Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.
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PMID:A genome-wide association study identifies novel risk loci for type 2 diabetes. 1729 79

New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D-in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1-and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
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PMID:Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. 1746 46

Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.
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PMID:A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. 1746 48

The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.
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PMID:Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. 1746 49

Recently, Genome Wide Association (GWA) studies identified novel single nucleotide polymorphisms (SNPs), highly associated with type 2 diabetes (T2D) in several case-control studies of European descent. However, the impact of these markers on glucose homeostasis in a population-based study remains to be clarified. The French prospective D.E.S.I.R. study (N = 4,707) was genotyped for 22 polymorphisms within 14 loci showing nominal to strong association with T2D in recently published GWA analyses (CDKAL1, IGFBP2, CDKN2A/2B, EXT2, HHEX, LOC646279, SLC30A8, MMP26, KCTD12, LDLR, CAMTA1, LOC38776, NGN3 and CXCR4). We assessed their effects on quantitative traits related to glucose homeostasis in 4,283 normoglycemic middle-aged participants at baseline and their contribution to T2D incidence during 9 years of follow-up. Individuals carrying T2D risk alleles of CDKAL1 or SLC30A8 had lower fasting plasma insulin level (rs7756992 P = 0.003) or lower basal insulin secretion (rs13266634 P = 0.0005), respectively, than non-carriers. Furthermore, NGN3 and MMP26 risk alleles associated with higher fasting plasma glucose levels (rs10823406 P = 0.01 and rs2499953 P = 0.04, respectively). However, for these SNPs, only modest associations were found with a higher incidence of T2D: hazard ratios of 2.03 [1.00-4.11] for MMP26 (rs2499953 P = 0.05) and 1.33 [1.02-1.73] for NGN3 (rs10823406 P = 0.03). We confirmed deleterious effects of SLC30A8, CDKAL1, NGN3 and MMP26 risk alleles on glucose homeostasis in the D.E.S.I.R. prospective cohort. However, in contrast to TCF7L2, the contribution of novel loci to T2D incidence seems only modest in the general middle-aged French population and should be replicated in larger cohorts.
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PMID:Analysis of novel risk loci for type 2 diabetes in a general French population: the D.E.S.I.R. study. 1821 30

Genome-wide association (GWA) studies identified novel gene variants that are associated with type 2 diabetes. However, results were not always consistent across different populations. Thus, the aims of this study were (i) to replicate findings from previous GWA studies in mainly Northern European populations using data from the German KORA 500 K diabetes project and (ii) to assess the impact of BMI on associations between single nucleotide polymorphisms (SNPs) and type 2 diabetes. The KORA 500 K diabetes project includes 433 cases with validated type 2 diabetes and 1 438 nondiabetic controls from two population-based KORA surveys. Genotyping was performed using the Affymetrix GeneChip Human Mapping 500 K Array Set. We investigated associations between SNPs and type 2 diabetes in 10 genes that have been reported to increase the risk of type 2 diabetes or were in complete or near-complete linkage disequilibrium with these variants. SNPs in the CDKAL1 gene showed the strongest association with type 2 diabetes [range of age and sex-adjusted odds ratios (OR): 1.30-1.39, p-values 0.0008-0.0004]. In addition, we found evidence for association of SNPs in the genes PPARG, IGF2BP2, HHEX, TCF7L2, and FTO with type 2 diabetes in the same directions as previously described (p<0.05), but not for WFS1, CDKN2A/B, KCNJ11, or EXT2. Adjustment for BMI slightly strengthened the link between CDKAL1 and type 2 diabetes, but had almost no impact on the other associations. We conclude that gene variants of CDKAL1, PPARG, IGF2BP2, HHEX, TCF7L2, and FTO predispose to type 2 diabetes in the German KORA 500 K study population. These associations appear to be independent of BMI.
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PMID:Variants of the PPARG, IGF2BP2, CDKAL1, HHEX, and TCF7L2 genes confer risk of type 2 diabetes independently of BMI in the German KORA studies. 1859 14

The promise of nutrigenomics is of personalized nutrition that will lead to optimization or maintenance of good health and/or prevention of the development of chronic diseases. Type 2 diabetes mellitus (T2DM) is a leading health problem throughout the world. Adherence to a Mediterranean-style diet, regulation of carbohydrate intake, and regular exercise may be desirable. Four key genes were originally identified: KCNJ11, potassium inwardly rectifying channel, subfamily J, member 11 gene; PPAR-gamma, peroxisome proliferator activated receptor-gamma; TCF2, transcription factor 2, hepatic; WFS1, Wolfram syndrome 1. However, genome-wide association studies are accelerating our knowledge of the genetics of complex diseases, and have identified seven other key genes in T2DM: CDKAL1, CDK5 regulatory subunit associated protein-like 1; CDKN2, cyclin-dependent kinase inhibitor 2A; FTO, fat mass and obesity associated; HHEX, haematopoietically expressed homeobox; IDE, insulin-degrading enzyme; IGF2BP2, insulin-like growth factor 2 mRNA-binding protein 2; SLC30A8, solute carrier family 30 (zinc transporter), member 8; TCF7L2, transcription factor 7-like 2 (T-cell specific, HMG-box). Gene-nutrient or gene-environment interactions may be important. For example, the PPAR-gamma variant genotype is responsive to different types and levels of lipids, while the effect of the FTO variant can be partly overcome by exercise. Several of these genes act through their effect on the gastrointestinal tract. There are analytical challenges in analyzing the high-dimensional datasets relating genes, nutrients, and other variables to their influence on health and disease processes. An even greater challenge may be in implementing population level changes in diet and behavior to fully exploit the potential of this field.
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PMID:Dissecting the nutrigenomics, diabetes, and gastrointestinal disease interface: from risk assessment to health intervention. 1871 Mar 64

According to recent genome-wide association studies, a number of single nucleotide polymorphisms (SNPs) are reported to be associated with type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the association among the polymorphisms of SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1 and KCNQ1 and the risk of T2DM in the Korean population. This study was based on a multicenter case-control study, including 908 patients with T2DM and 502 non-diabetic controls. We genotyped rs13266634, rs1111875, rs10811661, rs4402960, rs8050136, rs734312, rs7754840 and rs2237892 and measured the body weight, body mass index and fasting plasma glucose in all patients and controls. The strongest association was found in a variant of CDKAL1 [rs7754840, odds ratio (OR) = 1.77, 95% CI = 1.50-2.10, p = 5.0 x 10(-11)]. The G allele of rs1111875 (OR = 1.43, 95% CI = 1.18-1.72, p = 1.8 x 10(-4)) in HHEX), the T allele of rs10811661 (OR = 1.47, 95% CI = 1.23-1.75, p = 2.1 x 10(-5)) in CDKN2A/B) and the C allele of rs2237892 (OR = 1.31, 95% CI = 1.10-1.56, p = 0.003) in KCNQ1 showed significant associations with T2DM. Rs13266634 (OR = 1.19, 95% CI = 1.00-1.42, p = 0.045) in SLC30A8 showed a nominal association with the risk of T2DM, whereas SNPs in IGF2BP2, FTO and WFS1 were not associated. In conclusion, we have shown that SNPs in HHEX, CDKN2A/B, CDKAL1, KCNQ1 and SLC30A8 confer a risk of T2DM in the Korean population.
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PMID:Association between polymorphisms in SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1, KCNQ1 and type 2 diabetes in the Korean population. 1899 Oct 55

TCF7L2, HHEX and IDE on chromosome 10q23-25 reside within the linkage region for type 2 diabetes (T2D). Previous studies including ours have demonstrated that genetic polymorphisms in these three loci are associated with T2D, respectively. But, it is unclear whether TCF7L2, independently or interactively with HHEX and IDE, confer the susceptibility to T2D. In the present study, we first replicated genetic association study of the TCF7L2 gene in a Swedish cohort including 528 non-diabetic healthy controls and 243 T2D patients and then evaluated combining effect from common risk polymorphisms in TCF7L2-HHEX-IDE loci. T2D patients were diagnosed in the intermediate study time. To avoid influence from anti-diabetic treatment, baseline data in all T2D patients were used for analysis. We found that SNPs rs7901695, rs4506565, rs7903146 and rs12255372 in the TCF7L2 gene were strongly associated with T2D (p<0.004). In rs7903146, T2D patients carrying genotypes CT or TT had higher fasting plasma glucose (FPG) levels (p=0.042) and lower HOMA-beta index (p=0.015) and BMI (p=0.015) compared to the patients carrying CC genotype. Furthermore, the risk alleles from TCF7L2 rs7903146 polymorphism either with IDE rs2251101 polymorphism (p=0.0257, OR=1.398) or with HHEX rs1544210 polymorphism (p=0.0024, OR=1.514) were significantly associated with T2D. When risk alleles from three loci were combined, the association with T2D remained significant (p=0.0018, OR=1.506). The present study thus provides evidence that TCF7L2, as the main gene, together with HHEX and IDE loci have combining effects on genetic predisposition to T2D.
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PMID:Loci of TCF7L2, HHEX and IDE on chromosome 10q and the susceptibility of their genetic polymorphisms to type 2 diabetes. 1905 27

Several single nucleotide polymorphisms (SNPs) for type 2 diabetes mellitus (T2DM) risk have been identified by genome wide association studies (GWAS). The objective of the present study was to investigate the impact of these SNPs on T2DM intermediate phenotypes in order to clarify the physiological mechanisms through which they exert their effects on disease etiology. We analysed 23 SNPs in 9 T2DM genes (CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8, TCF2, TCF7L2 and WFS1) in a maximum of 712 men and women from the Quebec Family Study. The participants underwent a 75 g oral glucose tolerance test (OGTT) and were measured for glucose, insulin and C-peptide levels. Indices of insulin sensitivity and insulin secretion were derived from fasting and OGTT measurements. We confirmed the significant associations of variants in CDKAL1, CDKN2B, HHEX/IDE, KCNJ11 and TCF7L2 with insulin secretion and also found associations of some of these variants with insulin sensitivity and glucose tolerance. IGF2BP2 and SLC30A8 SNPs were not associated with insulin secretion but were with insulin sensitivity and glucose tolerance (0.002 <or= P <or= 0.02). To examine the joint effects of these variants and their contribution to T2DM endophenotypes variance, stepwise regression models were used and the model R (2) was computed. The variance in the phenotypes explained by combinations of variants ranged from 2.0 to 8.5%. Diabetes-associated variants in CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8 and TCF7L2 are associated with physiological alterations leading to T2DM, such as glucose intolerance, impaired insulin secretion or insulin resistance, supporting their role in the disease aetiology. These variants were found to account for 2.0-8.5% of the variance of T2DM-related traits.
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PMID:Association between insulin secretion, insulin sensitivity and type 2 diabetes susceptibility variants identified in genome-wide association studies. 1908 21


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