A Genome Scan for Type 2 Diabetes Susceptibility Loci in a Genetically Isolated Population

Permutt, M. A.; Wasson, Jon; Suarez, Brian K.; Lin, Jennifer Y.; Thomas, Jeffrey; Meyer, Joanne M.; Lewitzky, Steve; Rennich, Jean S.; Parker, Alex; Duprat, Laura J.; Maruti, Sanchit; Chayen, S.; Gläser, Benjamin

doi:10.2337/diabetes.50.3.681

Cited by 125 publications

(87 citation statements)

References 31 publications

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“…9,10 In addition, linkage studies in several populations have reported some indication of linkage with obesity, type 2 diabetes mellitus and insulin resistance in a region on chromosome 4q that encompasses the Clock gene. [40][41][42][43][44][45] It has also recently been reported that the expression of several components of the molecular clock (Per2,Cry1, Bmal1) in adipose tissue are associated with features of the metabolic syndrome in man. 46 …”

Section: Discussionmentioning

confidence: 98%

Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man

2007

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Objective: Accumulating evidence raises the hypothesis that dysregulation of intrinsic clock mechanisms are involved in the development of the metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease. The aim of the present study was to investigate the relationship between three known common polymorphisms in the Clock gene and features of the metabolic syndrome in man. Methods: Genotype and haplotype analysis was carried out in a cohort of 537 individuals from 89 families characterized for inflammatory, atherothrombotic and metabolic risk associated with insulin resistance. Results: Heritability of the metabolic syndrome, defined according to International Diabetes Federation criteria, was 0.40. Haplotype analysis indicated three common haplotypes: CAT, TGT and CGC (rs4864548-rs3736544-rs1801260) with frequencies of 31, 33 and 28%, respectively. The CGC haplotype was less prevalent in subjects with the metabolic syndrome (P ¼ 0.0015) and was associated with lower waist circumference (P ¼ 0.007), lower hip circumference (P ¼ 0.023), lower body mass index (P ¼ 0.043) and lower leptin levels (P ¼ 0.028). The CAT haplotype was significantly associated with the presence of the metabolic syndrome (P ¼ 0.020). Conclusions: These findings suggest that the Clock gene CGC haplotype may be protective for the development of obesity and support the hypothesis that genetic variation in the Clock gene may play a role in the development of the metabolic syndrome, type 2 diabetes and cardiovascular disease.

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Section: Discussionmentioning

confidence: 98%

Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man

2007

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“…In fact, the mean age of onset in this sample was 45.6 years (42). Permutt et al (46) recently published the fifth study supporting this region (Z score 2.05) as an interesting candidate region for diabetes. Impaired insulin secretion seems to be the trigger for EOD.…”

Section: Discussionmentioning

confidence: 90%

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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“…All subjects were participants in a genome scan of Type II diabetes in Ashkenazi Jews as described previously [8]. The study was approved by the institutional review board of Washington University School of Medicine.…”

Section: Methodsmentioning

confidence: 99%

“…Mean BMI of Type II diabetic patients was higher than that of control subjects (29.3 0.7 vs. 25.5 0.4 kg/m 2 , mean -SEM, p < 0.001). The ages of the two groups differ (p < 0.001) because patients (55.0 1.2 years) were initially recruited only if Type II diabetes was present in at least one family member who was under 55 years of age, and control subjects were selected for normal glucose tolerance by 75 g OGTT in an older population (75.4 1.1 years) [8].…”

Section: Methodsmentioning

confidence: 99%

“…Genomic DNA was extracted from whole blood using the Puregene Genomic DNA extraction kit (Gentra System, Minneapolis, Minn., USA). For the SNP screening by denaturing high-performance liquid chromatography (DHPLC), 30 unrelated probands who had the highest evidence of linkage to chromosome 14 q based on the identity-by-descent (IBD) probability of 5 markers between D14S606 and D14S267 were selected from a large set of affected sib pairs [8]. An association study using individual SNPs was carried out by comparing allelic and genotypic frequencies in Type II diabetes patients (n = 69) and control subjects (n = 65).…”

Section: Methodsmentioning

confidence: 99%

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Isolation and characterization of the human AKT1 gene, identification of 13 single nucleotide polymorphisms (SNPs), and their lack of association with Type II diabetes

et al. 2001

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The AKT (murine thymoma viral (v-akt) oncogene homologue), also termed protein kinase B (PKB) or RAC protein kinase, is a serine and threonine protein kinase homologous to protein kinases A and C [1] [2].Three mammalian isoforms (AKT1±3) have been cloned. For maximal enzymatic activation of AKT1, Thr-308 and Ser-473 are required to be phosphorylated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and 3-phosphoinositide-dependent protein kinase-2 (PDK2) respectively, while PDK2 has yet to be identified. AKTs are important for many cellular processes such as growth and differentiation and have anti-apoptotic effects through several target molecules. AKT also mediates a variety of peripheral metabolic actions of insulin.Recent experiments in transgenic mice, including tissue-specific disruptions of the islet beta cell insulin receptor (IR) and the insulin receptor substrates Diabetologia (2001) Abstract Aims/hypothesis. AKT1, a serine/threonine protein kinase, is an important downstream target of the insulin-signalling pathway, with both anti-apoptotic and peripheral metabolic effects. Because impaired insulin signalling is a major hallmark of Type II (non-insulin-dependent) diabetes mellitus, we considered whether the AKT1 gene could be a candidate gene involved in susceptibility of this condition. To test this possibility, we isolated and characterized the human AKT1 gene. We also looked for single nucleotide polymorphisms in the gene and examined their association with Type II diabetes mellitus in the Ashkenazi Jewish population. Methods. Human BAC/P1 genomic libraries were screened to isolate the AKT1 gene. To obtain structural information and the sequences of the exon-intron boundaries, BAC/P1 clones were directly sequenced. Identification of single nucleotide polymorphisms was done by polymerase chain reaction of each exon, followed by denaturing high performance liquid chromatography. Six single nucleotide polymorphisms were genotyped in Ashkenazi Jewish patients with Type II diabetes mellitus and in control subjects.Results. The human AKT1 gene was at least 24.6 kb in length and comprised 14 exons. Altogether 13 putative intragenic single nucleotide polymorphisms, with minor-allele frequencies ranging from 0.011 to 0.354, were identified. The allelic and the genotypic frequencies of 6 single nucleotide polymorphisms were the same in diabetic patients and in control subjects. Conclusion/interpretation. The results of our studies show that the AKT1 gene is not a major contributor to susceptibility to Type II diabetes mellitus in Ashkenazi Jews. [Diabetologia (2001) 44: 910±913]

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A Genome Scan for Type 2 Diabetes Susceptibility Loci in a Genetically Isolated Population

Cited by 125 publications

References 31 publications

Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man

Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man

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

Isolation and characterization of the human AKT1 gene, identification of 13 single nucleotide polymorphisms (SNPs), and their lack of association with Type II diabetes

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