PPARGC1A (PGC-1α) variation associated with DNA damage, diabetes and cardiovascular diseases: the Boston Puerto Rican Health Study

Abstract

Objective: Individuals with type 2 diabetes exhibit higher DNA damage and increased risk of cardiovascular disease (CVD). However, mechanisms underlying the association between DNA damage and development of type 2 diabetes and CVD are not understood. We sought to link peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PPARGC1A), a master transcriptional regulator of mitochondrial oxidative phosphorylation and cellular energy metabolism, with DNA damage, type 2 diabetes and CVD.

Research Design and Methods: We measured DNA damage as urinary 8-hydroxydeoxyguanosine (8-OHdG) concentration and examined the relationship between nine PPARGC1A genetic variants, DNA damage, type 2 diabetes, and self-reported CVD in 959 participants of the Boston Puerto Rican Health Study.

Results: With respect to urinary 8-OHdG, PPARGC1A variants showed significant association, whereas PPARGC1A haplotypes exhibited significant association after correction for multiple testing. Two independent PPARGC1A variants associated significantly with type 2 diabetes (OR=1.35 and 2.46, P=0.045 and <0.001). Carriers of minor alleles of two other PPARGC1A variants, both in strong LD and associated with lower DNA damage, showed lower prevalence of CVD (OR=0.53 and 0.65, P=0.030 and 0.175). Moreover, we found that physical activity correlated negatively with DNA damage.

Conclusions: Low physical activity combined with risk haplotyes plausibly forms the basis for the high prevalence of type 2 diabetes in this population. We propose that PPARGC1A influences development of type 2 diabetes and CVD via DNA damage. Increasing physical activity, which induces PPARGC1A expression, is a potential strategy to slow DNA damage, thereby decreasing the risk of CVD for individuals with type 2 diabetes.