Physiologic Characterization of Type 2 Diabetes–Related Loci

Grarup, Niels; Sparsø, Thomas; Hansen, Torben

doi:10.1007/s11892-010-0154-y

Cited by 49 publications

(43 citation statements)

References 82 publications

(84 reference statements)

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“…The hypothesis of a potential association between common variation in OxPhos genes and type 2 diabetes was strongly supported a priori by numerous metabolic and physiological studies [7][8][9][10][11][12][13][14][15][16][17][18]. This makes our study unique compared with replication studies and meta-analysis of previously identified type 2 diabetes risk alleles, for most of which knowledge of the underlying phenotype leading to type 2 diabetes is limited [23]. The present study is, to our knowledge, the first to replicate a nominal association between OxPhos gene variants and type 2 diabetes.…”

Section: Discussionsupporting

confidence: 52%

“…However, it remains to be established whether mitochondrial dysfunction is a cause or consequence of insulin resistance and/or beta cell dysfunction in type 2 diabetes. To date, genome-wide association (GWA) studies have shown 38 common genetic variants to be robustly associated with type 2 diabetes, with 16 additional loci associated with traits of glucose homeostasis [23]. Together, they explain approximately 10% of type 2 diabetes heritability.…”

Section: Introductionmentioning

confidence: 99%

“…Together, they explain approximately 10% of type 2 diabetes heritability. Most of these risk alleles are located in genes believed to influence beta cell function [23], while only a few variants seem to be associated with insulin resistance, e.g. a variant upstream of IRS1 [24].…”

Section: Introductionmentioning

confidence: 99%

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Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes

et al. 2011

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Aims/hypothesis There is substantial evidence that mitochondrial dysfunction is linked to insulin resistance and is present in several tissues relevant to the pathogenesis of type 2 diabetes. Here, we examined whether common variation in genes involved in oxidative phosphorylation (OxPhos) contributes to type 2 diabetes susceptibility or influences diabetes-related metabolic traits. Methods OxPhos gene variants (n=10) that had been nominally associated (p<0.01) with type 2 diabetes in a recent genome-wide meta-analysis (n=10,108) were selected for follow-up in 3,599 type 2 diabetic and 4,956 glucosetolerant Danish individuals. A meta-analysis of these variants was performed in 11,729 type 2 diabetic patients and 43,943 non-diabetic individuals. The impact on OGTT-derived metabolic traits was evaluated in 5,869 treatment-naive individuals from the Danish Inter99 study.Results The minor alleles of COX10 rs9915302 (p=0.02) and COX5B rs1466100 (p = 0.005) showed nominal association with type 2 diabetes in our Danish cohort. However, in the meta-analysis, none of the investigated variants showed a robust association with type 2 diabetes after correction for multiple testing. Among the alleles potentially associated with type 2 diabetes, none negatively influenced surrogate markers of insulin sensitivity in non-diabetic participants, while the minor alleles of UQCRC1 rs2228561 and COX10 rs10521253 showed a weak (p<0.01 to p<0.05) negative influence on indices of glucose-stimulated insulin secretion. Conclusions/interpretation We cannot rule out the possibility that common variants in or near OxPhos genes may influence beta cell function in non-diabetic individuals. However, our quantitative trait studies and a sufficiently large meta-analysis indicate that common variation in Electronic supplementary material The online version of this article

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

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Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes

et al. 2011

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“…In this respect, our data extend previous molecular-genetic studies that tested association of T2DM SNPs with CAD. (10;38)…”

Section: Discussionmentioning

confidence: 99%

Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk

Jansen¹,

Loley²,

Lieb³

et al. 2015

Atherosclerosis

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Background The mechanisms underlying the association between diabetes and coronary artery disease (CAD) risk are unclear. We aimed to assess this association by studying genetic variants that have been shown to associate with type 2 diabetes (T2DM). If the association between diabetes and CAD is causal, we expected to observe an association of these variants with CAD as well. Methods and Results We studied all genetic variants currently known to be associated with T2DM at a genome-wide significant level (p<5*10−8) in CARDIoGRAM, a genome-wide data-set of CAD including 22,233 CAD cases and 64,762 controls. Out of the 44 published T2DM SNPs 10 were significantly associated with CAD in CARDIoGRAM (OR>1, p<0.05), more than expected by chance (p=5.0*10−5). Considering all 44 SNPs, the average CAD risk observed per individual T2DM risk allele was 1.0076 (95% confidence interval (CI), 0.9973–1.0180). Such average risk increase was significantly lower than the increase expected based on i) the published effects of the SNPs on T2DM risk and ii) the effect of T2DM on CAD risk as observed in the Framingham Heart Study, which suggested a risk of 1.067 per allele (p=7.2*10−10 vs. the observed effect). Studying two risk scores based on risk alleles of the diabetes SNPs, one score using individual level data in 9856 subjects, and the second score on average effects of reported beta-coefficients from the entire CARDIoGRAM data-set, we again observed a significant - yet smaller than expected - association with CAD. Conclusions Our data indicate that an association between type 2 diabetes related SNPs and CAD exists. However, the effects on CAD risk appear to be by far lower than what would be expected based on the effects of risk alleles on T2DM and the effect of T2DM on CAD in the epidemiological setting.

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“…Finally, the selected variants were scanned for the previously introduced gene set implicated in glucose metabolism [12]. These are the genes with an essential role in pancreatic beta cells, genes previously known to cause monogenic diabetes or associated syndromes and genes from the genome-wide association data of type 2 diabetes [19,20,21,22,23,24,25,26]. The list of genes of interest is shown in table 2.…”

Section: Methodsmentioning

confidence: 99%

Identification of Candidate Gene Variants in Korean MODY Families by Whole-Exome Sequencing

et al. 2015

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Aims: To date, 13 genes causing maturity-onset diabetes of the young (MODY) have been identified. However, there is a big discrepancy in the genetic locus between Asian and Caucasian patients with MODY. Thus, we conducted whole-exome sequencing in Korean MODY families to identify causative gene variants. Methods: Six MODY probands and their family members were included. Variants in the dbSNP135 and TIARA databases for Koreans and the variants with minor allele frequencies >0.5% of the 1000 Genomes database were excluded. We selected only the functional variants (gain of stop codon, frameshifts and nonsynonymous single-nucleotide variants) and conducted a case-control comparison in the family members. The selected variants were scanned for the previously introduced gene set implicated in glucose metabolism. Results: Three variants c.620C>T:p.Thr207Ile in PTPRD, c.559C>G:p.Gln187Glu in SYT9, and c.1526T>G:p.Val509Gly in WFS1 were respectively identified in 3 families. We could not find any disease-causative alleles of known MODY 1-13 genes. Based on the predictive program, Thr207Ile in PTPRD was considered pathogenic. Conclusions: Whole-exome sequencing is a valuable method for the genetic diagnosis of MODY. Further evaluation is necessary about the role of PTPRD, SYT9 and WFS1 in normal insulin release from pancreatic beta cells.

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Physiologic Characterization of Type 2 Diabetes–Related Loci

Cited by 49 publications

References 82 publications

Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes

Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes

Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk

Identification of Candidate Gene Variants in Korean MODY Families by Whole-Exome Sequencing

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