Submitted on March 19, 2008
Revised on April 18, 2008
Accepted on May 4, 2008
The Gly482Ser genotype at the PPARGC1A gene and elevated blood pressure: a meta-analysis of 13,949 individuals
Karani S Vimaleswaran, Jian'an Luan, Gitte Andersen, Y. Li Muller, Eleanor Wheeler, Ema C Brito, Stephen O'Rahilly1, Oluf Pedersen, Leslie J. Baier, William C Knowler, Ines Barroso, Nicholas J. Wareham, Ruth JF Loos2, and Paul W Franks PhD3*
1 Cambridge University
2 MRC Epidemiology
3 MRC Epidemiology Unit
* To whom correspondence should be addressed. E-mail: paul.franks{at}medicin.umu.se.
The PPARGC1A gene product is expressed at high levels in metabolically active tissues and controls oxidative stress via reactive oxygen species detoxification. Recent reports suggest that the PPARGC1A Gly482Ser (rs8192678) missense polymorphism may relate inversely with blood pressure. We used meta-analysis to assess associations between Gly482Ser and systolic (SBP) or diastolic (DBP) blood pressures or hypertension in 13,949 individuals from 17 studies, of which 6,042 were previously unpublished observations. The cohorts included White European adults, Asian and American Indian adults, and South American adolescents. Ethnicity-stratified analyses were conducted to control for population-stratification. Pooled genotype frequencies were 0.47 (Gly482Gly), 0.42 (Gly482Ser) and 0.11 (Ser482Ser). We found no evidence of association between Gly482Ser and SBP (P=0.409) or DBP (P=0.651), nor of genotype-sex interactions (SBP, Pinteraction=0.966; DBP, Pinteraction=0.715), as reported elsewhere. We were also unable to confirm the previously reported association between the Ser482 allele and hypertension (odds ratio: 0.97,95% CI=0.87-1.08,P=0.585). Results were materially unchanged when analyses were focused on Whites. However, statistical evidence of gene-age interaction was apparent (DBP: Pinteraction<0.0001; SBP: Pinteraction=0.026); in younger individuals (<50yrs; n=2511) the 482Ser allele was associated with higher DBP (P=4.20x10-12) and SBP (P=7.20x10-12), but no association was evident in those older than 50yrs (n=5088) (SBP, P=0.41; DBP, P=0.51). Our findings suggest that the PPARGC1A Gly482Ser genotype may be associated with higher blood pressure, but this is only apparent in younger adults. Such interactions may be driven by the modifying effects of age-specific environmental exposures such as diet or physical activity levels.
