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

Lena Sønder Snogdal; Mette Wod; Niels Grarup; M Vestmar; Thomas Hempel Sparsø; T Jørgensen; Torsten Lauritzen; Henning Beck-Nielsen; J E Henriksen; Oluf Pedersen; Torben Hansen; K Højlund

doi:10.1007/s00125-011-2377-0

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

Lena Sønder Snogdal, Mette Wod, Niels Grarup, M Vestmar, Thomas Hempel Sparsø, T Jørgensen, Torsten Lauritzen, Henning Beck-Nielsen, J E Henriksen, Oluf Pedersen, Torben Hansen, K Højlund

5 Citations (Scopus)

Abstract

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 glucose-tolerant 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 proximity to the examined OxPhos genes is not a major cause of insulin resistance or type 2 diabetes.

Original language	English
Journal	Diabetologia
Volume	55
Issue number	2
Pages (from-to)	340-8
Number of pages	9
ISSN	0012-186X
DOIs	https://doi.org/10.1007/s00125-011-2377-0
Publication status	Published - Feb 2012

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10.1007/s00125-011-2377-0

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

abstract = "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 glucose-tolerant 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 proximity to the examined OxPhos genes is not a major cause of insulin resistance or type 2 diabetes.",

author = "Snogdal, {Lena S{\o}nder} and Mette Wod and Niels Grarup and M Vestmar and Spars{\o}, {Thomas Hempel} and T J{\o}rgensen and Torsten Lauritzen and Henning Beck-Nielsen and Henriksen, {J E} and Oluf Pedersen and Torben Hansen and K H{\o}jlund",

year = "2012",

month = feb,

doi = "10.1007/s00125-011-2377-0",

language = "English",

volume = "55",

pages = "340--8",

journal = "Diabetologia",

issn = "0012-186X",

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TY - JOUR

T1 - Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes

AU - Snogdal, Lena Sønder

AU - Wod, Mette

AU - Grarup, Niels

AU - Vestmar, M

AU - Sparsø, Thomas Hempel

AU - Jørgensen, T

AU - Lauritzen, Torsten

AU - Beck-Nielsen, Henning

AU - Henriksen, J E

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Højlund, K

PY - 2012/2

Y1 - 2012/2

N2 - 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 glucose-tolerant 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 proximity to the examined OxPhos genes is not a major cause of insulin resistance or type 2 diabetes.

AB - 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 glucose-tolerant 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 proximity to the examined OxPhos genes is not a major cause of insulin resistance or type 2 diabetes.

U2 - 10.1007/s00125-011-2377-0

DO - 10.1007/s00125-011-2377-0

M3 - Journal article

C2 - 22095239

SN - 0012-186X

VL - 55

SP - 340

EP - 348

JO - Diabetologia

JF - Diabetologia

IS - 2

ER -

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

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