Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families

Freedman, Barry I.; Rich, Stephen S.; Sale, Michèle M.; Heiss, Gerardo; Djoussé, Luc; Pankow, James S.; Province, Michael A.; Rao, D. C.; Lewis, Cora E.; Chen, Y. D.I.; Beck, Stephanie R

doi:10.1007/s00125-005-1679-5

Cited by 20 publications

(7 citation statements)

References 25 publications

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“…Searching for quantitative trait loci (QTLs) that explain the variation in the “intermediate” phenotypes of T2DM has therefore been considered a plausible way to tease out the genetic factors involved in biological pathways that lead to development of diabetes 3 . So far, a number of genome-wide linkage scans have been carried out to identify the QTLs for the related intermediate phenotypes of T2DM in Pima Indian 4 , Mexican Americans 5 6 , Han Chinese 7 8 , Japanese Americans 9 , Caucasians 10 , European Americans and African Americans 11 , and multiethnic population 12 . A QTL for the age of onset of T2DM was identified in a set of French families 13 .…”

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confidence: 99%

Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population

Chang

Chiu

Sheu

et al. 2015

Sci Rep

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Proprotein convertase subtilisin/kexin type 2 (PCSK2) is a prohormone processing enzyme involved in insulin and glucagon biosynthesis. We previously found the genetic polymorphism of PCSK2 on chromosome 20 was responsible for the linkage peak of several glucose homeostasis parameters. The aim of this study is to investigate the association between genetic variants of PCSK2 and glucose homeostasis parameters and incident diabetes. Total 1142 Chinese participants were recruited from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study, and 759 participants were followed up for 5 years. Ten SNPs of the PCSK2 gene were genotyped. Variants of rs6044695 and rs2284912 were associated with fasting plasma glucose, and variants of rs2269023 were associated with fasting plasma glucose and 1-hour plasma glucose during OGTT. Haplotypes of rs4814605/rs1078199 were associated with fasting plasma insulin levels and HOMA-IR. Haplotypes of rs890609/rs2269023 were also associated with fasting plasma glucose, fasting insulin and HOMA-IR. In the longitudinal study, we found individuals carrying TA/AA genotypes of rs6044695 or TC/CC genotypes of rs2284912 had lower incidence of diabetes during the 5-year follow-up. Our results indicated that PCSK2 gene polymorphisms are associated with pleiotropic effects on various traits of glucose homeostasis and incident diabetes.

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confidence: 99%

Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population

Chang

Chiu

Sheu

et al. 2015

Sci Rep

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“…Many of our linkage signals were linked to chromosomal regions observed by other genome scans for hypertension [25,26], fasting insulin [27,28], dyslipidemia [29], visceral fat area [30] and/or low metabolic rates [31]. Interestingly, several of these regions were also linked to obstructive sleep apnoea [32] which is closely associated with obesity.…”

Section: Discussionmentioning

confidence: 92%

Genome-wide linkage scan for factors of metabolic syndrome in a Chinese population

Tam

Lam

et al. 2010

BMC Genet

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BackgroundShared genetic factors may contribute to the phenotypic clustering of different components of the metabolic syndrome (MES). This study aims to identify genetic loci that contribute to individual or multiple factors related to MES.ResultsWe studied 478 normoglycemic subjects ascertained through 163 families participating in the Hong Kong Family Diabetes Study. Factor analysis on 15 MES-related traits yielded 6 factors including adiposity factor (body mass index, waist and hip circumferences), insulin factor (fasting insulin and insulin AUC during OGTT), glucose factor (fasting glucose and glucose AUC during OGTT), TC-LDLC factor (total cholesterol and LDL-cholesterol), blood pressure factor (systolic and diastolic blood pressure) and TG-HDLC factor (triglycerides and HDL-cholesterol). Genome-wide linkage analyses were performed on these factors using variance component approach. Suggestive evidence for linkage (LOD = 1.24 - 2.46) were observed for adiposity factor (chromosome 1 at 187 cM, chromosome 9 at 34 cM and chromosome 17 at 10 cM), insulin factor (chromosome 2 at 128 cM, chromosome 5 at 21 cM and chromosome 12 at 7 cM), glucose factor (chromosome 7 at 155 cM), TC-LDLC factor (chromosome 7 at 151 cM and chromosome 13 at 15 cM) and TG-HDLC factor (chromosome 7 at 155 cM).ConclusionsIn summary, our findings suggest the presence of susceptibility loci that influence either single (chromosomes 1, 2, 5, 9, 12, 13 and 17) or multiple factors (chromosome 7) for MES in Hong Kong Chinese without diabetes.

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“…HOMA-IR was calculated as (fasting insulin x (fasting glucose x 0.056))/22.3, with glucose in the units of mg/dL, and insulin in the units of µIU/L. The measurement of fasting glucose in HyperGEN has been described [19].…”

Section: Methodsmentioning

confidence: 99%

Genome-Wide Detection of Allele Specific Copy Number Variation Associated with Insulin Resistance in African Americans from the HyperGEN Study

et al. 2011

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African Americans have been understudied in genome wide association studies of diabetes and related traits. In the current study, we examined the joint association of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with fasting insulin and an index of insulin resistance (HOMA-IR) in the HyperGEN study, a family based study with proband ascertainment for hypertension. This analysis is restricted to 1,040 African Americans without diabetes. We generated allele specific CNV genotypes at 872,243 autosomal loci using Birdsuite, a freely available multi-stage program. Joint tests of association for SNPs and CNVs were performed using linear mixed models adjusting for covariates and familial relationships. Our results highlight SNPs associated with fasting insulin and HOMA-IR (rs6576507 and rs8026527, 3.7*10−7≤P≤1.1*10−5) near ATPase, class V, type 10A (ATP10A), and the L Type voltage dependent calcium channel (CACNA1D, rs1401492, P≤5.2*10−6). ATP10A belongs to a family of aminophospholipid-transporting ATPases and has been associated with type 2 diabetes in mice. CACNA1D has been linked to pancreatic beta cell generation in mice. The two most significant copy variable markers (rs10277702 and rs361367; P<2.0*10−4) were in the beta variable region of the T-cell receptor gene (TCRVB). Human and mouse TCR has been shown to mimic insulin and its receptor and could contribute to insulin resistance. Our findings differ from genome wide association studies of fasting insulin and other diabetes related traits in European populations, highlighting the continued need to investigate unique genetic influences for understudied populations such as African Americans.

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Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families

Cited by 20 publications

References 25 publications

Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population

Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population

Genome-wide linkage scan for factors of metabolic syndrome in a Chinese population

Genome-Wide Detection of Allele Specific Copy Number Variation Associated with Insulin Resistance in African Americans from the HyperGEN Study

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