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)

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

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

Prediction of the disease status is one of the most important objectives of genetic studies. To select the genes with strong evidence of the association with type 2 diabetes mellitus, we validated the associations of the seven candidate loci extracted in our earlier study by genotyping the samples in two independent sample panels. However, except for KCNQ1, the association of none of the remaining seven loci was replicated. We then selected 11 genes, KCNQ1, TCF7L2, CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX, GCKR, HNF1B, KCNJ11 and PPARG, whose associations with diabetes have already been reported and replicated either in the literature or in this study in the Japanese population. As no evidence of the gene-gene interaction for any pair of the 11 loci was shown, we constructed a prediction model for the disease using the logistic regression analysis by incorporating the number of the risk alleles for the 11 genes, as well as age, sex and body mass index as independent variables. Cumulative risk assessment showed that the addition of one risk allele resulted in an average increase in the odds for the disease of 1.29 (95% CI=1.25-1.33, P=5.4 x 10(-53)). The area under the receiver operating characteristic curve, an estimate of the power of the prediction model, was 0.72, thereby indicating that our prediction model for type 2 diabetes may not be so useful but has some value. Incorporation of data from additional risk loci is most likely to increase the predictive power.
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PMID:Construction of a prediction model for type 2 diabetes mellitus in the Japanese population based on 11 genes with strong evidence of the association. 1924 72

The pathophysiology of latent autoimmune diabetes in adults (LADA) is considered less understood than its much better characterized counterparts of type 1 and type 2 diabetes (T1D and T2D), where its clinical presentation exhibits some features of each of these two main diseases, earning it a reputation as being "type 1.5 diabetes". The etiology of LADA remains unknown, but a genetic component has been implicated from recent reports of T1D and T2D genes playing a role in its pathogenesis. One way to shed much needed light on the classification of LADA is to determine the discrete genetic factors conferring risk to the pathogenesis of this specific phenotype and to determine to what extent LADA shares genetic similarities with T1D and T2D. For instance, no conclusive support for a role of the T1D-associated INS gene has been reported in T2D; conversely, but similarly, no evidence has been found for the role of the T2D-associated genes IDE/HHEX, SLC30A8, CDKAL1, CDKN2A/B, IGF2BP2, FTO, and TCF7L2 in T1D. However, and somewhat at odds with current thinking, TCF7L2, the most strongly associated gene with T2D to date, is strongly associated with LADA, a disorder considered by the World Health Organization to be a slowly progressing form of T1D. In this review, we address recent advances in the genetics of T1D and T2D and how such discoveries have in turn shed some light on the genetics of LADA as being potentially at the "genetic intersection" of these two major diseases.
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PMID:Can the genetics of type 1 and type 2 diabetes shed light on the genetics of latent autoimmune diabetes in adults? 2000 22

There is a known inverse association between type 2 diabetes (T2D) and prostate cancer (PrCa) that is poorly understood. Genetic studies of the T2D-PrCa association may provide insight into the underlying mechanisms of this association. We evaluated associations in the Atherosclerosis Risk in Communities study between PrCa and nine T2D single nucleotide polymorphisms from genome-wide association studies of T2D (in CDKAL1, CDKN2A/B, FTO, HHEX, IGF2BP2, KCNJ11, PPARG, SLC30A8, and TCF7L2) and four T2D single nucleotide polymorphisms from pre-genome-wide association studies (in ADRB2, CAPN10, SLC2A2, and UCP2). From 1987 to 2000, there were 397 incident PrCa cases among 6,642 men ages 45 to 64 years at baseline. We used race-adjusted Cox proportional hazards models to estimate associations between PrCa and increasing number of T2D risk-raising alleles. PrCa was positively associated with the CAPN10 rs3792267 G allele [hazard ratio (HR) 1.20; 95% confidence interval (CI), 1.00-1.44] and inversely associated with the SLC2A2 rs5400 Thr110 allele (HR, 0.85; 95% CI, 0.72, 1.00), the UCP2 rs660339 Val55 allele (HR, 0.84; 95% CI, 0.73, 0.97) and the IGF2BP2 rs4402960 T allele (HR, 0.79; 95% CI, 0.61-1.02; blacks only). The TCF7L2 rs7903146 T allele was inversely associated with PrCa using a dominant genetic model (HR, 0.79; 95% CI, 0.65-0.97). Further knowledge of T2D gene-PrCa mechanisms may improve understanding of PrCa etiology.
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PMID:Diabetes genes and prostate cancer in the Atherosclerosis Risk in Communities study. 2014 50

Recent genomewide association studies have identified several new gene variants associated with type 2 diabetes mellitus (T2D) mostly in European populations. These need to be replicated in other populations. We studied 926 unrelated T2D and 812 normal glucose-tolerant subjects randomly selected from the Chennai Urban Rural Epidemiology Study in Southern India. A total of 45 single nucleotide polymorphisms (SNPs) from 15 genes and 13 unannotated loci identified from recent genomewide association T2D studies were genotyped. Only 6 of 45 SNPs studied were replicated in this South Indian population. Three SNPs-rs7756992 (P = .007), rs7754840 (P = .015), and rs6931514 (P = .029)-of the CDKAL1, rs7020996 (P = .003) of the CDKN2A/B gene, rs7923837 (P = .038) of the HHEX gene, and rs12056034 (P = .033) of the BAZ1B gene were associated with T2D in our population. Large-scale studies are needed in our population to validate our findings.
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PMID:Replication of recently described type 2 diabetes gene variants in a South Indian population. 2058 33


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