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Novel Meta-Analysis-Derived Type 2 Diabetes Risk Loci Do Not Determine Prediabetic Phenotypes

BACKGROUND: Genome-wide association (GWA) studies identified a series of novel type 2 diabetes risk loci. Most of them were subsequently demonstrated to affect insulin secretion of pancreatic β-cells. Very recently, a meta-analysis of GWA data revealed nine additional risk loci with still undefined...

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Autores principales: Staiger, Harald, Machicao, Fausto, Kantartzis, Konstantinos, Schäfer, Silke A., Kirchhoff, Kerstin, Guthoff, Martina, Silbernagel, Günther, Stefan, Norbert, Fritsche, Andreas, Häring, Hans-Ulrich
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2500187/
https://www.ncbi.nlm.nih.gov/pubmed/18714373
http://dx.doi.org/10.1371/journal.pone.0003019
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author Staiger, Harald
Machicao, Fausto
Kantartzis, Konstantinos
Schäfer, Silke A.
Kirchhoff, Kerstin
Guthoff, Martina
Silbernagel, Günther
Stefan, Norbert
Fritsche, Andreas
Häring, Hans-Ulrich
author_facet Staiger, Harald
Machicao, Fausto
Kantartzis, Konstantinos
Schäfer, Silke A.
Kirchhoff, Kerstin
Guthoff, Martina
Silbernagel, Günther
Stefan, Norbert
Fritsche, Andreas
Häring, Hans-Ulrich
author_sort Staiger, Harald
collection PubMed
description BACKGROUND: Genome-wide association (GWA) studies identified a series of novel type 2 diabetes risk loci. Most of them were subsequently demonstrated to affect insulin secretion of pancreatic β-cells. Very recently, a meta-analysis of GWA data revealed nine additional risk loci with still undefined roles in the pathogenesis of type 2 diabetes. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of the nine latest genetic variants with the predominant prediabetes traits, i.e., obesity, impaired insulin secretion, and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: One thousand five hundred and seventy-eight metabolically characterized non-diabetic German subjects were genotyped for the reported candidate single nucleotide polymorphisms (SNPs) JAZF1 rs864745, CDC123/CAMK1D rs12779790, TSPAN8/LGR5 rs7961581, THADA rs7578597, ADAMTS9 rs4607103, NOTCH2 rs10923931, DCD rs1153188, VEGFA rs9472138, and BCL11A rs10490072. Insulin sensitivity was derived from fasting glucose and insulin concentrations, oral glucose tolerance test (OGTT), and hyperinsulinemic-euglycemic clamp. Insulin secretion was estimated from OGTT data. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons (corrected α-level: p = 0.0014), none of the SNPs was reliably associated with adiposity, insulin sensitivity, or insulin secretion (all p≥0.0117, dominant inheritance model). The risk alleles of ADAMTS9 SNP rs4607103 and VEGFA SNP rs9472138 tended to associate with more than one measure of insulin sensitivity and insulin secretion, respectively, but did not reach formal statistical significance. The study was sufficiently powered (1-β = 0.8) to detect effect sizes of 0.19≤d≤0.25 (α = 0.0014) and 0.13≤d≤0.16 (α = 0.05). CONCLUSIONS/SIGNIFICANCE: In contrast to the first series of GWA-derived type 2 diabetes candidate SNPs, we could not detect reliable associations of the novel risk loci with prediabetic phenotypes. Possible weak effects of ADAMTS9 SNP rs4607103 and VEGFA SNP rs9472138 on insulin sensitivity and insulin secretion, respectively, await further confirmation by larger studies.
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spelling pubmed-25001872008-08-20 Novel Meta-Analysis-Derived Type 2 Diabetes Risk Loci Do Not Determine Prediabetic Phenotypes Staiger, Harald Machicao, Fausto Kantartzis, Konstantinos Schäfer, Silke A. Kirchhoff, Kerstin Guthoff, Martina Silbernagel, Günther Stefan, Norbert Fritsche, Andreas Häring, Hans-Ulrich PLoS One Research Article BACKGROUND: Genome-wide association (GWA) studies identified a series of novel type 2 diabetes risk loci. Most of them were subsequently demonstrated to affect insulin secretion of pancreatic β-cells. Very recently, a meta-analysis of GWA data revealed nine additional risk loci with still undefined roles in the pathogenesis of type 2 diabetes. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of the nine latest genetic variants with the predominant prediabetes traits, i.e., obesity, impaired insulin secretion, and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: One thousand five hundred and seventy-eight metabolically characterized non-diabetic German subjects were genotyped for the reported candidate single nucleotide polymorphisms (SNPs) JAZF1 rs864745, CDC123/CAMK1D rs12779790, TSPAN8/LGR5 rs7961581, THADA rs7578597, ADAMTS9 rs4607103, NOTCH2 rs10923931, DCD rs1153188, VEGFA rs9472138, and BCL11A rs10490072. Insulin sensitivity was derived from fasting glucose and insulin concentrations, oral glucose tolerance test (OGTT), and hyperinsulinemic-euglycemic clamp. Insulin secretion was estimated from OGTT data. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons (corrected α-level: p = 0.0014), none of the SNPs was reliably associated with adiposity, insulin sensitivity, or insulin secretion (all p≥0.0117, dominant inheritance model). The risk alleles of ADAMTS9 SNP rs4607103 and VEGFA SNP rs9472138 tended to associate with more than one measure of insulin sensitivity and insulin secretion, respectively, but did not reach formal statistical significance. The study was sufficiently powered (1-β = 0.8) to detect effect sizes of 0.19≤d≤0.25 (α = 0.0014) and 0.13≤d≤0.16 (α = 0.05). CONCLUSIONS/SIGNIFICANCE: In contrast to the first series of GWA-derived type 2 diabetes candidate SNPs, we could not detect reliable associations of the novel risk loci with prediabetic phenotypes. Possible weak effects of ADAMTS9 SNP rs4607103 and VEGFA SNP rs9472138 on insulin sensitivity and insulin secretion, respectively, await further confirmation by larger studies. Public Library of Science 2008-08-20 /pmc/articles/PMC2500187/ /pubmed/18714373 http://dx.doi.org/10.1371/journal.pone.0003019 Text en Staiger et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Staiger, Harald
Machicao, Fausto
Kantartzis, Konstantinos
Schäfer, Silke A.
Kirchhoff, Kerstin
Guthoff, Martina
Silbernagel, Günther
Stefan, Norbert
Fritsche, Andreas
Häring, Hans-Ulrich
Novel Meta-Analysis-Derived Type 2 Diabetes Risk Loci Do Not Determine Prediabetic Phenotypes
title Novel Meta-Analysis-Derived Type 2 Diabetes Risk Loci Do Not Determine Prediabetic Phenotypes
title_full Novel Meta-Analysis-Derived Type 2 Diabetes Risk Loci Do Not Determine Prediabetic Phenotypes
title_fullStr Novel Meta-Analysis-Derived Type 2 Diabetes Risk Loci Do Not Determine Prediabetic Phenotypes
title_full_unstemmed Novel Meta-Analysis-Derived Type 2 Diabetes Risk Loci Do Not Determine Prediabetic Phenotypes
title_short Novel Meta-Analysis-Derived Type 2 Diabetes Risk Loci Do Not Determine Prediabetic Phenotypes
title_sort novel meta-analysis-derived type 2 diabetes risk loci do not determine prediabetic phenotypes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2500187/
https://www.ncbi.nlm.nih.gov/pubmed/18714373
http://dx.doi.org/10.1371/journal.pone.0003019
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