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Alidoust L, Sharafshah A, Keshavarz P. Haplotype-based association study of TCF7L2 gene variants with the development of diabetic retinopathy in an Iranian population. Ophthalmic Genet 2024; 45:226-232. [PMID: 38514248 DOI: 10.1080/13816810.2024.2318611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 01/24/2024] [Accepted: 02/09/2024] [Indexed: 03/23/2024]
Abstract
BACKGROUND Diabetic retinopathy (DR) is recognized as one of the most prevalent complications of diabetes and a major cause of morbidity. Transcription factor 7-like 2 (TCF7L2), a pivotal component in the Wnt-signaling pathway, plays a significant role in β-cell development, blood-glucose homeostasis, cell survival, cell migration, and cell proliferation. Thus, this study aimed to assess the association between TCF7L2 variants (rs7903146, rs11196205, and rs12255372) with DR in a population-based association study. MATERIALS AND METHODS DNA was extracted from whole blood of all subjects by salting-out procedure. Total 524 T2DM patients including 234 T2DM individuals without DR and 290 T2DM individuals with DR were genotyped by TaqMan assay technology. Clinical characteristics of subjects were conducted to evaluate the plausible association between TCF7L2 variants and DR with univariate linear regression analysis. RESULTS Demographic analysis between case and control groups revealed significant differences in FBS, HbA1c, lipidemia, heart disease, and family history of T2DM (p < 0.05). No significant difference was observed in either genotypes distribution or allele frequency (p > 0.05) between T2DM individuals with and without DR in any models of inheritance. Genotype-phenotype association showed no significant association. Result of analysis indicated that HbAlc with adjusted OR of 1.8 (p < 0.0001) and first-degree relatives of family history with adjusted OR of 3.04 (p < 0.0001) were significantly associated with DR. Finally, haplotype analysis showed no noticeable association. CONCLUSION In conclusion, there was no significant genetic association between rs7903146, rs11196205, and rs12255372 with DR among T2DM Iranians; however, these variants may play unknown roles in other populations.
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Affiliation(s)
- Leila Alidoust
- Department of Medical Genetics, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Alireza Sharafshah
- Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Biotechnology, University of Isfahan, Isfahan, Iran
| | - Parvaneh Keshavarz
- Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
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Mohamed SA, Fernadez-Tajes J, Franks PW, Bennet L. GWAS in people of Middle Eastern descent reveals a locus protective of kidney function-a cross-sectional study. BMC Med 2022; 20:76. [PMID: 35227251 PMCID: PMC8886846 DOI: 10.1186/s12916-022-02267-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 01/18/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Type 2 diabetes is one of the leading causes of chronic kidney failure, which increases globally and represents a significant threat to public health. People from the Middle East represent one of the largest immigrant groups in Europe today. Despite poor glucose regulation and high risk for early-onset insulin-deficient type 2 diabetes, they have better kidney function and lower rates of all-cause and cardiovascular-specific mortality compared with people of European ancestry. Here, we assessed the genetic basis of estimated glomerular filtration rate (eGFR) and other metabolic traits in people of Iraqi ancestry living in southern Sweden. METHODS Genome-wide association study (GWAS) analyses were performed in 1201 Iraqi-born residents of the city of Malmö for eGFR and ten other metabolic traits using linear mixed-models to account for family structure. RESULTS The strongest association signal was detected for eGFR in CST9 (rs13037490; P value = 2.4 × 10-13), a locus previously associated with cystatin C-based eGFR; importantly, the effect (major) allele here contrasts the effect (minor) allele in other populations, suggesting favorable selection at this locus. Additional novel genome-wide significant loci for eGFR (ERBB4), fasting glucose (CAMTA1, NDUFA10, TRIO, WWC1, TRAPPC9, SH3GL2, ABCC11), quantitative insulin-sensitivity check index (METTL16), and HbA1C (CAMTA1, ME1, PAK1, RORA) were identified. CONCLUSIONS The genetic effects discovered here may help explain why people from the Middle East have better kidney function than those of European descent. Genetic predisposition to preserved kidney function may also underlie the observed survival benefits in Middle Eastern immigrants with type 2 diabetes.
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Affiliation(s)
- Siham A Mohamed
- Lund University Diabetes Center, Lund University, Malmö, Sweden.,Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Juan Fernadez-Tajes
- Lund University Diabetes Center, Lund University, Malmö, Sweden.,Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Paul W Franks
- Lund University Diabetes Center, Lund University, Malmö, Sweden. .,Department of Clinical Sciences, Lund University, Malmö, Sweden.
| | - Louise Bennet
- Department of Clinical Sciences, Lund University, Malmö, Sweden. .,Clinical Research and Trial Center, Lund University Hospital, Lund, Sweden.
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Yousefi R, Mohammadtaghvaei N, Zakerkish M, Yaghooti H, Akhormeh AK, Tavakoli R. Association between plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) and lipids with rs7903146 polymorphisms of the TCF7L2 gene in diabetic patients. Int J Diabetes Dev Ctries 2019. [DOI: 10.1007/s13410-018-0647-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Jaghutriz BA, Heni M, Lutz SZ, Fritsche L, Machicao F, Staiger H, Peter A, Häring HU, Fritsche A, Wagner R. Gene x Gene Interactions Highlight the Role of Incretin Resistance for Insulin Secretion. Front Endocrinol (Lausanne) 2019; 10:72. [PMID: 30846969 PMCID: PMC6393347 DOI: 10.3389/fendo.2019.00072] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 01/24/2019] [Indexed: 12/18/2022] Open
Abstract
Introduction: Genetic polymorphisms in TCF7L2 are the strongest common risk variants for type 2 diabetes mellitus (T2D). We and others have shown that genetic variation in TCF7L2 and WFS1 affect incretin-stimulated insulin secretion. A recent genome-wide association study discovered genetic variants associated with incretin levels. We hypothesized that these SNPs (single nucleotide polymorphisms) interact with the well-known TCF7L2 variant rs7903146 on insulin secretion due to their incretin altering effect. Methods: In this retrospective analysis, we used data from the cross-sectional TUEF-cohort (n = 2929) and a hyperglycemic clamp study using additional GLP-1 infusion at the end of the clamp (n = 76). Insulin secretion was measured by evaluating OGTT-derived indexes of insulin secretion and insulin/C-peptide levels during clamp. We genotyped rs7903146 in TCF7L2, rs10010131 in WFS1, and six SNPs associated with GLP-1 and GIP levels. Results: One of the six incretin-associated SNPs, rs17681684 in GLP2R, exhibited significant SNP x SNP interactions with rs7903146 in TCF7L2 on insulin secretion (p = 0.0024) after correction for multiple testing. Three further SNP's showed nominally significant interactions (p < 0.05). In the hyperglycemic clamp study, rs7903146 in TCF7L2 also interacted with rs17681684 on AUC C-peptide during the GLP-1 stimulation phase, thereby replicating the above finding. Conclusion: The findings exemplify the role of SNP x SNP interactions in the genetics of type 2 diabetes mellitus and corroborate the existence of clinically relevant differences in incretin sensitivity.
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Affiliation(s)
- Benjamin Assad Jaghutriz
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
- *Correspondence: Martin Heni
| | - Stefan Zoltán Lutz
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Louise Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
| | - Fausto Machicao
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Institute of Experimental Genetics, Helmholtz Center Munich, Neuherberg, Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Department of Pharmacy and Biochemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas Peter
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Róbert Wagner
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
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Udenze I, Taiwo I, Ojewunmi O. Contribution of single-nucleotide polymorphism in transcription factor 7-like 2 gene to cardiometabolic risk in adult Nigerians. INTERNATIONAL JOURNAL OF NONCOMMUNICABLE DISEASES 2019. [DOI: 10.4103/jncd.jncd_1_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Katsoulis K, Paschou SA, Hatzi E, Tigas S, Georgiou I, Tsatsoulis A. TCF7L2 gene variants predispose to the development of type 2 diabetes mellitus among individuals with metabolic syndrome. Hormones (Athens) 2018; 17:359-365. [PMID: 29971604 DOI: 10.1007/s42000-018-0047-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 06/19/2018] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Transcription factor 7-like 2 (TCF7L2) gene variants rs12255372 and rs7903146 have been consistently shown to raise genetic risk for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the possible role of these variants in the development of impaired glucose metabolism (IGM), including impaired fasting glucose (IFG) or T2DM, in patients with metabolic syndrome (MS). PATIENTS AND METHODS The study population consisted of 228 patients with MS who were divided into two groups. The first group consisted of 148 patients with MS and IGM [39M/109F, 59.8 ± 14.6 (mean ± SD) years] and the second group of 80 patients with MS and normoglycemia (NGM) (16M/64F, 56.1 ± 15.8 years). The diagnosis of MS was based on the criteria proposed by the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) Scientific Statement. Anthropometric parameters including BMI and waist circumference were recorded and blood samples were obtained after overnight fasting for biochemical tests. The rs12255372 and rs7903146 TCF7L2 polymorphisms were genotyped in peripheral blood leucocytes. RESULTS Analysis of the distribution of the TCF7L2 polymorphic alleles revealed that the frequency of the T allele of the TCF7L2 variant rs12255372 was 38.2% in the study population, while the frequency of the T allele of the TCF7L2 rs7903146 variant was 35.3%. The T allele of the rs12255372 variant was more frequently present in patients with MS and IGM (48.3%) compared to patients with MS and NGM (19.4%, p < 0.001). Also, the T allele of rs7903146 was more frequently present in patients with MS and IGM (44.6%) compared to patients with MS and NGM (18.1%, p < 0.001). Logistic regression analysis followed and revealed that the presence of the T allele for both rs12255372 and rs7903146 TCF7L2 gene variants is a very powerful predictor of the presence of glucose disorders, increasing the risk more than fourfold in patients with MS and after adjustment for potential confounders, such as age, gender, BMI, and waist circumference (TCF7L2 rs12255372: Exp(B) 4.917, p < 0.001 and TCF7L2 rs7903146: Exp(B) 5.460, p < 0.001). CONCLUSION The presence of the rs12255372 and rs7903146 TCF7L2 gene variants plays an important role in the development of T2DM among individuals with MS. These findings support the notion that among subjects with MS, those who finally develop T2DM have a genetic predisposition to β-cell dysfunction.
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Affiliation(s)
- Konstantinos Katsoulis
- Department of Endocrinology and Diabetes, Medical School, University of Ioannina, 45110, Ioannina, Greece
| | - Stavroula A Paschou
- Department of Endocrinology and Diabetes, Medical School, University of Ioannina, 45110, Ioannina, Greece
- Division of Endocrinology and Diabetes, "Aghia Sophia" Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Elissavet Hatzi
- Laboratory of Human Reproductive Genetics, University of Ioannina, Ioannina, Greece
| | - Stelios Tigas
- Department of Endocrinology and Diabetes, Medical School, University of Ioannina, 45110, Ioannina, Greece
| | - Ioannis Georgiou
- Laboratory of Human Reproductive Genetics, University of Ioannina, Ioannina, Greece
| | - Agathocles Tsatsoulis
- Department of Endocrinology and Diabetes, Medical School, University of Ioannina, 45110, Ioannina, Greece.
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Ebrahimi-Mameghani M, Asghari-Jafarabadi M, Rezazadeh K. TCF7L2-rs7903146 polymorphism modulates the effect of artichoke leaf extract supplementation on insulin resistance in metabolic syndrome: a randomized, double-blind, placebo-controlled trial. JOURNAL OF INTEGRATIVE MEDICINE-JIM 2018; 16:329-334. [DOI: 10.1016/j.joim.2018.05.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Accepted: 05/06/2018] [Indexed: 01/13/2023]
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Mandour I, Darwish R, Fayez R, Naguib M, El-Sayegh S. TCF7L2 Gene Polymorphisms and Susceptibility to Type 2 Diabetes Mellitus, A Pilot Study. ACTA ACUST UNITED AC 2018. [DOI: 10.13005/bpj/1465] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Transcription factor 7-like 2 (TCF7L2) variants are known risk factors of type 2 diabetes (T2DM).However, this association is not consistent among different populations. The current study aimed at investigating the relationship between rs 7903146, rs 12255372 variants of TCF7L2 and susceptibility to T2DM and different metabolic parameters in a cohort of Egyptian type 2 diabetic patients. This case control study included 60 diabetic patients and 60 matched unrelated healthy controls. Genotyping was performed by using Real Time-PCR. The frequency of genotypes, alleles, anthropometric measures, glycemic indices, HOMA-IR and lipid profile were evaluated in patients and control. Regarding rs 7903146, TT genotype was more frequent in healthy controls (43.3%) than diabetic patients (20%) (OR = 0.291, 95% CI = 0.108-0.788, P = 0.015). T allele was more frequent in healthy control (61.7%) than diabetic patients (44.2%) and it was associated with lower risk of diabetes (OR = 0.492, 95% CI = 0.294-0.823, P = 0.007).However, there was no significant difference between patients with CC, CT and TT genotypes of rs7903146 regarding HbA1C (p=0.549), HOMA-IR (p=0.359), total cholesterol (p=0.482). In contrast, T allele of rs12255372 had no significant relation to diabetes risk (OR = 0.602, 95% CI = 0.361-1.005, P = 0.052). There was no statistically significant difference of frequency of any rs12255372 genotypes between cases and controls In addition, patients with GG,GT, TT genotypes of rs12255372 had no significant difference regarding HbA1C (p=0.393), HOMA-IR (p=0.985), total cholesterol (p=0.368). The study confirmed the association of TCF7L2 (rs 7903146) and T2DM, while failed to detect any association between TCF7L2 (rs 12255372) and susceptibility to T2DM. No significant difference in respect to metabolic parameters between different genotypes of rs7930146 and rs12255372.
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Affiliation(s)
- Iman Mandour
- Department of Clinical and Chemical pathology, Kasr Al-Ainy, Cairo University, Egypt
| | - Rania Darwish
- Department of Clinical and Chemical pathology, Kasr Al-Ainy, Cairo University, Egypt
| | - Randa Fayez
- Department of Internal Medicine, Kasr Al-Ainy, Cairo University, Egypt
| | - Mervat Naguib
- Department of Internal Medicine, Kasr Al-Ainy, Cairo University, Egypt
| | - Sarah El-Sayegh
- Department of Clinical and Chemical pathology, Kasr Al-Ainy, Cairo University, Egypt
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Palizban A, Rezaei M, Khanahmad H, Fazilati M. Transcription factor 7-like 2 polymorphism and context-specific risk of metabolic syndrome, type 2 diabetes, and dyslipidemia. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2017; 22:40. [PMID: 28465699 PMCID: PMC5393097 DOI: 10.4103/1735-1995.202141] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Revised: 09/03/2016] [Accepted: 12/03/2016] [Indexed: 01/22/2023]
Abstract
BACKGROUND The transcription factor 7-like 2 gene (TCF7L2) is an element of the Wnt signaling pathway. There is lack of evidence if TCF7L2 has a functional role in lipid metabolism and regulation of the components constitutes the metabolic syndrome (MetSyn). The aims of this study were to evaluate whether the risk allele of TCF7L2 gene polymorphism is associated with dyslipidemia and MetSyn. MATERIALS AND METHODS The MetSyn subjects were participated only based on the National Cholesterol Education Program - Third Adult Treatment Panel criteria. In this case-control study, the DNA from MetSyn patients without (n = 90) and with type 2 diabetes (T2D) (n = 94) were genotyped. RESULTS The results show that the genotype-phenotype for CC, CT/TT of TCF7L2 gene polymorphism correlated with body mass index and waist circumference in MetSyn and MetSyn + T2D subjects (r = -0.949 and r = -0.963, respectively). The subjects that only possess MetSyn but are not diabetics show the 2 h postprandial glucose and fasting blood glucose, glycated hemoglobin significantly lower (P < 0.05) than those subjects have both abnormality. The level of triglyceride in CT/TT carriers in MetSyn was higher than CC carriers (P = 0.025). A comparison with the controls subjects, the frequencies of the T allele in the groups of MetSyn (46.66%) and MetSyn + T2D (47.34%) show significantly different (P < 0.05). The odds ratios for T allele in (MetSyn)/(normal), (MetSyn + T2D)/(normal), and in (MetSyn + T2D)/(MetSyn) were 3.59 (95% confidence interval [CI], 1.33-9.67, P = 0.0093), 3.76 (95% CI, 1.40-10.07, P = 0.0068), and 1.08 (95% CI: 0.55- 2.11, P = 0.834), respectively. CONCLUSION The results revealed the important insights essential for the role of TCF7L2 that the T allele of TCF7L2 plays a significant role in the susceptibility to dyslipidemia, MetSyn, and T2D.
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Affiliation(s)
- Abbasali Palizban
- Department of Clinical Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahnaz Rezaei
- Department of Biochemistry, Isfahan Payame Noor University, Isfahan, Iran
| | - Hossein Khanahmad
- Department of Medical Genetics, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Fazilati
- Department of Biochemistry, Isfahan Payame Noor University, Isfahan, Iran
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Homozygous carriers of the TCF7L2 rs7903146 T-allele show altered postprandial response in triglycerides and triglyceride-rich lipoproteins. Sci Rep 2017; 7:43128. [PMID: 28220878 PMCID: PMC5318936 DOI: 10.1038/srep43128] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 01/19/2017] [Indexed: 12/14/2022] Open
Abstract
The TCF7L2 rs7903146 T-allele shows the strongest association with type 2 diabetes (T2D) among common gene variants. The aim of this study was to assess circulating levels of metabolites following a meal test in individuals carrying the high risk rs790346 TT genotype (cases) and low-risk CC genotype (controls). Sixty-two men were recruited based on TCF7L2 genotype, 31 were TT carriers and 31 were age- and BMI-matched CC carriers. All participants consumed a test meal after 12 hours of fasting. Metabolites were measured using proton nuclear magnetic resonance (NMR) spectroscopy. Metabolomic profiling of TCF7L2 carriers were performed for 141 lipid estimates. TT carriers had lower fasting levels of L-VLDL-L (total lipids in large very low density lipoproteins, p = 0.045), L-VLDL-CE (cholesterol esters in large VLDL, p = 0.03), and L-VLDL-C (total cholesterol in large VLDL, p = 0.045) compared to CC carriers. Additionally, TT carriers had lower postprandial levels of total triglycerides (TG) (q = 0.03), VLDL-TG (q = 0.05, including medium, small and extra small, q = 0.048, q = 0.0009, q = 0.04, respectively), HDL-TG (triglycerides in high density lipoproteins q = 0.037) and S-HDL-TG (q = 0.00003). In conclusion, TT carriers show altered postprandial triglyceride response, mainly influencing VLDL and HDL subclasses suggesting a genotype-mediated effect on hepatic lipid regulation.
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Type 2 Diabetes Genetic Variants and Risk of Diabetic Retinopathy. Ophthalmology 2016; 124:336-342. [PMID: 28038984 DOI: 10.1016/j.ophtha.2016.11.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 11/11/2016] [Accepted: 11/11/2016] [Indexed: 02/05/2023] Open
Abstract
PURPOSE Genetic association studies to date have not identified any robust risk loci for diabetic retinopathy (DR). We hypothesized that individuals with more diabetes genetic risk alleles have a higher risk of developing DR. DESIGN Case-control genetic association study. PARTICIPANTS We evaluated the aggregate effects of multiple type 2 diabetes-associated genetic variants on the risk of DR among 1528 participants with diabetes from the Singapore Epidemiology of Eye Diseases Study, of whom 547 (35.8%) had DR. METHODS Participants underwent a comprehensive ocular examination, including dilated fundus photography. Retinal photographs were graded using the modified Airlie House classification system to assess the presence and severity of DR following a standardized protocol. We identified 76 previously discovered type 2 diabetes-associated single nucleotide polymorphisms (SNPs) and constructed multilocus genetic risk scores (GRSs) for each individual by summing the number of risk alleles for each SNP weighted by the respective effect estimates on DR. Two GRSs were generated: an overall GRS that included all 76 discovered type 2 diabetes-associated SNPs, and an Asian-specific GRS that included a subset of 55 SNPs previously found to be associated with type 2 diabetes in East and/or South Asian ancestry populations. Associations between the GRSs with DR were determined using logistic regression analyses. Discriminating ability of the GRSs was determined by the area under the receiver operating characteristic curve (AUC). MAIN OUTCOME MEASURES Odds ratios on DR. RESULTS Participants in the top tertile of the overall GRS were 2.56-fold more likely to have DR compared with participants in the lowest tertile. Participants in the top tertile of the Asian-specific GRS were 2.00-fold more likely to have DR compared with participants in the bottom tertile. Both GRSs were associated with higher DR severity levels. However, addition of the GRSs to traditional risk factors improved the AUC only modestly by 3% to 4%. CONCLUSIONS Type 2 diabetes-associated genetic loci were significantly associated with higher risks of DR, independent of traditional risk factors. Our findings may provide new insights to further our understanding of the genetic pathogenesis of DR.
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Dhawan D, Padh H. Genetic variations in TCF7L2 influence therapeutic response to sulfonylureas in Indian diabetics. Diabetes Res Clin Pract 2016; 121:35-40. [PMID: 27639123 DOI: 10.1016/j.diabres.2016.08.018] [Citation(s) in RCA: 12] [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: 03/27/2016] [Revised: 08/17/2016] [Accepted: 08/25/2016] [Indexed: 12/25/2022]
Abstract
Sulfonylureas are widely used to treat type 2 diabetes, with considerable inter-individual variation in the hypoglycaemic response to sulfonylureas. Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes. This study aimed to study the effect of variations in TCF7L2 on therapeutic response to sulfonylureas in Type 2 diabetes mellitus patients. The effect of TCF7L2 rs12255372, rs7903146 and rs4506565 genotypes on glycaemic response was observed in 250 diabetic patients treated with sulfonylureas and sulfonylureas along with metformin. The genotyping tests were done by allele-specific multiplex PCR. Glycated haemoglobin (HbA1c) levels were used as phenotypic marker. 60% of sulfonylurea users did not achieve a target HbA1c levels of ⩽6.5% (48mmol/mol) (which denotes good control in diabetics). Genotype influenced response to sulfonylureas, with more treatment failure in the TT homozygotes in case of rs12255372 and rs4506565. The GG genotype at rs12255372 favourably influences treatment success with sulfonylurea therapy in patients with type 2 diabetes (p⩽0.05). At rs12255372, 70.5% GT or TT genotype failed to achieve therapeutic target, an absolute difference of 19% compared to GG homozygotes. Our preliminary data show that genetic variation at rs12255372 has a direct correlation with therapeutic success with sulfonylureas in type 2 diabetes, hence paving the way for better treatment outcomes in diabetics.
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Affiliation(s)
- Dipali Dhawan
- B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054, Gujarat, India.
| | - Harish Padh
- B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054, Gujarat, India
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Singh S, Usman K, Banerjee M. Pharmacogenetic studies update in type 2 diabetes mellitus. World J Diabetes 2016; 7:302-315. [PMID: 27555891 PMCID: PMC4980637 DOI: 10.4239/wjd.v7.i15.302] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 05/30/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs (OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control. Genetic variations in the human genome not only disclose the risk of T2DM development but also predict the personalized response to drug therapy. Inter-individual variability in response to OADs is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters (SLC22A1, SLC22A2, SLC22A3, SLC47A1 and SLC47A2) are actively involved in glycemic/HbA1c management of metformin. In addition, CYP gene encoding Cytochrome P450 enzymes also play a crucial role with respect to metabolism of drugs. Pharmacogenetic studies provide insights on the relationship between individual genetic variants and variable therapeutic outcomes of various OADs. Clinical utility of pharmacogenetic study is to predict the therapeutic dose of various OADs on individual basis. Pharmacogenetics therefore, is a step towards personalized medicine which will greatly improve the efficacy of diabetes treatment.
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Pharmacogenomics in type 2 diabetes: oral antidiabetic drugs. THE PHARMACOGENOMICS JOURNAL 2016; 16:399-410. [DOI: 10.1038/tpj.2016.54] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 05/08/2016] [Accepted: 05/11/2016] [Indexed: 02/06/2023]
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Jin T. Current Understanding on Role of the Wnt Signaling Pathway Effector TCF7L2 in Glucose Homeostasis. Endocr Rev 2016; 37:254-77. [PMID: 27159876 DOI: 10.1210/er.2015-1146] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The role of the Wnt signaling pathway in metabolic homeostasis has drawn our intensive attention, especially after the genome-wide association study discovery that certain polymorphisms of its key effector TCF7L2 are strongly associated with the susceptibility to type 2 diabetes. For a decade, great efforts have been made in determining the function of TCF7L2 in various metabolic organs, which have generated both considerable achievements and disputes. In this review, I will briefly introduce the canonical Wnt signaling pathway, focusing on its effector β-catenin/TCF, including emphasizing the bidirectional feature of TCFs and β-catenin post-translational modifications. I will then summarize the observations on the association between TCF7L2 polymorphisms and type 2 diabetes risk. The main content, however, is on the intensive functional exploration of the metabolic role of TCF7L2, including the disputes generated on determining its role in the pancreas and liver with various transgenic mouse lines. Finally, I will discuss those achievements and disputes and present my future perspectives.
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Affiliation(s)
- Tianru Jin
- Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
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Eizadi M, Ravasi AA, Soory R, Baesi K, Choobineh S. The Effect of Three Months of Resistance Training on TCF7L2 Expression in Pancreas Tissues of Type 2 Diabetic Rats. AVICENNA JOURNAL OF MEDICAL BIOCHEMISTRY 2016. [DOI: 10.17795/ajmb-34014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Ding Y, Hu Z, Yuan S, Xie P, Liu Q. Association between transcription factor 7-like 2 rs7903146 polymorphism and diabetic retinopathy in type 2 diabetes mellitus: A meta-analysis. Diab Vasc Dis Res 2015; 12:436-44. [PMID: 26316572 DOI: 10.1177/1479164115598274] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
As one of the vascular complications of type 2 diabetes mellitus, the incidence of diabetes retinopathy is greatly increasing worldwide. Both genetic and environmental factors are involved in the pathologies. A meta-analysis was conducted to assess the association between transcription factor 7-like 2 polymorphism (rs7903146) and type 2 diabetic retinopathy. Published literature from PubMed, Web of Science and China National Knowledge Infrastructure were retrieved. Pooled odds ratios with 95% confidence intervals were calculated to estimate the strength of the association. Eight studies including 6422 participants were included in the final meta-analysis. Our analysis provides substantial evidence that the rs7903146 variant is significantly associated with the risk of diabetic retinopathy in Caucasian populations while not in East Asian populations. The variant of rs7903146 appeared more likely to be a promising genetic biomarker of diabetic retinopathy in Caucasians.
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Affiliation(s)
- Yuzhi Ding
- The First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Zizhong Hu
- The First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Songtao Yuan
- The First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Ping Xie
- The First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Qinghuai Liu
- The First Affiliated Hospital, Nanjing Medical University, Nanjing, China
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Allahdini M, Kamalidehghan B, Akbari L, Azadfar P, Rahmani A, Ahmadipour F, Meng GY, Masserrat A, Houshmand M. Prevalence of the rs7903146C>T polymorphism in TCF7L2 gene for prediction of type 2 diabetes risk among Iranians of different ethnicities. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:5835-41. [PMID: 26604685 PMCID: PMC4629960 DOI: 10.2147/dddt.s82485] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Background Pharmacogenetics is the study of genetic polymorphisms affecting responses to drug therapy. The common rs7903146 (C>T) polymorphism of the TCF7L2 gene has recently been associated with type 2 diabetes (T2D). In this study, prevalence of the rs7903146 (C>T) polymorphism in the TCF7L2 gene for prediction of T2D risk was examined in an Iranian population of different ethnicities. Methods The prevalence of rs7903146 (C>T) and the predicted phenotypes, including extensive metabolizers, intermediate metabolizers, and poor metabolizers were investigated in blood samples of 300 unrelated healthy individuals in an Iranian population, including Fars, Turk, Lure, and Kurd, using polymerase chain reaction restriction fragment length polymorphism and direct genomic DNA sequencing. Results The homozygous wild-type (C/C), heterozygous (C/T), and homozygous (T/T) allelic frequencies of rs7903146 (C>T) in the TCF7L2 gene were 29% (extensive metabolizers), 66.34% (intermediate metabolizers), and 4.66% (poor metabolizers), respectively. The C/C, C/T, and T/T genotypic frequencies of the rs7903146 (C>T) allele were significantly different (P<0.01) among Iranians of different ethnicities. The frequency of the homozygous T/T variant of the rs7903146 (C>T) allele was significantly low in the Lure (P<0.01) and high in the Fars (P<0.001) ethnicities. Additionally, the frequency of the T/T variant of the rs7903146 (C>T) allele in the South of Iran was the highest (P<0.04), while the East of Iran had the lowest frequency (P<0.01). Conclusion The prediction of rs7903146 (C>T) is required in drug research and routine treatment, where the information would be helpful for clinicians to optimize therapy and adverse drug reactions and predict drug response in individuals at risk of T2D.
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Affiliation(s)
- Mojgan Allahdini
- Department of Molecular Biology, Ahar Branch Islamic Azad University, Ahar, Iran
| | - Behnam Kamalidehghan
- Pharmacy Department, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Leila Akbari
- Department of Biology, Sciences and Research Branch, Azad University, Tehran, Iran
| | - Parisa Azadfar
- Department of Biology, Sciences and Research Branch, Azad University, Tehran, Iran
| | - Ali Rahmani
- Department of Molecular Biology, Ahar Branch Islamic Azad University, Ahar, Iran
| | - Fatemeh Ahmadipour
- Pharmacy Department, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Goh Yong Meng
- Department of Veterinary Preclinical Sciences, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
| | | | - Massoud Houshmand
- Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
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Pineda-Tenor D, Berenguer J, Jiménez-Sousa MA, Carrero A, García-Álvarez M, Aldámiz-Echevarria T, García-Broncano P, Diez C, Guzmán-Fulgencio M, Fernández-Rodríguez A, Resino S. rs7903146 polymorphism at transcription factor 7 like 2 gene is associated with total cholesterol and lipoprotein profile in HIV/hepatitis C virus-coinfected patients. AIDS Res Hum Retroviruses 2015; 31:326-34. [PMID: 25353718 DOI: 10.1089/aid.2014.0195] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Transcription factor 7 like 2 (TCF7L2) rs7903146 polymorphism has been associated with metabolic disturbance and cardiovascular disease. The aim of this study was to analyze the association between TCF7L2 rs7903146 polymorphism and potential disturbances on the lipid profile in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. We performed a cross-sectional study on 263 HIV/HVC-coinfected patients. TCF7L2 polymorphism was genotyped by GoldenGate assay. The analysis was performed by linear and logistic regression under a dominant model of inheritance. The variables analyzed were total cholesterol (TC), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), non-HDL-C, and triglycerides. Patients harboring the rs7903146 TT/TC genotype showed a diminished concentration of TC (p=0.003), LDL-C (p=0.004), HDL-C (p=0.012), and non-HDL-C (p=0.013), a lower percentage of TC≥200 mg/dl (p=0.038), and a higher percentage of HDL≤40 mg/dl (p=0.023). In addition, we observed that rs7903146 was differently related to fasting serum lipid levels according to the HCV-genotype (HCV-GT). With regard to HCV-GT1 patients, the rs7903146 TT/TC genotype was associated with lower levels of HDL-C [adjusted arithmetic mean ratio (aAMR)=0.91; p=0.049] and an elevated percentage of patients with HDL-C≤40 mg/dl [adjusted odds ratio (aOR)=3.26; p=0.003]. For HCV-GT3 patients, the rs7903146 TT/TC genotype was associated with lower serum values of TC (aAMR=0.81; p=0.037), LDL-C (aAMR=0.67; p=0.001), and non-HDL-C (aAMR=0.75; p=0.002) and a reduced percentage of TC≥200 mg/dl (aOR=0.089; p=0.037). In conclusion, the TCF7L2 rs7903146 TT/TC genotype was associated with lower levels of TC, LDL, and HDL in HCV-GT3 patients, and lower levels of HDL-C in HCV-GT1 patients, suggesting a role in cardiovascular disease and a potential use as a biomarker in HIV/HCV-coinfected patients.
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Affiliation(s)
- Daniel Pineda-Tenor
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Juan Berenguer
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - María A. Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Ana Carrero
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Mónica García-Álvarez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Teresa Aldámiz-Echevarria
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Pilar García-Broncano
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Cristina Diez
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - María Guzmán-Fulgencio
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Amanda Fernández-Rodríguez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
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Wang S, Song K, Srivastava R, Fathzadeh M, Li N, Mani A. The Protective Effect of Transcription Factor 7-Like 2 Risk Allele rs7903146 against Elevated Fasting Plasma Triglyceride in Type 2 Diabetes: A Meta-Analysis. J Diabetes Res 2015; 2015:468627. [PMID: 26576435 PMCID: PMC4631899 DOI: 10.1155/2015/468627] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 03/17/2015] [Accepted: 03/28/2015] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The results from published studies regarding association of transcription factor 7-like 2 (TCF7L2) variant rs7903146 with dyslipidemia have been conflicting and inconclusive. METHODS We carried out a meta-analysis that aimed to investigate the association of the rs7903146 variant with plasma lipid levels using electronic database and published studies. Data was extracted by a standard algorithm. Dominant, recessive, homozygote, and heterozygote comparison models were utilized. RESULTS 24 studies incorporating 52,785 subjects were included in this meta-analysis. Overall, the minor allele (T) was associated with lower risk for hypertriglyceridemia in subjects with type 2 diabetes (dominant model: SMD = -0.04, 95% CI (-0.08, 0.00), P = 0.048, P heterogeneity = 0.47; recessive model: SMD = -0.10, 95% CI (-0.18, -0.02), P = 0.01, P heterogeneity = 0.56). No association was found between minor (T) allele and plasma TC, LDL-c, or HDL-c levels in subjects with type 2 diabetes or metabolic syndrome (MetS) and no association was found between minor (T) allele and plasma TG levels in nondiabetic subjects. CONCLUSIONS Our meta-analysis indicated the association between TCF7L2 rs7903146 polymorphism and low plasma triglyceride (TG) level in subjects with type 2 diabetes. No association was found between rs7903146 variant and plasma lipids in nondiabetic subjects.
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Affiliation(s)
- Shuxia Wang
- The Geriatric Cardiology Department, Chinese PLA General Hospital, Beijing 100853, China
- Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Kangxing Song
- The Geriatric Cardiology Department, Chinese PLA General Hospital, Beijing 100853, China
- Department of Cardiology, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing 100853, China
| | - Roshni Srivastava
- Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Mohsen Fathzadeh
- Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Na Li
- Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Arya Mani
- Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
- *Arya Mani:
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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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Abstract
Multiple studies have shown that genetic factors may play an important role in determining an individual's risk for the development of diabetic retinopathy (DR) and progression to proliferative DR. However, consistent and definitive genetic associations with DR across broad populations have been not been established. Numerous genes have been studied for their association with DR and the results of these investigations have most specifically pointed to three specific genes that are likely involved in DR development and progression. The gene coding for vascular endothelial growth factor, aldose reductase, and the receptor for advanced glycation end products have been extensively evaluated, and specific polymorphisms of these genes have been suggested to potentially increase the risk of DR development. In this paper, we have reviewed the published literature on the genetics of DR and the potential implications for DR development and progression.
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Affiliation(s)
- Ahmed F Omar
- Joslin Diabetes Center, Beetham Eye Institute , Boston, Massachusetts , USA and
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Corella D, Carrasco P, Sorlí JV, Estruch R, Rico-Sanz J, Martínez-González MÁ, Salas-Salvadó J, Covas MI, Coltell O, Arós F, Lapetra J, Serra-Majem L, Ruiz-Gutiérrez V, Warnberg J, Fiol M, Pintó X, Ortega-Azorín C, Muñoz MÁ, Martínez JA, Gómez-Gracia E, González JI, Ros E, Ordovás JM. Mediterranean diet reduces the adverse effect of the TCF7L2-rs7903146 polymorphism on cardiovascular risk factors and stroke incidence: a randomized controlled trial in a high-cardiovascular-risk population. Diabetes Care 2013; 36:3803-3811. [PMID: 23942586 PMCID: PMC3816851 DOI: 10.2337/dc13-0955] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 06/17/2013] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Transcription factor 7-like 2 (TCF7L2) polymorphisms are strongly associated with type 2 diabetes, but controversially with plasma lipids and cardiovascular disease. Interactions of the Mediterranean diet (MedDiet) on these associations are unknown. We investigated whether the TCF7L2-rs7903146 (C>T) polymorphism associations with type 2 diabetes, glucose, lipids, and cardiovascular disease incidence were modulated by MedDiet. RESEARCH DESIGN AND METHODS A randomized trial (two MedDiet intervention groups and a control group) with 7,018 participants in the PREvención con DIetaMEDiterránea study was undertaken and major cardiovascular events assessed. Data were analyzed at baseline and after a median follow-up of 4.8 years. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for cardiovascular events. RESULTS The TCF7L2-rs7903146 polymorphism was associated with type 2 diabetes (odds ratio 1.87 [95% CI 1.62-2.17] for TT compared with CC). MedDiet interacted significantly with rs7903146 on fasting glucose at baseline (P interaction = 0.004). When adherence to the MedDiet was low, TT had higher fasting glucose concentrations (132.3 ± 3.5 mg/dL) than CC+CT (127.3 ± 3.2 mg/dL) individuals (P = 0.001). Nevertheless, when adherence was high, this increase was not observed (P = 0.605). This modulation was also detected for total cholesterol, LDL cholesterol, and triglycerides (P interaction < 0.05 for all). Likewise, in the randomized trial, TT subjects had a higher stroke incidence in the control group (adjusted HR 2.91 [95% CI 1.36-6.19]; P = 0.006 compared with CC), whereas dietary intervention with MedDiet reduced stroke incidence in TT homozygotes (adjusted HR 0.96 [95% CI 0.49-1.87]; P = 0.892 for TT compared with CC). CONCLUSIONS Our novel results suggest that MedDiet may not only reduce increased fasting glucose and lipids in TT individuals, but also stroke incidence.
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Ciccacci C, Di Fusco D, Cacciotti L, Morganti R, D'Amato C, Novelli G, Sangiuolo F, Spallone V, Borgiani P. TCF7L2 gene polymorphisms and type 2 diabetes: association with diabetic retinopathy and cardiovascular autonomic neuropathy. Acta Diabetol 2013; 50:789-99. [PMID: 22843023 DOI: 10.1007/s00592-012-0418-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Accepted: 07/13/2012] [Indexed: 12/14/2022]
Abstract
Type 2 diabetes (T2DM) is a complex disease resulting from the contribution of both environmental and genetic factors. Recently, the list of genes implicated in the susceptibility to T2DM has substantially grown, also as a consequence of the great development of the genome-wide association studies in the last decade. Common polymorphisms in TCF7L2 gene have shown to have a strong effect with respect to many other involved genes. The aims of our study were to confirm the role of TCF7L2 in the susceptibility to T2DM in the Italian population and to investigate whether TCF7L2 genotypes also contribute to the clinical phenotypes variability and to diabetic complications development. Three TCF7L2 polymorphisms (rs7903146, rs7901695 and rs12255372) have been analyzed by allelic discrimination assays in a cohort of 154 Italian patients with T2DM and 171 healthy controls. A case-control association study and a genotype-phenotype correlation study have been carried out. Consistent with previous studies, all three SNPs showed a strong association with susceptibility to T2DM, both at genotypic (P = 0.003, P = 0.004 and P = 0.012) and at allelic level (P = 0.0004, P = 0.0004 and P = 0.003). Moreover, we observed associations between TCF7L2 variants and the following diabetic complications: diabetic retinopathy, cardiovascular disease and coronary artery disease. We also found a strong correlation between the rs7903146 and the presence of cardiovascular autonomic neuropathy (P = 0.02 with a high OR = 8.28). In conclusion, our study, in addition to confirming the involvement of TCF7L2 gene in the T2DM susceptibility, has shown that TCF7L2 genetic variability also contributes to the development of diabetic complications such as retinopathy and cardiovascular autonomic neuropathy.
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Affiliation(s)
- Cinzia Ciccacci
- Department of Biomedicine and Prevention, Section of Medical Genetics, School of Medicine, University of Rome "Tor Vergata", 00133, Rome, Italy,
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Phillips CM. Nutrigenetics and metabolic disease: current status and implications for personalised nutrition. Nutrients 2013; 5:32-57. [PMID: 23306188 PMCID: PMC3571637 DOI: 10.3390/nu5010032] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2012] [Revised: 12/12/2012] [Accepted: 12/21/2012] [Indexed: 12/11/2022] Open
Abstract
Obesity, particularly central adiposity, is the primary causal factor in the development of insulin resistance, the hallmark of the metabolic syndrome (MetS), a common condition characterized by dyslipidaemia and hypertension, which is associated with increased risk of cardiovascular disease (CVD) and type 2 diabetes (T2DM). Interactions between genetic and environmental factors such as diet and lifestyle, particularly over-nutrition and sedentary behavior, promote the progression and pathogenesis of these polygenic diet-related diseases. Their current prevalence is increasing dramatically to epidemic proportions. Nutrition is probably the most important environmental factor that modulates expression of genes involved in metabolic pathways and the variety of phenotypes associated with obesity, the MetS and T2DM. Furthermore, the health effects of nutrients may be modulated by genetic variants. Nutrigenomics and nutrigenetics require an understanding of nutrition, genetics, biochemistry and a range of “omic” technologies to investigate the complex interaction between genetic and environmental factors relevant to metabolic health and disease. These rapidly developing fields of nutritional science hold much promise in improving nutrition for optimal personal and public health. This review presents the current state of the art in nutrigenetic research illustrating the significance of gene-nutrient interactions in the context of metabolic disease.
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Affiliation(s)
- Catherine M Phillips
- HRB Centre for Diet and Health Research, Department of Epidemiology and Public Health, University College Cork, College Road, Cork, Ireland.
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Peng S, Zhu Y, Lü B, Xu F, Li X, Lai M. TCF7L2 gene polymorphisms and type 2 diabetes risk: a comprehensive and updated meta-analysis involving 121,174 subjects. Mutagenesis 2012. [PMID: 23188737 DOI: 10.1093/mutage/ges048] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Recently, many new loci associated with type 2 diabetes have been uncovered by genetic association studies and genome-wide association studies. As more reports are made, particularly with respect to varying ethnicities, there is a need to determine more precisely the effect sizes in each major racial group. In addition, some reports have claimed ethnic-specific associations with alternative single-nucleotide polymorphisms (SNPs), and to that end there has been a degree of confusion. We conducted a meta-analysis using an additive genetic model. Eight polymorphisms in 155 studies with 121174 subjects (53385 cases and 67789 controls) were addressed in this meta-analysis. Significant associations were found between type 2 diabetes and rs7903146, rs12255372, rs11196205, rs7901695, rs7895340 and rs4506565, with summary odds ratios (ORs) (95% confidence interval) of 1.39 (1.34-1.45), 1.33 (1.27-1.40), 1.20 (1.14-1.26), 1.32 (1.25-1.39), 1.21 (1.13-1.29) and 1.39 (1.29-1.49), respectively. In addition, no significant associations were found between the two polymorphisms (rs290487 and rs11196218) and type 2 diabetes. The summary ORs for the six statistically significant associations (P < 0.05) were further evaluated by estimating the false-positive report probability, with results indicating that all of the six significant associations were considered noteworthy, and may plausibly be true associations. Significant associations were found between the six polymorphisms (rs7903146, rs12255372, rs11196205, rs7901695, rs7895340 and rs4506565) in the TCF7L2 gene and type 2 diabetes risk, and the other two polymorphisms (rs11196218 and rs290487) were not found to be significantly associated with type 2 diabetes. Subgroups analyses show that significant associations are not found between the six SNPs (rs7903146, rs12255372, rs11196205, rs7901695, rs7895340, and rs4506565) and the type 2 diabetes in some ethnic populations.
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Affiliation(s)
- Sihua Peng
- Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, PR China
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Pilling LC, Harries LW, Powell J, Llewellyn DJ, Ferrucci L, Melzer D. Genomics and successful aging: grounds for renewed optimism? J Gerontol A Biol Sci Med Sci 2012; 67:511-9. [PMID: 22454374 DOI: 10.1093/gerona/gls091] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Successful aging depends in part on delaying age-related disease onsets until later in life. Conditions including coronary artery disease, Alzheimer's disease, prostate cancer, and type 2 diabetes are moderately heritable. Genome-wide association studies have identified many risk associated single-nucleotide polymorphisms for these conditions, but much heritability remains unaccounted for. Nevertheless, a great deal is being learned. METHODS Here, we review age-related disease associated single-nucleotide polymorphisms and identify key underlying pathways including lipid handling, specific immune processes, early tissue development, and cell cycle control. RESULTS Most age-related disease associated single-nucleotide polymorphisms do not affect coding regions of genes or protein makeup but instead influence regulation of gene expression. Recent evidence indicates that evolution of gene regulatory sites is fundamental to interspecies differences. Animal models relevant to human aging may therefore need to focus more on gene regulation rather than testing major disruptions to fundamental pathway genes. Recent larger scale human studies of in vivo genome-wide expression (notably from the InCHIANTI aging study) have identified changes in splicing, the "fine tuning" of protein sequences, as a potentially important factor in decline of cellular function with age. Studies of expression with muscle strength and cognition have shown striking concordance with certain mice models of muscle repair and beta-amyloid phagocytosis respectively. CONCLUSIONS The emerging clearer picture of the genetic architecture of age-related diseases in humans is providing new insights into the underlying pathophysiological pathways involved. Translation of genomics into new approaches to prevention, tests and treatments to extend successful aging is therefore likely in the coming decades.
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Affiliation(s)
- L C Pilling
- Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK
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Abstract
Several candidate gene studies on the metabolic syndrome (MetS) have been conducted. However, for most single nucleotide polymorphisms (SNPs) no systematic review on their association with MetS exists. A systematic electronic literature search was conducted until the 2nd of June 2010, using HuGE Navigator. English language articles were selected. Only genes of which at least one SNP-MetS association was studied in an accumulative total population ≥ 4000 subjects were included. Meta-analyses were conducted on SNPs with three or more studies available in a generally healthy population. In total 88 studies on 25 genes were reviewed. Additionally, for nine SNPs in seven genes (GNB3, PPARG, TCF7L2, APOA5, APOC3, APOE, CETP) a meta-analysis was conducted. The minor allele of rs9939609 (FTO), rs7903146 (TCF7L2), C56G (APOA5), T1131C (APOA5), C482T (APOC3), C455T (APOC3) and 174G>C (IL6) were more prevalent in subjects with MetS, whereas the minor allele of Taq-1B (CETP) was less prevalent in subjects with the MetS. After having systematically reviewed the most studied SNP-MetS associations, we found evidence for an association with the MetS for eight SNPs, mostly located in genes involved in lipid metabolism.
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Affiliation(s)
- C M Povel
- National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
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Cho HJ, Lee SY, Kim YG, Oh SY, Kim JW, Huh W, Ko JW, Kim HG. Effect of genetic polymorphisms on the pharmacokinetics and efficacy of glimepiride in a Korean population. Clin Chim Acta 2011; 412:1831-1834. [PMID: 21704609 DOI: 10.1016/j.cca.2011.06.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Revised: 06/10/2011] [Accepted: 06/11/2011] [Indexed: 12/31/2022]
Abstract
BACKGROUNDS Glimepiride is a commonly used sulfonylurea hypoglycemic agent. There is considerable interindividual variation in the response to sulfonylurea for patients with type 2 diabetes. The purpose of this study was to investigate whether genetic variations influence the efficacy of glimepiride in healthy Korean subjects. METHODS A single 2-mg oral dose of glimepiride was administered to 46 healthy volunteers. Serial blood sampling for 12h after oral dosing was performed for determination of plasma glimepiride, glucose and insulin levels. We tested the association of seven single nucleotide polymorphisms (SNPs) in four candidate genes with the efficacy of glimepiride. RESULTS Pharmacodynamic profiles for plasma glucose and insulin showed no statistically significant differences among genotype groups, and parameters were not different from one another. There were no association of the KCNJ11, NOS1AP, TCF7L2 and ABCC8 gene polymorphisms and the efficacy of glimepiride. CONCLUSIONS Knowledge of these polymorphisms provides no clinical useful information for the pharmacogenetic therapeutic approach for Korean patients with type 2 diabetes.
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Affiliation(s)
- Hyun-Jung Cho
- Department of Laboratory Medicine, Konyang University Hospital, College of Medical Science Konyang University, Daejon, Republic of Korea
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Buraczynska M, Swatowski A, Markowska-Gosik D, Kuczmaszewska A, Ksiazek A. Transcription factor 7-like 2 (TCF7L2) gene polymorphism and complication/comorbidity profile in type 2 diabetes patients. Diabetes Res Clin Pract 2011; 93:390-5. [PMID: 21641671 DOI: 10.1016/j.diabres.2011.05.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Revised: 04/11/2011] [Accepted: 05/09/2011] [Indexed: 02/07/2023]
Abstract
Transcription factor 7-like 2 gene (TCF7L2) has been associated with type 2 diabetes. We investigated the association of the rs7903146 SNP in this gene with clinical profile of type 2 diabetes (T2DM) patients. The study involved 980 patients with diabetic nephropathy (44%), diabetic retinopathy (42%), CVD (65%) and early onset of diabetes (45%) and 924 healthy controls. Subjects were genotyped for rs7903146 by PCR-RFLP. Genotype frequencies significantly differed between T2DM patients and controls (p<0.01, odds ratio (OR) for TT genotype 2.49 (95% confidence interval (CI) 1.84-3.39). An association was observed between rs7903146 and nephropathy (p<0.001), with 22% of TT homozygotes in this subgroup vs. 11% in patients without nephropathy (p=0.006, OR for TT 2.83, 95% CI 1.94-4.13). Association was stronger in patients with early onset of diabetes (34% of TT vs. 12% in the late onset, p<0.001). In DN group 71% of TT homozygotes had an early onset (OR 7.64, 95% CI 4.98-11.73 vs. controls). Our results confirm association of rs7903146 in the TCF7L2 gene with increased risk of type 2 diabetes. The T allele is strongly associated with nephropathy, especially in early onset of diabetes.
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Affiliation(s)
- Monika Buraczynska
- Laboratory for DNA Analysis and Molecular Diagnostics, Department of Nephrology, Medical University of Lublin, Dr K. Jaczewskiego 8, 20-954 Lublin, Poland.
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Klünder-Klünder M, Mejía-Benitez MA, Flores-Huerta S, Burguete-García AI, García-Mena J, Cruz M. rs12255372 variant of TCF7L2 gene is protective for obesity in Mexican children. Arch Med Res 2011; 42:495-501. [PMID: 22136959 DOI: 10.1016/j.arcmed.2011.05.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Accepted: 05/12/2011] [Indexed: 11/17/2022]
Abstract
BACKGROUND AND AIMS Variants in the transcription factor 7-like 2 (TCF7L2) gene are consistently associated with type 2 diabetes in adults, but the association of TCF7L2 with weight-related traits and body fat in humans is unclear. The aim of this study was to determine the relationship between the TCF7L2 gene (rs12255372) and obese phenotype in Mexican school-age children. METHODS The study was performed in schools in Mexico City; 186 obese and 194 control children were studied. Fasting insulin and glucose, total cholesterol, LDL-C, HDL-C and triglycerides concentration were determined. The variant rs12255372 of the TCF7L2 gene was genotyped. We used age- and sex-adjusted linear models to test for association with metabolic measurements with this variant. RESULTS Genotype of the TCF7L2 rs12255372 gene was associated with lower fasting plasma glucose (p = 0.001) and lower homeostasis model assessment of insulin resistance (HOMA-R; p = 0.001) in nonobese children. Heterozygous carriers for this variant were more prevalent in lean children (32.5%) than in the obese group (23.7%), which resulted in a strong protective effect for the normal weight condition (OR = 0.56, 0.32-0.97). CONCLUSIONS TCF7L2 rs12255372 polymorphism protects Mexican children from obesity. Further research in other large, population-based studies is needed to replicate these findings.
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Affiliation(s)
- Miguel Klünder-Klünder
- Community Health Research Department, Hospital Infantil de México Federico Gómez, Ministry of Health, Mexico City, Mexico
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Dietary saturated fat, gender and genetic variation at the TCF7L2 locus predict the development of metabolic syndrome. J Nutr Biochem 2011; 23:239-44. [PMID: 21543200 DOI: 10.1016/j.jnutbio.2010.11.020] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2010] [Revised: 11/11/2010] [Accepted: 11/29/2010] [Indexed: 12/12/2022]
Abstract
Transcription factor 7-like 2 (TCF7L2) is the strongest genetic determinant of type 2 diabetes (T2DM) and insulin-related phenotypes to date. Dietary fat is a key environmental factor which may interact with genotype to affect risk of metabolic syndrome (MetS) and T2DM. This study investigated the relationship between the TCF7L2 rs7903146 polymorphism, insulin sensitivity/resistance and MetS in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n=1754) and determined potential interactions with dietary fat intake. Female minor T allele carriers of rs7903146 had increased MetS risk (odds ratio [OR] 1.66, confidence interval [CI] 1.02-2.70, P=.04) and displayed elevated insulin concentrations (P=.005), impaired insulin sensitivity (P=.011), increased abdominal obesity (P=.008) and body mass index (P=.001) and higher blood pressure (P<.05) compared to the CC homozygotes. Metabolic syndrome risk was also modulated by dietary saturated fat (SFA) intake (P=.035 for interaction). High dietary SFA intake (≥15.5% energy) exacerbated MetS risk (OR 2.35, 95% CI 1.29-4.27, P=.005) and was associated with further impaired insulin sensitivity in the T allele carriers relative to the CC homozygotes (P=.025) and particularly to the T allele carriers with the lowest SFA intake (P=.008). No significant genotype effect on MetS risk or insulin sensitivity was evident among low-SFA consumers. In conclusion, the TCF7L2 rs7903146 polymorphism influences MetS risk, which is augmented by both gender and dietary SFA intake, suggesting novel gene-diet-gender interactions.
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Hansson O, Zhou Y, Renström E, Osmark P. Molecular function of TCF7L2: Consequences of TCF7L2 splicing for molecular function and risk for type 2 diabetes. Curr Diab Rep 2010; 10:444-51. [PMID: 20878273 DOI: 10.1007/s11892-010-0149-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
TCF7L2 harbors the variant with the strongest effect on type 2 diabetes (T2D) identified to date, yet the molecular mechanism as to how variation in the gene increases the risk for developing T2D remains elusive. The phenotypic changes associated with the risk genotype suggest that T2D arises as a consequence of reduced islet mass and/or impaired function, and it has become clear that TCF7L2 plays an important role for several vital functions in the pancreatic islet. TCF7L2 comprises 17 exons, five of which are alternative (ie, exons 4 and 13-16). In pancreatic islets four splice variants of TCF7L2 are predominantly expressed. The regulation of these variants and the functional consequences at the protein level are still poorly understood. A clear picture of the molecular mechanism will be necessary to understand how an intronic variation in TCF7L2 can influence islet function.
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Affiliation(s)
- Ola Hansson
- Department of Clinical Sciences, CRC, Malmö University Hospital, Lund University, Malmö, Sweden.
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36
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Abstract
A variety of treatment modalities exist for individuals with type 2 diabetes mellitus (T2D). In addition to dietary and physical activity interventions, T2D is also treated pharmacologically with nine major classes of approved drugs. These medications include insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs), meglitinides, α-glucosidase inhibitors, amylin analogues, incretin hormone mimetics, and dipeptidyl peptidase 4 (DPP4) inhibitors. Pharmacological treatment strategies for T2D are typically based on efficacy, yet favorable responses to such therapeutics are oftentimes variable and difficult to predict. Characterization of drug response is expected to substantially enhance our ability to provide patients with the most effective treatment strategy given their individual backgrounds, yet pharmacogenetic study of diabetes medications is still in its infancy. To date, major pharmacogenetic studies have focused on response to sulfonylureas, biguanides, and TZDs. Here, we provide a comprehensive review of pharmacogenetics investigations of these specific anti-diabetes medications. We focus not only on the results of these studies, but also on how experimental design, study sample issues, and definition of 'response' can significantly impact our interpretation of findings. Understanding the pharmacogenetics of anti-diabetes medications will provide critical baseline information for the development and implementation of genetic screening into therapeutic decision making, and lay the foundation for "individualized medicine" for patients with T2D.
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Affiliation(s)
- Johanna K. DiStefano
- Metabolic Diseases Division, Translational Genomics Research Institute, 445 N. 5th Street, Phoenix, AZ 85004, USA
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +1-602-343-8812; Fax: +1-602-343-8844
| | - Richard M. Watanabe
- Departments of Preventive Medicine and Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; E-Mail: (R.M.W.)
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Yan Y, North KE, Heiss G, Klein R, Girman CJ, Lange EM, Pankow JS, Brancati FL, Boerwinkle E. Transcription factor 7-like 2 (TCF7L2) polymorphism and context-specific risk of impaired fasting glucose in African American and Caucasian adults: the atherosclerosis risk in communities (ARIC) study. Diabetes Metab Res Rev 2010; 26:371-7. [PMID: 20578204 PMCID: PMC2990965 DOI: 10.1002/dmrr.1087] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Although variants in the transcription factor 7-like 2 (TCF7L2) gene are consistently associated with impaired fasting glucose (IFG) in Caucasians, data from large population-based studies of African Americans are lacking. Moreover, few studies have investigated the effects of TCF7L2 on IFG in the context of metabolic risk factors for diabetes. METHODS We investigated the association between the TCF7L2 rs7903146 polymorphism and incident IFG defined as fasting serum glucose levels of 100-125 mg/dL (5.6-6.9 mmol/L) in 1377 African American and 5152 Caucasian participants without diabetes and IFG at intake who participated in the Atherosclerosis Risk in Communities (ARIC) Study from 1987 to 1989 and were followed for 9 years. RESULTS Incident IFG was identified in 810 (58.8%) African American and 2652 (51.5%) Caucasian participants. Compared to homozygous CC Caucasian individuals, heterozygous CT [hazard ratio (HR) = 1.09 (95% CI = 1.03-1.15)] and homozygous TT [1.18 (1.05-1.33)] individuals had significantly higher risk of developing IFG over 9-year follow-up. The association between rs7903146 and IFG risk was stronger in Caucasians with obesity [HR(CTvs.CC) = 1.28 (1.12, 1.47); HR(TTvs.CC) = 1.65 (1.25, 2.17)] or high triglycerides [HR(CTvs.CC) = 1.31(1.10, 1.56); HR(TTvs.CC) = 1.72 (1.21, 2.43)]. No association of the TCF7L2 rs7903146 polymorphism and incident IFG was noted in African Americans. CONCLUSIONS Our study replicates the association between rs7903146 and IFG risk in a population-based, longitudinal cohort of Caucasians but not in African Americans. For the first time, our study provides evidence for interactions between TCF7L2 and metabolic risk factors on the occurrence of IFG in Caucasians.
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Affiliation(s)
- Yu Yan
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599-8050, USA
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Yan Y, Klein R, Heiss G, Girman CJ, Lange EM, Klein BE, Rose KM, Boerwinkle E, Pankow JS, Brancati FL, Ballantyne CM, Köttgen A, North KE. The transcription factor 7-like 2 (TCF7L2) polymorphism may be associated with focal arteriolar narrowing in Caucasians with hypertension or without diabetes: the ARIC Study. BMC Endocr Disord 2010; 10:9. [PMID: 20478041 PMCID: PMC2879252 DOI: 10.1186/1472-6823-10-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2009] [Accepted: 05/17/2010] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Transcription factor 7-like 2 (TCF7L2) has emerged as a consistently replicated susceptibility gene for type 2 diabetes, however, whether the TCF7L2 gene also has similar effects on the retinal microvasculature is less clear. We therefore aimed to investigate the association between the transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism and retinal microvascular phenotypes in the Atherosclerosis Risk in Communities (ARIC) Study (1993-1995). METHODS This was a population-based, cross-sectional study of 10,320 middle-aged African American (n = 2,199) and Caucasian (n = 8,121) men and women selected from four United States communities to examine the association between TCF7L2 rs7903146 polymorphism and retinal microvascular signs (retinopathy, focal arteriolar narrowing, arteriovenous nicking, arteriolar and venular calibers). Photographs on one randomly selected eye were graded for presence of retinal microvascular signs and used to measure retinal vessel calibres. RESULTS After adjusting for age, sex, study center, mean arterial blood pressure, total serum cholesterol, triglycerides, and other covariates, few associations of TCF7L2 rs7903146 and retinal microvascular signs were noted. TCF7L2 rs7903146 T risk allele was significantly associated with focal arteriolar narrowing in Caucasians with hypertension [odds ratio (OR)CT vs. CC (95% CI) = 1.25 (1.09-1.44); ORTT vs. CC = 1.56 (1.18-2.06); P = 0.002] and in Caucasians without diabetes [OR CT vs. CC = 1.18 (1.06-1.32); OR TT vs. CC = 1.40 (1.12, 1.75); P = 0.003]. No significant association of the TCF7L2 rs7903146 polymorphism and retinal vascular signs was noted among African American individuals. CONCLUSIONS TCF7L2 rs7903146 is not consistently associated with retinal microvascular signs. However, we report an association between the TCF7L2 rs7903146 polymorphism and focal arteriolar narrowing in Caucasians with hypertension or without diabetes. Further research in other large, population-based studies is needed to replicate these findings.
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Affiliation(s)
- Yu Yan
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
| | - Ronald Klein
- Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA
| | - Gerardo Heiss
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
| | - Cynthia J Girman
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
- Department of Epidemiology, Merck Research Laboratories, West Point, PA, USA
| | - Ethan M Lange
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
- Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC, USA
| | - Barbara E Klein
- Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA
| | - Kathryn M Rose
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
| | - Eric Boerwinkle
- Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA
| | - James S Pankow
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA
| | - Frederick L Brancati
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Christie M Ballantyne
- Department of Medicine, Atherosclerosis and Vascular Medicine, Baylor College of Medicine, Houston TX, USA
| | - Anna Köttgen
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Kari E North
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
- Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC, USA
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Abstract
PURPOSE OF REVIEW The number of studies investigating interactions between genes and nutrients for cardiovascular disease continues to grow, and holds tremendous potential for reducing disease risk at the level of the individual genotype. However, understanding the limitations and challenges of interaction studies, whether of observational or interventional design, is essential for critical evaluation of these studies. RECENT FINDINGS Nutrient-gene interactions for cardiovascular disease both parallel and extend nutrition studies, encompassing both traditional and novel cardiovascular risk factors. Fatty acid quality, lipid metabolism, inflammation, postprandial metabolism, fatty liver and macronutrient-gene interactions for obesity and metabolic syndrome represent a subset of the major areas of recent focus. With few exceptions, however, studies of gene-nutrient interactions are limited to a single population. SUMMARY Gene-nutrient research will continue to expand as genome-wide association studies uncover new sources of genetic variability associated with cardiovascular risk. However, in addition to investigation of newly discovered variants, continuing efforts must focus on the confirmation of previously reported genetic associations and interactions in additional populations.
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Affiliation(s)
- Caren E Smith
- Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA
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Tan S, Scherag A, Janssen OE, Hahn S, Lahner H, Dietz T, Scherag S, Grallert H, Vogel CIG, Kimmig R, Illig T, Mann K, Hebebrand J, Hinney A. Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS). BMC MEDICAL GENETICS 2010; 11:12. [PMID: 20092643 PMCID: PMC2824654 DOI: 10.1186/1471-2350-11-12] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2009] [Accepted: 01/21/2010] [Indexed: 12/17/2022]
Abstract
Background The polycystic ovary syndrome (PCOS), a common endocrine disorder in women of child-bearing age, mainly characterised by chronic anovulation and hyperandrogenism, is often associated with insulin resistance (IR) and obesity. Its etiology and the role of IR and obesity in PCOS are not fully understood. We examined the influence of validated genetic variants conferring susceptibility to obesity and/or type 2 diabetes mellitus (T2DM) on metabolic and PCOS-specific traits in patients with PCOS. Methods We conducted an association study in 386 patients with PCOS (defined by the Rotterdam-criteria) using single nucleotide polymorphisms (SNPs) in or in proximity to the fat mass and obesity associated gene (FTO), insulin-induced gene-2 (INSIG2), transcription factor 7-like 2 gene (TCF7L2) and melanocortin 4 receptor gene (MC4R). To compare the effect of FTO obesity risk alleles on BMI in patients with PCOS to unselected females of the same age range we genotyped 1,971 females from the population-based KORA-S4 study (Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4). Results The FTO risk allele was associated with IR traits and measures of increased body weight. In addition, the TCF7L2 SNP was associated with body weight traits. For the SNPs in the vicinity of INSIG2 and MC4R and for the other examined phenotypes there was no evidence for an association. In PCOS the observed per risk allele effect of FTO intron 1 SNP rs9939609 on BMI was +1.56 kg/m2, whereas it was +0.46 kg/m2 in females of the same age range from the general population as shown previously. Conclusion The stronger effect on body weight of the FTO SNP in PCOS might well have implications for the etiology of the disease.
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Affiliation(s)
- Susanne Tan
- Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany
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Yu M, Xu XJ, Yin JY, Wu J, Chen X, Gong ZC, Ren HY, Huang Q, Sheng FF, Zhou HH, Liu ZQ. KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) polymorphisms affect therapeutic efficacy of repaglinide in Chinese patients with type 2 diabetes. Clin Pharmacol Ther 2010; 87:330-5. [PMID: 20054294 DOI: 10.1038/clpt.2009.242] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
This study showed that the polymorphisms KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) are associated with a heightened risk of developing type 2 diabetes mellitus (T2DM). We also explored the effects of these polymorphisms on the efficacy of repaglinide therapy in Chinese patients with T2DM. A total of 259 patients with T2DM and 188 healthy controls were genotyped. Forty patients with various genotypes were randomly selected to undergo an 8-week repaglinide treatment regimen. Patients with the G allele of the KCNJ11 Lys23Glu polymorphism showed higher levels of fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) (P < 0.05). After repaglinide treatment, patients with the GA or AA genotype showed higher levels of FPG, PPG, and glycated hemoglobin (HbA(1c)) compared with patients with the GG genotype (P < 0.05). Patients with the C allele of TCF7L2 rs290487(C/T) had higher total cholesterol levels and lower body mass index (BMI) (P < 0.05). In patients with the TT genotype, the drug showed better efficacy with respect to levels of fasting insulin, triglycerides, and low-density lipoprotein cholesterol (LDL-c) than in patients with the CC or CT genotype (P < 0.05). The KCNJ11 and TCF7L2 polymorphisms were associated with repaglinide efficacy.
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Affiliation(s)
- M Yu
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Hunan, People's Republic of China
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Bo S, Gambino R, Ciccone G, Rosato R, Milanesio N, Villois P, Pagano G, Cassader M, Gentile L, Durazzo M, Cavallo-Perin P. Effects of TCF7L2 polymorphisms on glucose values after a lifestyle intervention. Am J Clin Nutr 2009; 90:1502-8. [PMID: 19864407 DOI: 10.3945/ajcn.2009.28379] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND TCF7L2 is the strongest locus linked to type 2 diabetes that has been identified thus far, and rs7903146 is the most significantly associated variant. Few intervention studies have shown that it has negative effects on metabolic improvement after lifestyle programs. OBJECTIVE Our objective was to assess the effects of this variant on lifestyle intervention-induced changes in glucose values and metabolic variables at 1- and 4-y follow-ups. DESIGN The rs7903146 variant was genotyped in 335 nondiabetic, dysmetabolic participants in a randomized lifestyle intervention trial. RESULTS Subjects with the unfavorable TT genotype showed higher values of fasting glucose and lower homeostasis model assessment of beta cell function at baseline. Lifestyle modifications were successful in the amelioration of metabolic traits in all genetic subgroups after 1 y. At 4-y follow-up most of the metabolic benefits had disappeared. In a multiple regression model, values for glucose and homeostasis model assessment of beta cell function at 4 y were significantly associated with the T allele (for glucose and homeostasis model assessments, respectively: beta = 6.6; 95% CI: 2.5, 10.7; P = 0.001; and beta = -0.37; 95% CI: -0.54, -0.20; P < 0.001) but not with intervention. There was no interaction between genotype and intervention. After 1 y, impaired fasting glucose and diabetes incidence were inversely associated with intervention. After 4 y, the presence of a T allele was associated with impaired fasting glucose (odds ratio: 3.04; 95% CI: 1.53, 6.04; P = 0.001) and diabetes (odds ratio: 2.63; 95% CI: 1.00, 6.96; P = 0.05) but not with intervention. CONCLUSIONS Lifestyle modifications improved the metabolic pattern in all genetic subgroups. At the end of the trial, however, weight gain occurred, and carriers of the T allele developed first hyperglycemia and decreased insulin secretion, which suggests the need for different "after-care" preventive approaches tailored to each genotype's metabolic risk.
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Affiliation(s)
- Simona Bo
- Department of Internal Medicine and the Unit of Cancer Epidemiology, University of Turin, Turin, Italy.
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Liu PH, Chang YC, Jiang YD, Chen WJ, Chang TJ, Kuo SS, Lee KC, Hsiao PC, Chiu KC, Chuang LM. Genetic variants of TCF7L2 are associated with insulin resistance and related metabolic phenotypes in Taiwanese adolescents and Caucasian young adults. J Clin Endocrinol Metab 2009; 94:3575-82. [PMID: 19509102 DOI: 10.1210/jc.2009-0609] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
OBJECTIVES The effect of TCF7L2 rs7903146 on glucose homeostasis is considered primarily due to impaired insulin secretion in European populations. Because we previously demonstrated that TCF7L2 rs290487 near the 3' end of TCF7L2 was significantly associated with type 2 diabetes (T2D) in Taiwanese subjects, we aimed to investigate potential mechanisms underlying the associations of rs290487 with T2D. METHODS Eighteen single nucleotide polymorphisms (SNPs) were tested for association with glucose/insulin homeostasis as well as other quantitative metabolic phenotypes using the quantitative transmission disequilibrium test in 525 Taiwanese adolescent twin-pairs and siblings. The results were further replicated in 116 nondiabetic normotensive Caucasian young adults. RESULTS Among the 18 SNPs, rs290487 C allele was significantly associated with higher 60-, 90-, and 120-min glucose concentrations (P = 0.001, 0.01, and 0.02, respectively); higher 60- and 90-min insulin concentrations (P = 0.01 and 0.01, respectively); and a lower insulin sensitivity index (P = 0.04). No association was found for rs290487 with measures of insulin secretion. The rs290487 C allele was also associated with HOMA-IR (P = 0.005) and insulin sensitivity index (P = 0.01) in Caucasian young adults. Another SNP, rs10749127 C allele located in intron 4, was also associated with features of the metabolic syndrome, including elevated systolic (P = 0.02) and diastolic (P = 2.0 x 10(-4)) blood pressure, triglycerides (P = 7.0 x 10(-4)), and uric acid (P = 0.03). In a meta-analysis, the rs290487 C allele was confirmed to be associated with an increased risk of T2D (odds ratio, 1.11; 95% confidence interval, 1.03-1.19; P = 0.005) across East Asian populations. CONCLUSIONS These findings support an important role for T2D risk-conferring gene TCF7L2 in insulin resistance in both Taiwanese and Caucasian youth and underscore the emerging role of Wnt signaling in insulin resistance.
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Affiliation(s)
- Pi-Hua Liu
- Research Center for Genes, Environment, and Human Health, Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei 100, Taiwan
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Cluett C, Melzer D. Human genetic variations: Beacons on the pathways to successful ageing. Mech Ageing Dev 2009; 130:553-63. [PMID: 19580824 DOI: 10.1016/j.mad.2009.06.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2009] [Revised: 06/19/2009] [Accepted: 06/26/2009] [Indexed: 01/25/2023]
Abstract
Avoiding age-related disease until late in life is key to 'successful' ageing. Over 300 genome-wide association study papers have been published. Over 50 variants have already been identified as associated with four key age-related diseases, namely cardiovascular disease, type 2 diabetes, osteoporosis and prostate cancer. We review these findings with reference to pathways linked to ageing, including cell cycle control or cell senescence, oxidative stress, insulin, IGF1 and other endocrine signalling, and inflammation. Many variants are disease specific or of unknown function. Of the remainder, those with functions likely to be relevant to ageing are predominantly in cell cycle control and therefore tissue repair. Three loci associated with two or more age-related diseases have been identified, two apparently related to cell cycle control. The third shared locus (near TERT), may be involved in telomerase activity and is associated with several environmentally caused age-related cancers. These findings challenge current ideas, suggesting large numbers of cell type specific effects, often driven by regulatory rather than coding changes. They also confirm the central role of cell cycle and re-growth as a key pathway underlying the human variation in successful ageing.
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Warodomwichit D, Arnett DK, Kabagambe EK, Tsai MY, Hixson JE, Straka RJ, Province M, An P, Lai CQ, Borecki I, Ordovas JM. Polyunsaturated fatty acids modulate the effect of TCF7L2 gene variants on postprandial lipemia. J Nutr 2009; 139:439-46. [PMID: 19141698 PMCID: PMC2714378 DOI: 10.3945/jn.108.096461] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The transcription factor 7-like 2 (TCF7L2) has been recently associated with diabetes risk, and it may exert its effect through metabolic syndrome (MetS)-related traits and be subjected to modification by environmental factors. We investigated the effect of single nucleotide polymorphisms (SNP), rs7903146 and rs12255372, within the TCF7L2 locus on postprandial lipemia and other MetS-related traits and their modulation by dietary fat. Data were collected from 1083 European Americans participating in the Genetics of Lipid Lowering Drugs and Diet Network Study. Carriers of the minor T allele at the C/T rs7903146 SNP had higher fasting plasma glucose (P = 0.012), lower homeostasis model assessment of beta cell function (P = 0.041), higher plasma VLDL (P = 0.035), and lower large LDL particle (P = 0.007) concentrations and higher risk of MetS (P = 0.011) than CC individuals. Moreover, we identified significant interactions between this SNP and PUFA intake modulating fasting VLDL particle concentrations (P = 0.016) and postprandial triglycerides (TG) (P = 0.028), chylomicrons (P = 0.025), total VLDL (P = 0.026), and large VLDL (P = 0.018) concentrations. Thus, only T allele carriers with a PUFA intake > or = 7.36% of energy had elevated fasting plasma VLDL concentrations and postprandial TG-rich lipoproteins. These variables did not differ in T allele carriers and noncarriers in the low-PUFA intake group. Moreover, these significant interactions were due exclusively to (n-6) PUFA intake. In summary, high (n-6) PUFA intakes (> or = 6.62% of energy intake) were associated with atherogenic dyslipidemia in carriers of the minor T allele at the TCF7L2 rs7903146 SNP and may predispose them to MetS, diabetes, and cardiovascular disease.
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Affiliation(s)
- Daruneewan Warodomwichit
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; University of Alabama, Birmingham, AL 55294; University of Minnesota, Minneapolis, MN 55455; University of Texas, School of Public Health, Houston, TX 77225, and Washington University School of Medicine, St. Louis, MO 63108
| | - Donna K. Arnett
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; University of Alabama, Birmingham, AL 55294; University of Minnesota, Minneapolis, MN 55455; University of Texas, School of Public Health, Houston, TX 77225, and Washington University School of Medicine, St. Louis, MO 63108
| | - Edmond K. Kabagambe
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; University of Alabama, Birmingham, AL 55294; University of Minnesota, Minneapolis, MN 55455; University of Texas, School of Public Health, Houston, TX 77225, and Washington University School of Medicine, St. Louis, MO 63108
| | - Michael Y. Tsai
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; University of Alabama, Birmingham, AL 55294; University of Minnesota, Minneapolis, MN 55455; University of Texas, School of Public Health, Houston, TX 77225, and Washington University School of Medicine, St. Louis, MO 63108
| | - James E. Hixson
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; University of Alabama, Birmingham, AL 55294; University of Minnesota, Minneapolis, MN 55455; University of Texas, School of Public Health, Houston, TX 77225, and Washington University School of Medicine, St. Louis, MO 63108
| | - Robert J. Straka
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; University of Alabama, Birmingham, AL 55294; University of Minnesota, Minneapolis, MN 55455; University of Texas, School of Public Health, Houston, TX 77225, and Washington University School of Medicine, St. Louis, MO 63108
| | - Michael Province
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; University of Alabama, Birmingham, AL 55294; University of Minnesota, Minneapolis, MN 55455; University of Texas, School of Public Health, Houston, TX 77225, and Washington University School of Medicine, St. Louis, MO 63108
| | - Ping An
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; University of Alabama, Birmingham, AL 55294; University of Minnesota, Minneapolis, MN 55455; University of Texas, School of Public Health, Houston, TX 77225, and Washington University School of Medicine, St. Louis, MO 63108
| | - Chao-Qiang Lai
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; University of Alabama, Birmingham, AL 55294; University of Minnesota, Minneapolis, MN 55455; University of Texas, School of Public Health, Houston, TX 77225, and Washington University School of Medicine, St. Louis, MO 63108
| | - Ingrid Borecki
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; University of Alabama, Birmingham, AL 55294; University of Minnesota, Minneapolis, MN 55455; University of Texas, School of Public Health, Houston, TX 77225, and Washington University School of Medicine, St. Louis, MO 63108
| | - Jose M. Ordovas
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; University of Alabama, Birmingham, AL 55294; University of Minnesota, Minneapolis, MN 55455; University of Texas, School of Public Health, Houston, TX 77225, and Washington University School of Medicine, St. Louis, MO 63108
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Webster RJ, Warrington NM, Weedon MN, Hattersley AT, McCaskie PA, Beilby JP, Palmer LJ, Frayling TM. The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits. Diabetologia 2009; 52:106-14. [PMID: 19018513 DOI: 10.1007/s00125-008-1175-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2008] [Accepted: 09/22/2008] [Indexed: 10/21/2022]
Abstract
AIMS/HYPOTHESIS Common genetic variants influence plasma triacylglycerol, HDL-cholesterol (HDL-C) and glucose levels in cross-sectional studies. However, the longitudinal effects of these established variants have not been studied. Our aim was to examine the longitudinal associations of four such variants in the apolipoprotein A-V (APOA5), lipoprotein lipase (LPL), and glucokinase (GCK) genes with fasting glucose or lipid levels. METHODS The individuals analysed were participants in the Busselton Health Survey (n = 4,554). Cross-sectional analyses of family data used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models. RESULTS The findings of cross-sectional association analyses replicated those of previous studies. We observed associations of the G and C alleles at the APOA5 single nucleotide polymorphisms (SNPs) rs662799 and rs3135506 with raised triacylglycerol levels (p = 0.0003 and p < 0.0001, respectively), the 447X allele at the LPL SNP rs328 with reduced triacylglycerol levels (p = 0.0004) and raised HDL-C levels (p = 0.0004), and the A allele of the GCK SNP rs1799884 with raised fasting glucose level (p = 0.015). Longitudinal association analyses showed that most of these associations did not change in the same individuals over an average follow-up time of 17.4 years, though there was some evidence that the association of the 447X allele of rs328 with raised HDL-C level significantly increased with age (p = 0.01), and that the association of the C allele of rs3135506 with raised triacylglycerol level significantly increased over time (p = 0.0007). CONCLUSIONS/INTERPRETATION The current study suggests that the effects of established gene variants on lipid and glucose traits do not tend to alter with age during adulthood or over time.
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Affiliation(s)
- R J Webster
- Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, B Block, Queen Elizabeth II Medical Centre, Nedlands, WA 6009, Australia.
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Enhörning S, Leosdottir M, Wallström P, Gullberg B, Berglund G, Wirfält E, Melander O. Relation between human vasopressin 1a gene variance, fat intake, and diabetes. Am J Clin Nutr 2009; 89:400-6. [PMID: 19056558 DOI: 10.3945/ajcn.2008.26382] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Male arginine vasopressin 1a receptor knockout mice (V1aR(-/-)) display a phenotype of low triglycerides and high glucose concentrations and high-fat-diet-induced obesity and diabetes. OBJECTIVE We investigated whether genetic variation of the human arginine vasopressin 1A (AVPR1A) gene is associated with phenotypic features resembling those of the V1aR(-/-) mouse. DESIGN In a population-based cross-sectional study in southern Sweden, middle-aged individuals (n = 6,055) were examined in 1991-1994. Associations between 4 AVPR1A tag single nucleotide polymorphisms (rs1042615, rs10784339, rs7308855, and rs10747983) and diabetes status, glucose and triglyceride concentrations, and BMI were analyzed. Furthermore, rs1042615 was related to diabetes status, glucose, and triglycerides within sex-specific quartiles of dietary fat intake (Q1(Fat)-Q4(Fat)) and BMI (Q1(BMI)-Q4(BMI)). RESULTS Subjects carrying the T allele of rs1042615 had lower concentrations of triglycerides than did CC carriers (1.36 +/- 0.77 compared with 1.42 +/- 0.89 mmol/L; P = 0.014), especially in nondiabetic subjects (P = 0.001). Carriers of the rs1042615 T allele had higher fasting blood glucose (5.20 +/- 1.44 mmol/L compared with 5.12 +/- 1.22 mmol/L; P = 0.036) and a tendency toward an increased prevalence of diabetes (odds ratio: 1.22; 95% CI: 0.99, 1.51; P = 0.067) compared with CC carriers. The less common rs10784339, rs7308855, and rs10747983 were not consistently associated with metabolic variables. Among men, the rs1042615 T allele was associated with diabetes exclusively within Q4(Fat) (odds ratio: 2.22; 95% CI: 1.05, 4.71; P = 0.04) and Q4(BMI) (odds ratio: 1.81; 95% CI: 1.11, 2.93; P = 0.02). CONCLUSION The rs1042615 T allele is associated with features resembling the phenotype of the V1aR(-/-) mouse, including uncoupling of the usual direct relation between glucose and triglycerides and an increased prevalence of diabetes in subjects with a high fat intake or who are overweight.
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Affiliation(s)
- Sofia Enhörning
- Department of Clinical Sciences, Lund University, Malmö, Sweden.
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Marquezine GF, Pereira AC, Sousa AGP, Mill JG, Hueb WA, Krieger JE. TCF7L2 variant genotypes and type 2 diabetes risk in Brazil: significant association, but not a significant tool for risk stratification in the general population. BMC MEDICAL GENETICS 2008; 9:106. [PMID: 19055834 PMCID: PMC2632659 DOI: 10.1186/1471-2350-9-106] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Accepted: 12/04/2008] [Indexed: 12/28/2022]
Abstract
Background Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population. Methods We genotyped the single nucleotide polymorphisms (SNP) rs7903146 of the TCF7L2 gene in 560 patients with known coronary disease enrolled in the MASS II (Medicine, Angioplasty, or Surgery Study) Trial and in 1,449 residents of Vitoria, in Southeast Brazil. The associations of this gene variant to diabetes risk and metabolic characteristics in these two different populations were analyzed. To access the potential benefit of using this marker for diabetes risk prediction in the general population we analyzed the impact of this genetic variant on a validated diabetes risk prediction tool based on clinical characteristics developed for the Brazilian general population. Results SNP rs7903146 of the TCF7L2 gene was significantly associated with type 2 diabetes in the MASS-II population (OR = 1.57 per T allele, p = 0.0032), confirming, in the Brazilian population, previous reports of the literature. Addition of this polymorphism to an established clinical risk prediction score did not increased model accuracy (both area under ROC curve equal to 0.776). Conclusion TCF7L2 rs7903146 T allele is associated with a 1.57 increased risk for type 2 diabetes in a Brazilian cohort of patients with known coronary heart disease. However, the inclusion of this polymorphism in a risk prediction tool developed for the general population resulted in no improvement of performance. This is the first study, to our knowledge, that has confirmed this recent association in a South American population and adds to the great consistency of this finding in studies around the world. Finally, confirming the biological association of a genetic marker does not guarantee improvement on already established screening tools based solely on demographic variables.
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Affiliation(s)
- G F Marquezine
- Heart Institute, University of São Paulo Medical School, Sao Paulo, Brazil.
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