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)

HNF4A encodes an orphan nuclear receptor that plays crucial roles in regulating hepatic gluconeogenesis and insulin secretion. The aim of the present study was to examine two rare missense polymorphisms of HNF4A, Thr130Ile and Val255Met, for altered function and for association with type 2 diabetes (T2D). We have examined these polymorphisms 1) by in vitro transactivation studies and 2) by genotyping the variants in 1409 T2D patients and in 4726 glucose-tolerant Danish white subjects. When tested in COS7 cells, both the Thr130Ile and the Val255Met variants showed a significant decrease in transactivation activity compared with wild-type (73% of wild-type, P = 0.02, and 76%, P = 0.04, respectively). The Thr130Ile variant had a significantly increased carrier frequency among T2D patients compared with glucose-tolerant subjects [odds ratio, 1.26 (1.01-1.57); P = 0.04]. The rare Val255Met polymorphism had a similar frequency among T2D patients and glucose-tolerant subjects. Heterozygous glucose-tolerant carriers of the variant showed, however, decreased levels of fasting serum C-peptide (76%; P = 0.03) and decreased fasting serum triglyceride (58%; P = 0.02). In conclusion, The Thr130Ile and the Val255Met polymorphisms decrease the transcriptional activity of HNF4A, and the Thr130Ile polymorphism associates with T2D, whereas the Val255Met variant associates with a decrease in fasting serum C-peptide.
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PMID:The functional Thr130Ile and Val255Met polymorphisms of the hepatocyte nuclear factor-4alpha (HNF4A): gene associations with type 2 diabetes or altered beta-cell function among Danes. 1572 4

Impaired insulin secretion is a fundamental defect in type 2 diabetes. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the genes regulating insulin secretion (SLC2A2 [encoding GLUT2], GCK, TCF1 [encoding HNF-1alpha], HNF4A, GIP, and GLP1R) are associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in participants of the Finnish Diabetes Prevention Study. With the exception of SLC2A2, other genes were not associated with the risk of type 2 diabetes. All four SNPs of SLC2A2 predicted the conversion to diabetes, and rs5393 (AA genotype) increased the risk of type 2 diabetes in the entire study population by threefold (odds ratio 3.04, 95% CI 1.34-6.88, P = 0.008). The risk for type 2 diabetes in the AA genotype carriers was increased in the control group (5.56 [1.78-17.39], P = 0.003) but not in the intervention group. We conclude that the SNPs of SLC2A2 predict the conversion to diabetes in obese subjects with IGT.
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PMID:Polymorphisms in the SLC2A2 (GLUT2) gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. 1598 30

Hepatocyte nuclear factor (HNF)-4alpha is a transcription factor known as a key molecule in the development and functions of the beta-cells. In a previously performed genome-wide scan of Japanese type 2 diabetic sibpairs, we observed linkage of type 2 diabetes to chromosome 20q12-q13, a region in which the HNF4A gene is located. Recent studies have reported associations between type 2 diabetes and polymorphisms in the P2 promoter region specific to beta-cells. In this study, we attempted to assess whether the HNF4A gene plays a role in the genetic susceptibility to type 2 diabetes in the Japanese population by analyzing polymorphisms and haplotypes of the HNF4A gene. Linkage disequilibrium across the P2 promoter region was preserved in the Japanese population, consistent with previous reports. Although none of the individual polymorphisms examined showed any significant association with type 2 diabetes, we found very strong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene (P = 3.82 x 10(-4)). In contrast, there was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The association was replicated using two additional cohorts (P = 1.51 x 10(-4) and 0.019, respectively). The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as-yet-unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene that directly influences susceptibility to type 2 diabetes.
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PMID:Hepatocyte nuclear factor-4alpha P2 promoter haplotypes are associated with type 2 diabetes in the Japanese population. 1664 80

Recently, it has been shown that mutations in the P2 promoter of the hepatocyte nuclear factor (HNF)-4 alpha gene (HNF4A) cause maturity-onset diabetes of the young (MODY), while single nucleotide polymorphisms in this locus are associated with type 2 diabetes. In this study, we examined 1,189 bp of the P2 promoter and the associated exon 1D of HNF4A for variations associated with diabetes in 114 patients with type 2 diabetes, 72 MODYX probands, and 85 women with previous gestational diabetes mellitus. A -192c/g mutation was found in five patients. We screened 1,587 diabetic subjects and 4,812 glucose-tolerant subjects for the -192c/g mutation and identified 5 diabetic and 1 glucose-tolerant mutation carriers (P=0.004). Examination of the families showed that carriers of the -192c/g mutation had a significantly impaired glucose-stimulated insulin release and lower levels of serum total cholesterol compared with matched control subjects. Furthermore, the mutation disrupted the binding of an unidentified sequence-specific DNA binding complex present in human islet extracts. Also, two novel linked polymorphisms in the P2 promoter at positions -1107g/t and -858c/t were identified. These variants were not significantly associated with type 2 diabetes or any pre-diabetic traits. In conclusion, a rare, novel mutation that disrupts a protein binding site in the pancreatic HNF4A promoter associates with late-onset diabetes.
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PMID:A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes. 1673 55

Variants in hepatocyte nuclear factor (HNF)-4alpha cause maturity-onset diabetes of the young, type 1 (MODY1) and may also be risk factors for type 2 diabetes. We sequenced the HNF4A gene of 95 MODY3-negative probands from the Norwegian MODY Registry. We found three novel coding variants in exon 8 of HNF4A: G326R, T339I, and W340X. In intron 7, we noted a single nucleotide polymorphism in the binding site of a previously published primer pair, which in some cases caused allelic drop out when amplifying exon 8. We also detected two novel sequence variants of the P2 promoter region, of which P2 -192C>G showed linkage with diabetes in two families (maximal logarithm of odds score of 3.1 and 0.8, respectively). This variant and a surrounding haplotype restricted by 3.7 Mb was also found in two Danish MODY pedigrees. The age of onset was higher in the P2 -192C>G carriers (median 45 years) compared with that reported for other MODY1 individuals. We could not support a biological role of the P2 promoter variant by in vitro transfection assays. In conclusion, we have identified three novel HNF4A mutations and a 3.7-Mb haplotype, including the HNF4A P2 promoter, which was linked with diabetes.
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PMID:A hepatocyte nuclear factor-4 alpha gene (HNF4A) P2 promoter haplotype linked with late-onset diabetes: studies of HNF4A variants in the Norwegian MODY registry. 1673 61

Hepatocyte nuclear factor 4alpha (HNF4alpha) is a transcription factor, which is necessary for normal function of human liver and pancreatic islets. We investigated whether single nucleotide polymorphisms (SNPs) of HNF4A, encoding HNF4alpha, influenced the conversion from impaired glucose tolerance (IGT) to type 2 diabetes mellitus in subjects of the STOP-NIDDM trial. This trial aimed at evaluating the effect of acarbose compared to placebo in the prevention of type 2 diabetes mellitus. Eight SNPs covering the intragenic and alternate P2 promoter regions of HNF4A were genotyped in study samples using the TaqMan Allelic Discrimination Assays. Three SNPs in the P2 promoter region (rs4810424, rs1884614, and rs2144908) were in almost complete association (D'>0.97, r (2)>0.95) and, therefore, only rs4810424 was included in further analyses. Female carriers of the less frequent C allele of rs4810424 had a 1.7-fold elevated risk [95% confidence interval (CI) 1.09-2.66; P=0.020] for the conversion to diabetes compared to women with the common genotype after the adjustment for age, treatment group (placebo or acarbose), smoking, weight at baseline, and weight change. No association was found in men. Haplotype analysis based on three SNPs (rs4810424, rs2071197, and rs3818247) representing the linkage disequilibrium blocks in our study population indicated that the conversion to type 2 diabetes mellitus was dependent on the number of risk alleles in different haplotypes in women. Our results suggest that SNPs of HNF4A and their haplotypes predispose to type 2 diabetes mellitus in female subjects of the STOP-NIDDM study population.
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PMID:Single nucleotide polymorphisms of the HNF4alpha gene are associated with the conversion to type 2 diabetes mellitus: the STOP-NIDDM trial. 1683 70

Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic beta-cell function are candidate susceptibility genes for type 2 diabetes. We examined the association of variants in genes encoding several transcription factors (TCF1, TCF2, HNF4A, ISL1, IPF1, NEUROG3, PAX6, NKX2-2, NKX6-1, and NEUROD1) and genes encoding the ATP-sensitive K(+) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) with type 2 diabetes in a Japanese cohort of 2,834 subjects. The exon 16 -3c/t variant rs1799854 in ABCC8 showed a significant association (P = 0.0073), and variants in several genes showed nominally significant associations (P < 0.05) with type 2 diabetes. Although the E23K variant rs5219 in KCNJ11 showed no association with diabetes in Japanese (for the K allele, odds ratio [OR] 1.08 [95% CI 0.97-1.21], P = 0.15), 95% CI around the OR overlaps in meta-analysis of European populations, suggesting that our results are not inconsistent with the previous studies. This is the largest association study so far conducted on these genes in Japanese and provides valuable information for comparison with other ethnic groups.
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PMID:Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects. 1687 4

Prior reports have suggested that variants in the genes for maturity-onset diabetes of the young (MODY) may confer susceptibility to type 2 diabetes, but results have been conflicting and coverage of the MODY genes has been incomplete. To complement our previous studies of HNF4A, we examined the other five known MODY genes for association with type 2 diabetes in Finnish individuals. For each of the five genes, we selected 1) nonredundant single nucleotide polymorphisms (SNPs) (r(2)< 0.8 with other SNPs) from the HapMap database or another linkage disequilibrium map, 2) SNPs with previously reported type 2 diabetes association, and 3) nonsynonymous coding SNPs. We tested 128 SNPs for association with type 2 diabetes in 786 index cases from type 2 diabetic families and 619 normal glucose-tolerant control subjects. We followed up 35 of the most significant SNPs by genotyping them on another 384 case subjects and 366 control subjects from Finland. We also supplemented our previous HNF4A results by genotyping 12 SNPs on additional Finnish samples. After correcting for testing multiple correlated SNPs within a gene, we find evidence of type 2 diabetes association with SNPs in five of the six known MODY genes: GCK, HNF1A, HNF1B, NEUROD1, and HNF4A. Our data suggest that common variants in several MODY genes play a modest role in type 2 diabetes susceptibility.
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PMID:Common variants in maturity-onset diabetes of the young genes contribute to risk of type 2 diabetes in Finns. 1693 1

Human chromosome 20q12-q13.1 has been linked to type 2 diabetes mellitus (T2DM) in multiple studies. We screened a 5.795-Mb region for diabetes-related susceptibility genes in a Caucasian cohort of 310 controls and 300 cases with T2DM and end-stage renal disease (ESRD), testing 390 SNPs for association with T2DM-ESRD. The most significant SNPs were found in the perigenic regions: HNF4A (hepatocyte nuclear factor 4alpha), SLC12A5 (potassium-chloride cotransporter member 5), CDH22 (cadherin-like 22), ELMO2 (engulfment and cell motility 2), SLC13A3 (sodium-dependent dicarboxylate transporter member 3), and PREX1 (phosphatidylinositol 3,4,5-triphosphate-dependent RAC exchanger 1). Haplotype analysis found six haplotype blocks globally associated with disease (p<0.05). We replicated the PREX1 SNP association in an independent case-control T2DM population and inferred replication of CDH22, ELMO2, SLC13A3, SLC12A5, and PREX1 using in silico perigenic analysis of two T2DM Genome-Wide Association Study data sets. We found substantial heterogeneity between study results.
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PMID:Heterogeneity in gene loci associated with type 2 diabetes on human chromosome 20q13.1. 1860 83

Hepatocyte nuclear factor 4alpha (HNF4alpha) is a critical transcription factor for pancreas and liver development and functions in islet beta cells to maintain glucose homeostasis. Mutations in the human HNF4A gene lead to maturity onset diabetes of the young (MODY1) and polymorphisms are associated with increased risk for type 2 diabetes mellitus (T2DM). Expression of six HNF4alpha variants, three each from two developmentally regulated promoters, has been firmly established. We have now detected a new set of HNF4alpha variants designated HNF4alpha10-12 expressed from distal promoter P2. These variants, generated by inclusion of previously undetected exon 1E (human=222 nt, rodent=136 nt) following exon 1D have an altered N-terminus but identical remaining reading frame. HNF4alpha10-alpha12 are expressed in pancreatic islets (and liver) and exhibit transactivation potentials similar to the corresponding alpha7-alpha9 isoforms. DNA-binding analyses implied much higher protein levels of HNF4alpha10-alpha12 in liver than expected from the RT-PCR data. Our results provide evidence for a more complex expression pattern of HNF4alpha than previously appreciated. We recommend inclusion of exon 1E and nearby DNA sequences in screening for HNF4alpha mutations and polymorphisms in genetic analyses of MODY1 and T2DM.
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PMID:Novel P2 promoter-derived HNF4alpha isoforms with different N-terminus generated by alternate exon insertion. 1935 66


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