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Association of genetic variation in the mitochondrial genome with blood pressure and metabolic traits.

ABSTRACT: Elevated blood pressure (BP) is a major risk factor for cardiovascular disease. Several studies have noted a consistent maternal effect on BP; consequently, mitochondrial DNA variation has become an additional target of investigation of the missing BP heritability. Analyses of common mitochondrial DNA polymorphisms, however, have not found evidence of association with hypertension. To explore associations of uncommon (frequency>5%) mitochon drial DNA variants with BP, we identified uncommon/rare variants through sequencing the entire mitochondrial genome in 32 unrelated individuals with extreme-high BP in the Framingham Heart Study and genotyped 40 mitochondrial single nucleotide polymorphisms in 7219 Framingham Heart Study participants. The nonsynonymous mitochondrial single nucleotide polymorphism 5913G>A (Asp4Asn) in the cytochrome c oxidase subunit 1 of respiratory complex IV demonstrated significant associations with BP and fasting blood glucose (FBG) levels. Individuals with the rare 5913A allele had, on average, 7-mm Hg higher systolic BP at baseline (Pempirical=0.05) and 17-mg/dL higher mean FBG over 25 years of follow-up (Pempirical=0.009). Significant associations with FBG levels were also detected for nonsynonymous mitochondrial single nucleotide polymorphism 3316G>A (Ala4Thr) in the NADH dehydrogenase subunit 1 of complex I. On average, individuals with rare allele 3316A had 17- and 25-mg/dL higher FBG at baseline (Pempirical=0.01) and over 25 years of follow-up (Pempirical=0.007). Our findings provide the first evidence of putative association of variants in the mitochondrial genome with systolic BP and FBG in the general population. Replication in independent samples, however, is needed to confirm these putative associations.

SUBMITTER: Liu C

PROVIDER: S-EPMC3753106 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Association of genetic variation in the mitochondrial genome with blood pressure and metabolic traits.

Liu Chunyu C Yang Qiong Q Hwang Shih-Jen SJ Sun Fengzhu F Johnson Andrew D AD Shirihai Orian S OS Vasan Ramachandran S RS Levy Daniel D Schwartz Faina F

Hypertension (Dallas, Tex. : 1979) 20120904 4

Elevated blood pressure (BP) is a major risk factor for cardiovascular disease. Several studies have noted a consistent maternal effect on BP; consequently, mitochondrial DNA variation has become an additional target of investigation of the missing BP heritability. Analyses of common mitochondrial DNA polymorphisms, however, have not found evidence of association with hypertension. To explore associations of uncommon (frequency>5%) mitochon drial DNA variants with BP, we identified uncommon/rare ...[more]

PMID: 22949535

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Project description:BackgroundMitochondria play a critical role in the cell and have DNA independent of the nuclear genome. There is much evidence that mitochondrial DNA (mtDNA) variation plays a role in human health and disease, however, this area of investigation has lagged behind research into the role of nuclear genetic variation on complex traits and phenotypic outcomes. Phenome-wide association studies (PheWAS) investigate the association between a wide range of traits and genetic variation. To date, this approach has not been used to investigate the relationship between mtDNA variants and phenotypic variation. Herein, we describe the development of a PheWAS framework for mtDNA variants (mt-PheWAS). Using the Metabochip custom genotyping array, nuclear and mitochondrial DNA variants were genotyped in 11,519 African Americans from the Vanderbilt University biorepository, BioVU. We employed both polygenic modeling and association testing with mitochondrial single nucleotide polymorphisms (mtSNPs) to explore the relationship between mtDNA variants and a group of eight cardiovascular-related traits obtained from de-identified electronic medical records within BioVU.ResultsUsing polygenic modeling we found evidence for an effect of mtDNA variation on total cholesterol and type 2 diabetes (T2D). After performing comprehensive mitochondrial single SNP associations, we identified an increased number of single mtSNP associations with total cholesterol and T2D compared to the other phenotypes examined, which did not have more significantly associated SNPs than would be expected by chance. Among the mtSNPs significantly associated with T2D we identified variant mt16189, an association previously reported only in Asian and European-descent populations.ConclusionsOur replication of previous findings and identification of novel associations from this initial study suggest that our mt-PheWAS approach is robust for investigating the relationship between mitochondrial genetic variation and a range of phenotypes, providing a framework for future mt-PheWAS.

Dataset Information

Association of genetic variation in the mitochondrial genome with blood pressure and metabolic traits.

Publications

Association of genetic variation in the mitochondrial genome with blood pressure and metabolic traits.

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