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1.
Patel S Minton JA Weedon MN Frayling TM Ricketts C Hitman GA McCarthy MI Hattersley AT Walker M Barrett TG 《Diabetologia》2006,49(6):1209-1213
Aims/hypothesis Alström syndrome is a rare monogenic disorder characterised by retinal dystrophy, deafness and obesity. Patients also have insulin resistance, central obesity and dyslipidaemia, thus showing similarities with type 2 diabetes. Rare mutations in the ALMS1 gene cause severe gene disruption in Alström patients; however, ALMS1 gene polymorphisms are common in the general population. The aim of our study was to determine whether common variants in ALMS1 contribute to susceptibility to type 2 diabetes in the UK population.Methods Direct sequencing was performed on coding regions and intron/exon boundaries of the ALMS1 gene in 30 unrelated probands with type 2 diabetes. The linkage disequilibrium (LD; D′ and r
2) and haplotype structure were examined for the identified variants. The common (minor allele frequency [MAF] >5%) single-nucleotide polymorphisms tagging the common haplotypes (tagged SNPs [tSNPs]) were identified and genotyped in 1985 subjects with type 2 diabetes, 2,047 control subjects and 521 families.Results We identified 18 variants with MAF between 6 and 38%. Three SNPs efficiently tagged three common haplotypes (rs1881245, rs3820700 and rs1320374). There was no association (all p>0.05) between the tSNPs and type 2 diabetes in the case–control study and minor alleles of the tSNPs were not overtransmitted to probands with type 2 diabetes in the family study.Conclusions/interpretation Common variations in the ALMS1 gene were not associated with type 2 diabetes in a large study of a white UK population.Electronic Supplementary Material Supplementary material is available for this article at 相似文献
2.
González-Sánchez JL Martínez-Larrad MT Zabena C Pérez-Barba M Serrano-Ríos M 《Diabetologia》2008,51(11):1993-1997
3.
Y. Liu D. Z. Zhou D. Zhang Z. Chen T. Zhao Z. Zhang M Ning X. Hu Y. F. Yang Z. F. Zhang L. Yu L. He H. Xu 《Diabetologia》2009,52(7):1315-1321
Aims/hypothesis Two recent genome-wide association studies have identified several novel type 2 diabetes susceptibility variants in intron
15 of the KCNQ1 gene. We aimed to evaluate the effects of the variants in KCNQ1 on type 2 diabetes and metabolic traits in the population of mainland China.
Methods Three candidate single nucleotide polymorphisms were genotyped in 1,912 individuals with type 2 diabetes and 2,041 normal
controls using the ligase detection reaction method.
Results We confirmed the association of KCNQ1 with type 2 diabetes in the population of mainland China. Allele frequency ORs of the three single nucleotide polymorphisms
(SNPs) were: rs2237892 (OR 1.19, 95% CI 1.08–1.31, p = 3.0 × 10−4); rs2237895 (OR 1.20, 95% CI 1.09–1.32, p = 1.9 × 10−4); and rs2237897 (OR 1.24, 95% CI 1.13–1.36, p = 3.9 × 10−5). We also found a significant difference in the distribution of the global haplotypes between the type 2 diabetes group and
the normal control group (p = 2.6 × 10−5). In addition, in the control group SNP rs2237892 was marginally associated with increasing fasting plasma glucose and SNPs
rs2237892 and rs2237897 were associated with HbA1c. Furthermore, for all three variants, homozygous carriers of the diabetes-associated allele had significantly decreased BMI
and waist circumferences.
Conclusions/interpretation Our investigation confirmed the effects of KCNQ1 variants on type 2 diabetes risk in the Chinese population.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
Y. Liu and D. Z. Zhou contributed equally to this study. 相似文献
4.
Aim/hypothesis Single-nucleotide polymorphisms (SNPs) in the protein tyrosine phosphatase 1B gene (PTPN1) have been reported to be associated with type 2 diabetes in white subjects, and insulin sensitivity and fasting glucose
levels in Hispanic Americans. In this study, we determined whether SNPs in PTPN1 also have a role in type 2 diabetes susceptibility in Pima Indians, a population with the world’s highest reported prevalence
and incidence rates of this disease.
Materials and methods Thirty-one SNPs across a 161-kb region encompassing PTPN1 were genotyped in 1,037 Pima Indians for association studies with type 2 diabetes and obesity.
Results Twenty-five of the SNPs had allele frequencies >0.05, and these SNPs fell into two linkage disequilibrium blocks (D′ > 0.9). Block 1 contains six SNPs that span a 61-kb region upstream of PTPN1, while block 2 contains 19 SNPs that cover the entire PTPN1 gene. None of the SNPs, analysed individually or as haplotypes, was associated with either type 2 diabetes or obesity. However,
three SNPs located in block 1 were nominally associated (p values ranging from 0.01 to 0.05) with insulin sensitivity as measured by the hyperinsulinaemic–euglycaemic clamp technique.
Conclusions/interpretation Based on our association results, we conclude that SNPs within PTPN1 are unlikely to have a major role in the aetiology of type 2 diabetes or obesity in Pima Indians.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
5.
Aiba Y Nakamura M Joshita S Inamine T Komori A Yoshizawa K Umemura T Horie H Migita K Yatsuhashi H Nakamuta M Fukushima N Saoshiro T Hayashi S Kouno H Ota H Muro T Watanabe Y Nakamura Y Komeda T Shimada M Masaki N Komatsu T Yagura M Sugi K Koga M Tsukamoto K Tanaka E Ishibashi H;PBC Study Group in NHOSLJ 《Journal of gastroenterology》2011,46(10):1203-1212
Background
Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). In order to dissect the genetic basis for the production of these autoantibodies, as well as the development and progression of PBC in Japanese patients, we examined single nucleotide polymorphisms (SNPs) in cytotoxic T-lymphocyte antigen 4 (CTLA4) and solute carrier family 4 anion exchanger, member 2 (SLC4A2), which have been associated with the pathogenesis of PBC in Caucasian patients.Methods
Four SNPs for both CTLA4 and SLC4A2 were genotyped, using the polymerase chain reaction?Crestriction fragment length polymorphism method and TaqMan assay, in 450 Japanese PBC patients and 371 sex-matched healthy controls.Results
The CTLA4 rs231775, rs3087243, and rs231725 SNPs were significantly associated with PBC susceptibility. The CTLA4 rs231725 SNP was significantly associated with progression to late-stage disease. The CTLA-4 haplotype 1 (rs231775 G, rs231777 C, rs3087243 G, rs231725 A; GCGA) was a risk factor for PBC susceptibility but a protective factor for PBC progression. Conversely, the CTLA-4 haplotype 2 (ACAG) was a protective and risk factor, respectively, for PBC susceptibility and progression. In addition, the CTLA4 rs231777 SNP and haplotype 3 (ATGG) was significantly associated with anti-gp210 antibody production, while SLC4A2 haplotype 4 (rs2069443 A, rs2303933 G, rs2303937 A, rs2303941 T; AGAT) and haplotype 3 (AAGC) were significantly associated with PBC susceptibility and anti-centromere antibody production, respectively.Conclusions
CTLA4 and SLC4A2 genetic polymorphisms are differentially associated with PBC development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients. 相似文献6.
Ho RH Leake BF Urquhart BL Gregor JC Dawson PA Kim RB 《Journal of gastroenterology and hepatology》2011,26(12):1740-1748
Background and Aim: The major transporter responsible for bile acid uptake from the intestinal lumen is the apical sodium‐dependent bile acid transporter (ASBT, SLC10A2). Analysis of the SLC10A2 gene has identified a variety of sequence variants including coding region single nucleotide polymorphisms (SNPs) that may influence bile acid homeostasis/intestinal function. In this study, we systematically characterized the effect of coding SNPs on SLC10A2 protein expression and bile acid transport activity. Methods: Single nucleotide polymorphisms in SLC10A2 from genomic DNA of ethnically‐defined healthy individuals were identified using a polymerase chain reaction (PCR)‐based temperature gradient capillary electrophoresis (TGCE) system. A heterologous gene expression system was used to assess transport activity of SLC10A2 nonsynonymous variants and missense mutations. Total and cell surface protein expression of wild‐type and variant ASBT was assessed by Western blot analysis and immunofluorescence confocal microscopy. Expression of ASBT mRNA and protein was also measured in human intestinal samples. Results: The studies revealed two nonsynonymous SNPs, 292G>A and 431G>A, with partially impaired in vitro taurocholate transport. A novel variant, 790A>G, was also shown to exhibit near complete loss of taurocholate transport, similar to the previously identified ASBT missense mutations. Examination of ASBT protein expression revealed no significant differences in expression or trafficking to the cell surface among variants versus wild‐type ASBT. Analysis of ASBT mRNA and protein expression in human intestinal samples revealed modest intersubject variability. Conclusions: Genome sequencing and in vitro studies reveal the presence of multiple functionally relevant variants in SLC10A2 that may influence bile acid homeostasis and physiology. 相似文献
7.
Qu Y Yang Z Jin F Sun L Feng J Tang L Zhang C Zhu X Shi X Sun H Wang B Wang L 《Diabetes research and clinical practice》2008,81(1):33-37
Leptin receptor (LEPR) plays an important physiological role in energy metabolism. The study addressed the relationship between leptin receptor gene variations and type 2 diabetes mellitus (T2DM). Three single nucleotide polymorphisms (SNPs) of LEPR gene, Arg109Lys (A/G), Asn656Lys (C/G) and Pro1019Pro (C/T) were detected in a northern population in China. Totally, 317 patients with T2DM and 282 healthy controls were recruited randomly from urban communities in Harbin area in the Northeast of China. All polymorphisms were genotyped by Sequenom SNP detection system in both case and control groups. Linkage disequilibria analysis showed moderate linkage disequilibria between the pair-wise SNPs for all three SNPs. Then, we identified the haplotype covering the three SNPs (AGC) with higher risk of T2DM (OR = 1.69 (1.09–2.61)), and showed that there existed significant difference between cases and controls (9.8% vs. 6.0%, P = 0.02). We also observed significant difference in frequencies of the heterozygous haplotype combination (GGT/AGC), that is 17.0% vs. 8.2% in cases and controls, respectively (P = 0.001). It further supported the evidence that the haplotype (AGC) was associated with T2DM. So, AGC haplotype in LEPR gene could be a risk factor associated with T2DM in Northern Chinese. 相似文献
8.
Effect of common polymorphisms in the HNF4α promoter on susceptibility to type 2 diabetes in the French Caucasian population 总被引:1,自引:0,他引:1
Vaxillaire M Dina C Lobbens S Dechaume A Vasseur-Delannoy V Helbecque N Charpentier G Froguel P 《Diabetologia》2005,48(3):440-444
Aims/hypothesis The gene encoding HNF-4, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the HNF-4 P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population.Methods Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a case-control study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the HNF4 region had been shown.Results The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNF-4 was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected p=0.022 for rs2144908; OR 0.82 uncorrected p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage.Conclusions/interpretation None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of HNF-4 and type 2 diabetes in several ethnic groups. 相似文献
9.
P. W. Franks O. Rolandsson S. L. Debenham K. A. Fawcett F. Payne C. Dina P. Froguel K. L. Mohlke C. Willer T. Olsson N. J. Wareham G. Hallmans I. Barroso M. S. Sandhu 《Diabetologia》2008,51(3):523-463
Aims/hypothesis Mutations at the gene encoding wolframin (WFS1) cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. Thus, our aim was to replicate those associations in a northern Swedish
case–control study of type 2 diabetes. We also performed a meta-analysis of published and previously unpublished data from
Sweden, Finland and France, to obtain updated summary effect estimates.
Methods Four WFS1 SNPs (rs10010131, rs6446482, rs752854 and rs734312 [H611R]) were genotyped in a type 2 diabetes case–control study (n = 1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex and BMI. We then performed a meta-analysis of 11 studies of type
2 diabetes, comprising up to 14,139 patients and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants.
Results In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk [odds ratio (OR)
0.85, 95% CI 0.75–0.96, p = 0.010]. Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent
replication studies for SNP rs10010131 and correlated variants showed evidence for statistical association (OR 0.87, 95% CI
0.82–0.93, p = 4.5 × 10−5). In an updated meta-analysis of all 11 studies, strong evidence of statistical association was also observed (OR 0.89, 95%
CI 0.86–0.92; p = 4.9 × 10−11).
Conclusions/interpretation In this study of WFS1 variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and
the risk of type 2 diabetes.
An erratum to this article can be found at 相似文献
10.
Hertel JK Johansson S Raeder H Midthjell K Lyssenko V Groop L Molven A Njølstad PR 《Diabetologia》2008,51(6):971-977
Aims/hypothesis Recent genome-wide association studies performed in selected patients and control participants have provided strong support
for several new type 2 diabetes susceptibility loci. To get a better estimation of the true risk conferred by these novel
loci, we tested a completely unselected population of type 2 diabetes patients from a Norwegian health survey (the HUNT study).
Methods We genotyped single nucleotide polymorphisms (SNPs) in PKN2, IGFBP2, FLJ39370 (also known as C4ORF32), CDKAL1, SLC30A8, CDKN2B, HHEX and FTO using a Norwegian population-based sample of 1,638 patients with type 2 diabetes and 1,858 non-diabetic control participants
(the HUNT Study), for all of whom data on BMI, WHR, cholesterol and triacylglycerol levels were available. We used diabetes,
measures of obesity and lipid values as phenotypes in case-control and quantitative association study designs.
Results We replicated the association with type 2 diabetes for rs10811661 in the vicinity of CDKN2B (OR 1.20, 95% CI: 1.06–1.37, p = 0.004), rs9939609 in FTO (OR 1.14, 95% CI: 1.04–1.25, p = 0.006) and rs13266634 in SLC30A8 (OR 1.20, 95% CI: 1.09–1.33, p = 3.9 × 10−4). We found borderline significant association for the IGFBP2 SNP rs4402960 (OR 1.10, 95% CI: 0.99–1.22). Results for the HHEX SNP (rs1111875) and the CDKAL1 SNP (rs7756992) were non-significant, but the magnitude of effect was similar to previous estimates. We found no support
for an association with the less consistently replicated FLJ39370 or PKN2 SNPs. In agreement with previous studies, FTO was most strongly associated with BMI (p = 8.4 × 10−4).
Conclusions/interpretation Our data show that SNPs near IGFBP2, CDKAL1, SLC30A8, CDKN2B, HHEX and FTO are also associated with diabetes in non-selected patients with type 2 diabetes.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
11.
Chieko Kyogoku Akio Morinobu Kunihiro Nishimura Daisuke Sugiyama Hiroshi Hashimoto Yoshiaki Tokano Tsuneyo Mimori Chikashi Terao Fumihiko Matsuda Takayoshi Kuno Shunichi Kumagai 《Modern rheumatology / the Japan Rheumatism Association》2009,19(4):401-406
Tyrosine kinase 2 (TYK2) is a type I interferon (IFN) signaling pathway gene and was previously reported to be a risk factor for systemic lupus erythematosus
(SLE) in Caucasian populations. In order to test for its genetic association with SLE in a Japanese population, TYK2 single nucleotide polymorphisms (SNPs), rs2304256, rs12720270 and rs280519, were genotyped. A case–control association study
was performed in a total of 411 Japanese SLE patients and 467 healthy controls. Linkage disequilibrium (LD) among TYK2 SNPs was examined. According to the data from 94 healthy controls, non-synonymous rs2304256 resulting in Val → Phe substitution
was revealed to be in a LD with rs12720270 and rs280519. Therefore, we further genotyped rs2304256 as a tag SNP in the full
sample sets. As a result, no differences in genotype distribution and allelic frequencies of rs2304256 were found between
SLE patients and healthy controls. In conclusion, TYK2 is not a genetic risk factor for SLE in a Japanese population. Our result suggests that there is an ethnic difference in
the susceptibility genes for SLE. 相似文献
12.
Polymorphisms in the IDE-KIF11-HHEX gene locus are reproducibly associated with type 2 diabetes in a Japanese population 总被引:3,自引:0,他引:3
Furukawa Y Shimada T Furuta H Matsuno S Kusuyama A Doi A Nishi M Sasaki H Sanke T Nanjo K 《The Journal of clinical endocrinology and metabolism》2008,93(1):310-314
CONTEXT: A genome-wide association study in the French population has detected that novel single-nucleotide polymorphisms (SNPs) in the IDE-KIF11-HHEX gene locus and the SLC30A8 gene locus are associated with susceptibility to type 2 diabetes. OBJECTIVE: We investigated whether SNPs in these loci were associated with type 2 diabetes in Japanese. DESIGN: Two SNPs, rs7923837 and rs1111875, in the IDE-KIF11-HHEX gene locus and one SNP, rs13266634, in the SLC30A8 gene locus were genotyped in Japanese type 2 diabetic patients (n = 405) and in nondiabetic control subjects (n = 340) using the TaqMan genotyping assay system. RESULTS: The G allele of rs7923837 was associated with type 2 diabetes [odds ratio 1.66, 95% confidence interval (CI) 1.28-2.15; P = 0.00014], following the same tendency as in the French population of the previous report. Heterozygous and homozygous carriers of the risk allele had odds ratios of 1.57 (95% CI 1.15-2.16; P = 0.0050) and 3.16 (95% CI 1.40-7.16; P = 0.0038) relative to noncarriers. Although the G allele was a major allele (66.5%) in the French population, it was a minor allele (23.8%) in Japanese. The G allele of rs1111875 was also associated with type 2 diabetes (odds ratio 1.42, 95% CI 1.13-1.78; P = 0.0024). Heterozygous and homozygous carriers of the risk allele had odds ratios of 1.31 (95% CI 0.97-1.77; P = 0.0810) and 2.40 (95% CI 1.34-4.32; P = 0.0028) relative to noncarriers. A significant association with type 2 diabetes was not observed for rs13266634. CONCLUSIONS: Polymorphisms in the IDE-KIF11-HHEX gene locus are associated with susceptibility to type 2 diabetes across the boundary of race. 相似文献
13.
14.
E. S. Stolerman A. K. Manning J. B. McAteer C. S. Fox J. Dupuis J. B. Meigs J. C. Florez 《Diabetologia》2009,52(4):614-620
Aims/hypothesis Common variants in the TCF7L2 gene are associated with type 2 diabetes via impaired insulin secretion. One hypothesis is that variation in TCF7L2 impairs insulin processing in the beta cell. In contrast, the association of related TCF7L2 polymorphisms with obesity is controversial in that it has only been shown in cohorts susceptible to ascertainment bias.
We reproduced the association of diabetes-associated variants with proinsulin/insulin ratios, and also examined the association
of a TCF7L2 haplotype with obesity in the Framingham Heart Study (FHS).
Methods We genotyped the TCF7L2 single nucleotide polymorphisms rs7903146 and rs12255372 (previously associated with type 2 diabetes) and rs10885406 and
rs7924080 (which tag haplotype A [HapA], a haplotype reported to be associated with obesity) in 2,512 FHS participants. We
used age- and sex-adjusted linear mixed-effects models to test for association with glycaemic traits, proinsulin/insulin ratios
and obesity measures.
Results As expected, the T risk allele of rs7903146 was associated with higher fasting plasma glucose (p = 0.01). T/T homozygotes had a 23.5% increase in the proinsulin/insulin ratio (p = 1 × 10−7) compared with C/C homozygotes. There was no association of HapA with BMI (p = 0.98), waist circumference (p = 0.89), subcutaneous adipose tissue (p = 0.32) or visceral adipose tissue (p = 0.92).
Conclusions/interpretation We confirmed that the risk allele of rs7903146 is associated with hyperglycaemia and a higher proinsulin/insulin ratio. We
did not detect any association of the TCF7L2 HapA with adiposity measures, suggesting that this may have been a spurious association from ascertainment bias, possibly
induced by the evaluation of obesity in separate groups of glycaemic cases and controls.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
15.
Duesing K Fatemifar G Charpentier G Marre M Tichet J Hercberg S Balkau B Froguel P Gibson F 《Diabetologia》2008,51(5):821-826
Aims/hypothesis Genome-wide association studies (GWASs) recently identified common variants in the CDKN2A/CDKN2B region on chromosome 9p as being strongly associated with type 2 diabetes. Since these association signals were not picked
up by the French-Canadian GWAS, we sought to replicate these findings in the French Europid population and to further characterise
the susceptibility variants at this novel locus.
Methods We genotyped 20 single nucleotide polymorphisms (SNPs) spanning the CDKN2A/CDKN2B locus in our type 2 diabetes case-control cohort. The association between CDKN2A/CDKN2B SNPs and quantitative metabolic traits was also examined in the normoglycaemic participants comprising the control cohort.
Results We report replication of the strong association of rs10811661 with type 2 diabetes found in the GWASs (; OR 1.43 [95% CI 1.24–1.64]). The other CDKN2A/CDKN2B susceptibility variant, rs564398, did not attain statistical significance (p = 0.053; OR 1.11 [95% CI 1.00–1.24]) in the present study. We also obtained several additional nominal association signals
(p < 0.05) at the CDKN2A/CDKN2B locus; however, only the rs3218018 result (p = 0.002) survived Bonferroni correction for multiple testing (adjusted p = 0.04).
Conclusions/interpretation Our comprehensive association study of common variation spanning the CDKN2A/CDKN2B locus confirms the strong association between the distal susceptibility variant rs10811661 and type 2 diabetes in the French
population. Further genetic and functional studies are required to identify the aetiological variants at this locus and determine
the cellular and physiological mechanisms by which they act to modulate type 2 diabetes susceptibility.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
K. Duesing and G. Fatemifar contributed equally to this work. 相似文献
16.
Variation near the hepatocyte nuclear factor (HNF)-4α gene associates with type 2 diabetes in the Danish population 总被引:12,自引:0,他引:12
Hansen SK Rose CS Glümer C Drivsholm T Borch-Johnsen K Jørgensen T Pedersen O Hansen T 《Diabetologia》2005,48(3):452-458
Aims/hypothesis The hepatocyte nuclear factor (HNF)-4 is an orphan nuclear receptor, which plays crucial roles in regulating hepatic gluconeogenesis and insulin secretion. The gene encoding HNF-4 (HNF4A) is located on chromosome 20q12–q13 in a region that in several studies has shown linkage with type 2 diabetes. Recently, two independent studies identified single nucleotide polymorphisms (SNPs) in a 90-kb region spanning HNF4A, which showed strong association with type 2 diabetes in the Finnish and Ashkenazi Jewish populations. In an attempt to replicate and extend these findings, we selected four SNPs in the same HNF4A region, which in the Finnish and Ashkenazi Jewish populations were associated with type 2 diabetes, and examined their relationships with type 2 diabetes and prediabetic phenotypes in the Danish Caucasian population.Methods The rs1884614, rs2425637, rs1885088 and rs3818247 were analysed in case-control studies of 1387, 1429, 1417 and 1371 type 2 diabetic patients and 4766, 4727, 4665 and 4748 glucose-tolerant subjects respectively. Genotype–quantitative trait analyses comprised 4430, 4394, 4336 and 4413 middle-aged glucose-tolerant subjects from the population-based Inter99 cohort for the rs1884614, rs2425637, rs1885088 and rs3818247 respectively.Results The risk allele of the rs1884614, which is located 4 kb upstream of the HNF4A P2 promoter, was associated with type 2 diabetes (odds ratio [OR]=1.14, p=0.02) and with a subtle increase in post-OGTT plasma glucose levels in glucose-tolerant subjects (additive model, p=0.05).Conclusions/interpretation Consistent with results from studies of Finnish and Ashkenazi Jewish subjects, variation near the P2 region of HNF4A is associated with type 2 diabetes in the Danish population. 相似文献
17.
Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population 总被引:1,自引:0,他引:1
Moritani M Nomura K Tanahashi T Osabe D Fujita Y Shinohara S Yamaguchi Y Keshavarz P Kudo E Nakamura N Yoshikawa T Ichiishi E Takata Y Yasui N Shiota H Kunika K Inoue H Itakura M 《Diabetologia》2007,50(6):1218-1227
Aims/hypothesis In order to identify type 2 diabetes disease susceptibility gene(s) in a Japanese population, we applied a region-wide case–control
association test to the 20.4 Mb region between D3S1293 and D3S2319 on chromosome 3p24.3-22.1, supported by linkage to type 2 diabetes and its related traits in Japanese and multiple populations.
Materials and methods We performed a two-stage association test using 1,762 Japanese persons with 485 gene-centric, evenly spaced, common single
nucleotide polymorphism (SNP) markers with minor allele frequency >0.1. For mouse studies, total RNA was extracted from various
organs of BKS.Cg-+Lepr
db
/+Lepr
db
and control mice, and from MIN6, NIH3T3 and C2C12 cell lines.
Results We detected a landmark SNP375 (A/G) (rs2051211, p = 0.000046, odds ratio = 1.33, 95% CI 1.16–1.53) in intron 5 of the endonuclease G-like 1 (ENDOGL1) gene. Systematic dense SNPs approach identified a susceptibility linkage disequilibrium (LD) block of 116.5 kb by |D′|,
an LD units map and a critical region of 2.1 kb by r
2 in ENDOGL1. A haplotype-based association test showed that an at-risk haplotype is associated with disease status (p = 0.00001). The expression of ENDOGL1 was rather ubiquitous with relatively abundant expression in the brain and also in a pancreatic islet beta cell line. Mouse
Endogl1 expression increased in pancreatic islets of hyperglycaemic BKS.Cg-+Lepr
db
/+Lepr
db
mice compared with that in control mice.
Conclusions/interpretation Based on the population genetics, fine mapping of LD block and haplotype analysis, we conclude that ENDOGL1 is a candidate disease-susceptibility gene for type 2 diabetes in a Japanese population. Further analysis in a larger sample
size is required to substantiate this conclusion.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
18.
Variations in the <Emphasis Type="Italic">HHEX</Emphasis> gene are associated with increased risk of type 2 diabetes in the Japanese population 总被引:1,自引:0,他引:1
Horikoshi M Hara K Ito C Shojima N Nagai R Ueki K Froguel P Kadowaki T 《Diabetologia》2007,50(12):2461-2466
Aims/hypothesis Recently, several groups have carried out whole-genome association studies in European and European-origin populations and
found novel type 2 diabetes-susceptibility genes, fat mass and obesity associated (FTO), solute carrier family 30 (zinc transporter), member 8 (SLC30A8), haematopoietically expressed homeobox (HHEX), exostoses (multiple) 2 (EXT2), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) (CDKN2B) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), which had not been in the list of functional candidates. The aim of this study was to determine the association between
single nucleotide polymorphisms (SNPs) in these genes and type 2 diabetes in participants from the Japanese population.
Methods Sixteen previously reported SNPs were genotyped in 864 Japanese type 2 diabetes individuals (535 men and 329 women; age 63.1 ± 9.5 years
(mean±SD), BMI 24.3 ± 3.9 kg/m2) and 864 Japanese control individuals (386 men and 478 women; age 69.5 ± 6.8 years, BMI 23.8 ± 3.7 kg/m2).
Results The SNPs rs5015480 [odds ratio (OR) = 1.46 (95% CI 1.20–1.77), p = 2.0 × 10−4], rs7923837 [OR = 1.40 (95% CI 1.17–1.68), p = 2.0 × 10−4] and rs1111875 [OR = 1.30 (95% CI 1.11–1.52), p = 0.0013] in HHEX were significantly associated with type 2 diabetes with the same direction as previously reported. SNP rs8050136 in FTO was nominally associated with type 2 diabetes [OR = 1.22 (95% CI 1.03–1.46), p = 0.025]. SNPs in other genes such as rs7756992 in CDKAL1, rs10811661 in CDKN2B and rs13266634 in SLC30A8 showed nominal association with type 2 diabetes. rs7756992 in CDKAL1 and rs10811661 in CDKN2B were correlated with impaired pancreatic beta cell function as estimated by the homeostasis model assessment beta index (p = 0.023, p = 0.0083, respectively).
Conclusions/interpretation
HHEX is a common type 2 diabetes-susceptibility gene across different ethnic groups.
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M. Horikoshi and K. Hara contributed equally to this study. 相似文献
19.
Aims
Pyruvate dehydrogenase kinase 4 (PDK4) plays a crucial role in glucose utilization and lipid metabolism by regulating the pyruvate dehydrogenase complex (PDC) and is an emerging therapeutic target for type 2 diabetes. To date, no study has specifically examined the relationship between PDK4 gene polymorphisms and type 2 diabetes or metabolic syndrome.Methods
The association of common single nucleotide polymorphisms (SNPs) was examined in PDK4 [−208A/G (rs10085637), IVS3 + 192C/T (rs3779478), IVS6 + 31A/G (rs2301630), IVS7 + 514A/G (rs12668651), IVS10 + 75C/T (rs10247649)] with type 2 diabetes and metabolic syndrome in 651 Korean subjects with type 2 diabetes and 350 nondiabetic Korean subjects. The association of these SNPs with clinical parameters related to metabolic syndromes including obesity, hyperglycemia, hypertension, and dyslipidemia was also examined.Results
No significant association was found between the studied SNPs and type 2 diabetes, metabolic syndrome, or clinical parameters. The PDK4 gene haplotype ACAGC showed a modest association with type 2 diabetes. However, the significance of this association was lost after considering for multiple comparisons.Conclusions
PDK4 polymorphisms may not be associated with type 2 diabetes or metabolic syndrome. Further studies utilizing a larger study population are required to confirm these results. 相似文献20.
Suk-Kyun Yang Yusun Jung Hyeri Kim Myunghee Hong Byong Duk Ye Kyuyoung Song 《Digestive and liver disease》2011,43(11):856-861