes are different and less clear. Also, beta cell destruction in type 1 diabetes occurs early and is the initial step in the pathogenetic process, while beta cell loss in type 2 diabetes after an initial phase of hyperinsulinemia due to the underlying insulin resistance occurs relatively late and it is less pronounced. Since diabetes mellitus is the most frequent endocrine disease, with an increasing high prevalence worldwide, huge efforts have been made over the past many decades to identify predisposing genetic, environmental, and nutritional factors in order to develop effective strategies to prevent the disease. In parallel, extensive studies in different cell systems and animal models have helped to elucidate our understanding of the physiologic function of islets and to gain insight into the immunological and non-immunological mechanisms of beta cell destruction and failure. Furthermore, currently emerging concepts of beta cell regeneration (e.g., the restoration of the beta cell pool by regenerative, proliferative and antiapoptotic processes, and recovery of physiologic islet function) apparently is yielding the first promising results. Recent insights into the complex endocrine and paracrine mechanisms regulating the physiologic function of pancreatic islets, as well as beta cell life and death, constitute an essential part of this new and exciting area of diabetology. For example, understanding of the physiological role of glucagon-like peptide 1 has resulted in the successful clinical implementation of incretin-based therapies over the last years. Further, recent data suggesting paracrine effects of growth hormone-releasing hormone and corticotropin-releasing hormone on the regulation of pancreatic islet function, survival, and proliferation as well as on local glucocorticoid metabolism provide evidence for a potential role of the pancreatic islet-stress axis in the pathophysiology of diabetes mellitus. In this chapter, we provide a comprehensive overview of current preventive and regenerative concepts as a basis for the development of novel therapeutic approaches to the treatment of diabetes mellitus. A particular focus is given on the potential of the pancreatic islet-stress axis in the development of novel regenerative strategies.
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Affiliation(s)
- Barbara Ludwig
- Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany; The Paul Langerhans Institute, Dresden, Germany; Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany.
| | - Andreas Barthel
- Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany; Endokrinologikum Ruhr, Bochum, Germany
| | - Andreas Reichel
- Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Norman L Block
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Medicine, Division of Hematology-Oncology, University of Miami Miller School of Medicine, Miami, Florida, USA; Veterans Administration Medical Center, Miami, Florida, USA
| | - Stefan Ludwig
- Department of Visceral, Thorax and Vascular Surgery, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Andrew V Schally
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Medicine, Division of Endocrinology, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Medicine, Division of Hematology-Oncology, University of Miami Miller School of Medicine, Miami, Florida, USA; Veterans Administration Medical Center, Miami, Florida, USA
| | - Stefan R Bornstein
- Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany; The Paul Langerhans Institute, Dresden, Germany; Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany
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Salas E, Rabhi N, Froguel P, Annicotte JS. Role of Ink4a/Arf locus in beta cell mass expansion under physiological and pathological conditions. J Diabetes Res 2014; 2014:873679. [PMID: 24672805 PMCID: PMC3941170 DOI: 10.1155/2014/873679] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 12/20/2013] [Indexed: 12/11/2022] Open
Abstract
The ARF/INK4A (Cdkn2a) locus includes the linked tumour suppressor genes p16INK4a and p14ARF (p19ARF in mice) that trigger the antiproliferative activities of both RB and p53. With beta cell self-replication being the primary source for new beta cell generation in adult animals, the network by which beta cell replication could be increased to enhance beta cell mass and function is one of the approaches in diabetes research. In this review, we show a general view of the regulation points at transcriptional and posttranslational levels of Cdkn2a locus. We describe the molecular pathways and functions of Cdkn2a in beta cell cycle regulation. Given that aging reveals increased p16Ink4a levels in the pancreas that inhibit the proliferation of beta cells and decrease their ability to respond to injury, we show the state of the art about the role of this locus in beta cell senescence and diabetes development. Additionally, we focus on two approaches in beta cell regeneration strategies that rely on Cdkn2a locus negative regulation: long noncoding RNAs and betatrophin.
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Affiliation(s)
- Elisabet Salas
- European Genomic Institute for Diabetes (EGID), CNRS UMR 8199, Lille 2 University, 59000 Lille, France
| | - Nabil Rabhi
- European Genomic Institute for Diabetes (EGID), CNRS UMR 8199, Lille 2 University, 59000 Lille, France
| | - Philippe Froguel
- European Genomic Institute for Diabetes (EGID), CNRS UMR 8199, Lille 2 University, 59000 Lille, France
- Department of Genomics of Common Disease, Hammersmith Hospital, Imperial College London, London W12 0NN, UK
| | - Jean-Sébastien Annicotte
- European Genomic Institute for Diabetes (EGID), CNRS UMR 8199, Lille 2 University, 59000 Lille, France
- *Jean-Sébastien Annicotte:
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