title: 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.
authors.affiliation: National Heart, Lung, and Blood Institute’s Framingham Heart Study, 73 Mt Wayte Ave, Suite 2, Framingham, MA 01702, USA. fschw@bu.edu
authors.forename: Chunyu
authors.initials: C
authors.lastname: Liu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Fengzhu
authors.initials: F
authors.lastname: Sun
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.forename: Faina
authors.initials: F
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000483:Alleles; D001794:Blood Pressure / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D054629:Genome, Mitochondrial / Q000235:genetics*; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D004272:DNA, Mitochondrial