Linkage of Genetic Markers on Human Chromosomes 20 and 12 to NIDDM in Caucasian Sib Pairs With a History of Diabetic Nephropathy

Bowden, Donald W.; Sale, Michèle M.; Howard, Timothy D.; Qadri, Asif; Spray, Beverly J.; Rothschild, Cynthia B.; Akots, Gita; Rich, Stephen S.; Freedman, Barry I.

doi:10.2337/diab.46.5.882

Cited by 169 publications

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“…Evidence for a type 2 diabetes locus in chromosome 20q12-q13 (OMIM no. 603694) has also been reported from studies in several Caucasian and Chinese populations (2)(3)(4)(5), suggesting that this region may harbor a susceptibility gene for type 2 diabetes common to these ethnic groups. The transcription factor HNF-4␣ (HNF4A) gene, the gene for maturity-onset diabetes of the young (MODY) type 1 (6), a dominantly inherited, earlyonset type 2 diabetes characterized by defective glucosedependent insulin secretion (7), is located in this region.…”

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confidence: 84%

Hepatocyte Nuclear Factor-4α P2 Promoter Haplotypes Are Associated With Type 2 Diabetes in the Japanese Population

Hara

Horikoshi²,

Kitazato³

et al. 2006

Diabetes

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Hepatocyte nuclear factor (HNF)-4␣ is a transcription factor known as a key molecule in the development and functions of the ␤-cells. In a previously performed genomewide 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 ␤-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 ؋ 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 ؋ 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. Diabetes

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confidence: 84%

Hepatocyte Nuclear Factor-4α P2 Promoter Haplotypes Are Associated With Type 2 Diabetes in the Japanese Population

Hara

Horikoshi²,

Kitazato³

et al. 2006

Diabetes

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“…The gene is located on chromosome 12q24, which has shown linkage to late-onset type 2 diabetes [4][5][6][7][8][9][10], and a private G319S missense variant has been associated with type 2 diabetes in Canadian OjiCree individuals [11]. Common variations in the HNF-1α gene have been associated with impaired insulin secretion [12,13].…”

Section: Introductionmentioning

confidence: 99%

Common variants in HNF-1 α and risk of type 2 diabetes

et al. 2006

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Aims/hypothesis Mutations in the hepatocyte nuclear factor 1-α gene (HNF-1α, now known as the transcription factor 1 gene [TCF1]) cause the most common monogenic form of diabetes, MODY3, but it is not known if common variants in HNF-1a are associated with decreased transcriptional activity or phenotypes related to type 2 diabetes, or whether they predict future type 2 diabetes. Subjects and methods We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1α gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo. Results Certain combinations of the I27L and A98V polymorphisms in the HNF-1α gene showed decreased transcriptional activity on the target promoters glucose transporter 2 (now known as solute carrier family 2 [facilitated glucose transporter], member 2) and albumin in both HeLa and INS-1 cells. In vivo, these polymorphisms were associated with a modest but significant impairment in insulin secretion in response to oral glucose. Insulin secretion deteriorated over time in individuals carrying the V allele of the A98V polymorphism (n=2,293; p=0.003). In a new case-control (n=1,511 and n=2,225 respectively) data set, the I27L polymorphism was associated with increased risk of type 2 diabetes, odds ratio (OR)=1.5 ( p=0.002; multiple logistic regression), particularly in

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“…It is interesting that linkage was observed between (42). This could be a corollary of EOD, as nephropathy is more likely to develop in patients with early onset disease.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Known and Unknown Susceptibility Genes to Early-Onset Diabetes in Scandinavia

et al. 2002

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In an attempt to identify novel susceptibility genes predisposing to early-onset diabetes (EOD), we performed a genome-wide scan using 433 markers in 222 individuals (119 with diabetes) from 29 Scandinavian families with >2 members with onset of diabetes <45 years. The highest nonparametric linkage (NPL) score, 2.7 (P < 0.01), was observed on chromosome 1p (D1S473/D1S438). Six other regions on chromosomes 3p, 7q, 11q, 18q, 20q, and 21q showed a nominal P value <0.05. Of the EOD subjects in these 29 families, 20% were GAD antibody positive and 68% displayed type 1 diabetes HLA risk alleles (DQB*02 or 0302). Mutations in maturity-onset diabetes of the young (MODY) 1-5 genes and the A3243G mitochondrial DNA mutation were detected by single-strand conformation polymorphism and direct sequencing. To increase homogeneity, we analyzed a subsample of five families with autosomal dominant inheritance of EOD (greater than or equal to two members with age at diagnosis <35 years). The highest NPL scores were found on chromosome 1p (D1S438 -D1S1665; NPL 3.0; P < 0.01) and 16q (D16S419; NPL 2.9; P < 0.01). After exclusion of three families with MODY1, MODY3, and mitochondrial mutations, the highest NPL scores were observed on chromosomes 1p (D1S438; NPL 2.6; P < 0.01), 3p (D3S1620; NPL 2.2; P < 0.03), 5q (D5S1465; NPL 2.1; P < 0.03), 7q (D7S820; NPL 2.0; P < 0.03), 18q (D18S535; NPL 1.9; P < 0.04), 20q (D20S195; NPL 2.5; P < 0.02), and 21q (D21S1446; NPL 2.2; P < 0.03). We conclude that considerable heterogeneity exists in Scandinavian subjects with EOD; 24% had MODY or maternally inherited diabetes and deafness, and ϳ60% were GAD antibody positive or had type 1 diabetes-associated HLA genotypes. Our data also point at putative chromosomal regions, which could harbor novel genes that contribute to EOD. Diabetes

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Linkage of Genetic Markers on Human Chromosomes 20 and 12 to NIDDM in Caucasian Sib Pairs With a History of Diabetic Nephropathy

Cited by 169 publications

References 0 publications

Hepatocyte Nuclear Factor-4α P2 Promoter Haplotypes Are Associated With Type 2 Diabetes in the Japanese Population

Hepatocyte Nuclear Factor-4α P2 Promoter Haplotypes Are Associated With Type 2 Diabetes in the Japanese Population

Common variants in HNF-1 α and risk of type 2 diabetes

Contribution of Known and Unknown Susceptibility Genes to Early-Onset Diabetes in Scandinavia

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