Genetic Variants Involved in Mitochondrial Oxidative Metabolism are associated with Type 2 Diabetes Mellitus in studies of 8,441 Danes

Lena Sønder Snogdal, Jan Erik Henriksen, Henning Beck-Nielsen, Torben Hansen, Oluf Pedersen, Niels Grarup, Torsten Lauritzen, Annelli Sandbæk, Daniel Rinse Witte, Torben Jørgensen, Mette Wod, Marie Vestmar, Kurt Højlund

Research output: Contribution to conference without publisher/journalConference abstract for conferenceResearch

Abstract

 

Aims: Type 2 Diabetes (T2D) is characterized by insulin resistance and failure of the pancreatic beta cells to compensate for this defect. Several studies have demonstrated a link between insulin resistance and impaired mitochondrial oxidative phosphorylation (OxPhos) in skeletal muscle. Recently, mitochondrial defects have also been implicated in beta-cell dysfunction in T2D. We hypothesized that single nucleotide polymorphisms (SNPs) in OxPhos genes could contribute to the pathogenesis of T2D.

 

Methods: Exploring results from a meta-analysis of genome wide association studies (GWAS) published by the Diabetes Genetics Replication And Meta-analysis Consortium (DIAGRAM), we found that among 1284 SNPs in 119 OxPhos genes, 39 SNPs in 7 genes showed potential association with T2D (p<0.01). Tagging by Haploview was used to exclude 28 SNPs that were in high linkage disequilibrium (r>0.8). One SNP with an allele frequency below 0.05 was not genotyped. The resulting 10 SNPs in or near 6 OxPhos genes were genotyped in 3,139 T2D patients and 5,302 control individuals with normal glucose tolerance (NGT).

-- page break --

 

Results: We found that rs1466100 in COX5B (OR=1.67, p=0.004) and rs9915302 in COX10 (OR=1.14, p=0.02) were significantly associated with T2D. In a subsequent meta-analysis combining our results with data from an avaliable subset of the DIAGRAM data, we demonstrated that three SNPs (rs10775377, rs8077302, rs9915302) in COX10 and a SNP (rs2267584) in a gene (UPK1A) next to COX6B1 were significantly associated with T2D. In particular, the rs9915302 variant in COX10 showed strong association with T2D in the meta-analysis (OR=1.14, p=7.7 x 10-6). Analysis of quantitative traits, applying an additive model and adjusting for age and sex, revealed significant associations (p<0.05) between a surrogate marker (BIG-AIR) for insulin secretion and variants in COX5B (rs11904110) and COX10 (rs10521253), and between fasting p-glucose and a variant in COX5B (rs11904110) and 2-h post-OGTT plasma glucose and a variant in NDUFV3 (rs8134542) (p<0.05).

 

Conclusions: Our data suggest that genetic variants in or near subunits in complex IV (COX5B, COX6B1, COX10) contribute to the pathogenesis of T2D. The association of other variants in COX5B and COX10 and a variant in the complex I gene, NDUFV3, with markers of insulin secretion and postprandial hyperglycaemia supports a role for mitochondrial defects in beta-cell dysfunction in T2D. It does, however, not exclude a role for variants in OxPhos genes in the link between mitochondrial dysfunction and insulin resistance in skeletal muscle in T2D.

Original languageEnglish
Publication date2010
Number of pages1
Publication statusPublished - 2010
EventDansk Endokrinologisk Årsmøde - Herlev, København, Denmark
Duration: 22. Jan 201023. Jan 2010

Conference

ConferenceDansk Endokrinologisk Årsmøde
CountryDenmark
CityHerlev, København
Period22/01/201023/01/2010

Fingerprint

Type 2 Diabetes Mellitus
Single Nucleotide Polymorphism
Oxidative Phosphorylation
Meta-Analysis
Insulin Resistance
Skeletal Muscle
Insulin
Genome-Wide Association Study
Insulin-Secreting Cells
Glucose Tolerance Test
Hyperglycemia
Fasting

Keywords

  • Type 2 Diabetes Mellitus
  • genetics
  • Mitochondrial dysfunction

Cite this

Snogdal, L. S., Henriksen, J. E., Beck-Nielsen, H., Hansen, T., Pedersen, O., Grarup, N., ... Højlund, K. (2010). Genetic Variants Involved in Mitochondrial Oxidative Metabolism are associated with Type 2 Diabetes Mellitus in studies of 8,441 Danes. Abstract from Dansk Endokrinologisk Årsmøde, Herlev, København, Denmark.
Snogdal, Lena Sønder ; Henriksen, Jan Erik ; Beck-Nielsen, Henning ; Hansen, Torben ; Pedersen, Oluf ; Grarup, Niels ; Lauritzen, Torsten ; Sandbæk, Annelli ; Witte, Daniel Rinse ; Jørgensen, Torben ; Wod, Mette ; Vestmar, Marie ; Højlund, Kurt. / Genetic Variants Involved in Mitochondrial Oxidative Metabolism are associated with Type 2 Diabetes Mellitus in studies of 8,441 Danes. Abstract from Dansk Endokrinologisk Årsmøde, Herlev, København, Denmark.1 p.
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title = "Genetic Variants Involved in Mitochondrial Oxidative Metabolism are associated with Type 2 Diabetes Mellitus in studies of 8,441 Danes",
abstract = "  Aims: Type 2 Diabetes (T2D) is characterized by insulin resistance and failure of the pancreatic beta cells to compensate for this defect. Several studies have demonstrated a link between insulin resistance and impaired mitochondrial oxidative phosphorylation (OxPhos) in skeletal muscle. Recently, mitochondrial defects have also been implicated in beta-cell dysfunction in T2D. We hypothesized that single nucleotide polymorphisms (SNPs) in OxPhos genes could contribute to the pathogenesis of T2D.  Methods: Exploring results from a meta-analysis of genome wide association studies (GWAS) published by the Diabetes Genetics Replication And Meta-analysis Consortium (DIAGRAM), we found that among 1284 SNPs in 119 OxPhos genes, 39 SNPs in 7 genes showed potential association with T2D (p<0.01). Tagging by Haploview was used to exclude 28 SNPs that were in high linkage disequilibrium (r>0.8). One SNP with an allele frequency below 0.05 was not genotyped. The resulting 10 SNPs in or near 6 OxPhos genes were genotyped in 3,139 T2D patients and 5,302 control individuals with normal glucose tolerance (NGT).-- page break --  Results: We found that rs1466100 in COX5B (OR=1.67, p=0.004) and rs9915302 in COX10 (OR=1.14, p=0.02) were significantly associated with T2D. In a subsequent meta-analysis combining our results with data from an avaliable subset of the DIAGRAM data, we demonstrated that three SNPs (rs10775377, rs8077302, rs9915302) in COX10 and a SNP (rs2267584) in a gene (UPK1A) next to COX6B1 were significantly associated with T2D. In particular, the rs9915302 variant in COX10 showed strong association with T2D in the meta-analysis (OR=1.14, p=7.7 x 10-6). Analysis of quantitative traits, applying an additive model and adjusting for age and sex, revealed significant associations (p<0.05) between a surrogate marker (BIG-AIR) for insulin secretion and variants in COX5B (rs11904110) and COX10 (rs10521253), and between fasting p-glucose and a variant in COX5B (rs11904110) and 2-h post-OGTT plasma glucose and a variant in NDUFV3 (rs8134542) (p<0.05).  Conclusions: Our data suggest that genetic variants in or near subunits in complex IV (COX5B, COX6B1, COX10) contribute to the pathogenesis of T2D. The association of other variants in COX5B and COX10 and a variant in the complex I gene, NDUFV3, with markers of insulin secretion and postprandial hyperglycaemia supports a role for mitochondrial defects in beta-cell dysfunction in T2D. It does, however, not exclude a role for variants in OxPhos genes in the link between mitochondrial dysfunction and insulin resistance in skeletal muscle in T2D.",
keywords = "type 2 diabetes mellitus, genetik, Mitokondriel dysfunktion, Type 2 Diabetes Mellitus, genetics, Mitochondrial dysfunction",
author = "Snogdal, {Lena S{\o}nder} and Henriksen, {Jan Erik} and Henning Beck-Nielsen and Torben Hansen and Oluf Pedersen and Niels Grarup and Torsten Lauritzen and Annelli Sandb{\ae}k and Witte, {Daniel Rinse} and Torben J{\o}rgensen and Mette Wod and Marie Vestmar and Kurt H{\o}jlund",
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Snogdal, LS, Henriksen, JE, Beck-Nielsen, H, Hansen, T, Pedersen, O, Grarup, N, Lauritzen, T, Sandbæk, A, Witte, DR, Jørgensen, T, Wod, M, Vestmar, M & Højlund, K 2010, 'Genetic Variants Involved in Mitochondrial Oxidative Metabolism are associated with Type 2 Diabetes Mellitus in studies of 8,441 Danes', Dansk Endokrinologisk Årsmøde, Herlev, København, Denmark, 22/01/2010 - 23/01/2010.

Genetic Variants Involved in Mitochondrial Oxidative Metabolism are associated with Type 2 Diabetes Mellitus in studies of 8,441 Danes. / Snogdal, Lena Sønder; Henriksen, Jan Erik; Beck-Nielsen, Henning; Hansen, Torben; Pedersen, Oluf; Grarup, Niels; Lauritzen, Torsten; Sandbæk, Annelli; Witte, Daniel Rinse; Jørgensen, Torben; Wod, Mette; Vestmar, Marie; Højlund, Kurt.

2010. Abstract from Dansk Endokrinologisk Årsmøde, Herlev, København, Denmark.

Research output: Contribution to conference without publisher/journalConference abstract for conferenceResearch

TY - ABST

T1 - Genetic Variants Involved in Mitochondrial Oxidative Metabolism are associated with Type 2 Diabetes Mellitus in studies of 8,441 Danes

AU - Snogdal, Lena Sønder

AU - Henriksen, Jan Erik

AU - Beck-Nielsen, Henning

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Grarup, Niels

AU - Lauritzen, Torsten

AU - Sandbæk, Annelli

AU - Witte, Daniel Rinse

AU - Jørgensen, Torben

AU - Wod, Mette

AU - Vestmar, Marie

AU - Højlund, Kurt

N1 - Sider: 1

PY - 2010

Y1 - 2010

N2 -   Aims: Type 2 Diabetes (T2D) is characterized by insulin resistance and failure of the pancreatic beta cells to compensate for this defect. Several studies have demonstrated a link between insulin resistance and impaired mitochondrial oxidative phosphorylation (OxPhos) in skeletal muscle. Recently, mitochondrial defects have also been implicated in beta-cell dysfunction in T2D. We hypothesized that single nucleotide polymorphisms (SNPs) in OxPhos genes could contribute to the pathogenesis of T2D.  Methods: Exploring results from a meta-analysis of genome wide association studies (GWAS) published by the Diabetes Genetics Replication And Meta-analysis Consortium (DIAGRAM), we found that among 1284 SNPs in 119 OxPhos genes, 39 SNPs in 7 genes showed potential association with T2D (p<0.01). Tagging by Haploview was used to exclude 28 SNPs that were in high linkage disequilibrium (r>0.8). One SNP with an allele frequency below 0.05 was not genotyped. The resulting 10 SNPs in or near 6 OxPhos genes were genotyped in 3,139 T2D patients and 5,302 control individuals with normal glucose tolerance (NGT).-- page break --  Results: We found that rs1466100 in COX5B (OR=1.67, p=0.004) and rs9915302 in COX10 (OR=1.14, p=0.02) were significantly associated with T2D. In a subsequent meta-analysis combining our results with data from an avaliable subset of the DIAGRAM data, we demonstrated that three SNPs (rs10775377, rs8077302, rs9915302) in COX10 and a SNP (rs2267584) in a gene (UPK1A) next to COX6B1 were significantly associated with T2D. In particular, the rs9915302 variant in COX10 showed strong association with T2D in the meta-analysis (OR=1.14, p=7.7 x 10-6). Analysis of quantitative traits, applying an additive model and adjusting for age and sex, revealed significant associations (p<0.05) between a surrogate marker (BIG-AIR) for insulin secretion and variants in COX5B (rs11904110) and COX10 (rs10521253), and between fasting p-glucose and a variant in COX5B (rs11904110) and 2-h post-OGTT plasma glucose and a variant in NDUFV3 (rs8134542) (p<0.05).  Conclusions: Our data suggest that genetic variants in or near subunits in complex IV (COX5B, COX6B1, COX10) contribute to the pathogenesis of T2D. The association of other variants in COX5B and COX10 and a variant in the complex I gene, NDUFV3, with markers of insulin secretion and postprandial hyperglycaemia supports a role for mitochondrial defects in beta-cell dysfunction in T2D. It does, however, not exclude a role for variants in OxPhos genes in the link between mitochondrial dysfunction and insulin resistance in skeletal muscle in T2D.

AB -   Aims: Type 2 Diabetes (T2D) is characterized by insulin resistance and failure of the pancreatic beta cells to compensate for this defect. Several studies have demonstrated a link between insulin resistance and impaired mitochondrial oxidative phosphorylation (OxPhos) in skeletal muscle. Recently, mitochondrial defects have also been implicated in beta-cell dysfunction in T2D. We hypothesized that single nucleotide polymorphisms (SNPs) in OxPhos genes could contribute to the pathogenesis of T2D.  Methods: Exploring results from a meta-analysis of genome wide association studies (GWAS) published by the Diabetes Genetics Replication And Meta-analysis Consortium (DIAGRAM), we found that among 1284 SNPs in 119 OxPhos genes, 39 SNPs in 7 genes showed potential association with T2D (p<0.01). Tagging by Haploview was used to exclude 28 SNPs that were in high linkage disequilibrium (r>0.8). One SNP with an allele frequency below 0.05 was not genotyped. The resulting 10 SNPs in or near 6 OxPhos genes were genotyped in 3,139 T2D patients and 5,302 control individuals with normal glucose tolerance (NGT).-- page break --  Results: We found that rs1466100 in COX5B (OR=1.67, p=0.004) and rs9915302 in COX10 (OR=1.14, p=0.02) were significantly associated with T2D. In a subsequent meta-analysis combining our results with data from an avaliable subset of the DIAGRAM data, we demonstrated that three SNPs (rs10775377, rs8077302, rs9915302) in COX10 and a SNP (rs2267584) in a gene (UPK1A) next to COX6B1 were significantly associated with T2D. In particular, the rs9915302 variant in COX10 showed strong association with T2D in the meta-analysis (OR=1.14, p=7.7 x 10-6). Analysis of quantitative traits, applying an additive model and adjusting for age and sex, revealed significant associations (p<0.05) between a surrogate marker (BIG-AIR) for insulin secretion and variants in COX5B (rs11904110) and COX10 (rs10521253), and between fasting p-glucose and a variant in COX5B (rs11904110) and 2-h post-OGTT plasma glucose and a variant in NDUFV3 (rs8134542) (p<0.05).  Conclusions: Our data suggest that genetic variants in or near subunits in complex IV (COX5B, COX6B1, COX10) contribute to the pathogenesis of T2D. The association of other variants in COX5B and COX10 and a variant in the complex I gene, NDUFV3, with markers of insulin secretion and postprandial hyperglycaemia supports a role for mitochondrial defects in beta-cell dysfunction in T2D. It does, however, not exclude a role for variants in OxPhos genes in the link between mitochondrial dysfunction and insulin resistance in skeletal muscle in T2D.

KW - type 2 diabetes mellitus

KW - genetik

KW - Mitokondriel dysfunktion

KW - Type 2 Diabetes Mellitus

KW - genetics

KW - Mitochondrial dysfunction

M3 - Conference abstract for conference

ER -

Snogdal LS, Henriksen JE, Beck-Nielsen H, Hansen T, Pedersen O, Grarup N et al. Genetic Variants Involved in Mitochondrial Oxidative Metabolism are associated with Type 2 Diabetes Mellitus in studies of 8,441 Danes. 2010. Abstract from Dansk Endokrinologisk Årsmøde, Herlev, København, Denmark.