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PPARGC1A Variation Associated With DNA Damage, Diabetes, and Cardiovascular Diseases

The Boston Puerto Rican Health Study

¹ Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
² Dietary Assessment and Epidemiology Research Program, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
³ Biostatistics Research Center, Tufts New England Medical Center, Boston, Massachusetts
⁴ Vascular Biology Laboratory JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts

Address correspondence and reprint requests to Chao-Qiang Lai, Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St., Boston, MA 02111. E-mail: chaoqiang.lai{at}ars.usda.gov

Key Words: 8-OHdG, 8-hydroxydeoxyguanosine • 8-OHG, 8-hydroxyguanosine • AGE, advanced glycation end product • CRP, C-reactive protein • CVD, cardiovascular disease • GPX1, glutathione peroxidase 1 • HNF4A, hepatocyte nuclear factor 4 • mtDNA, mitochondrial DNA • NIH, National Institutes of Health • PPARGC1A, peroxisome proliferator-activated receptor- coactivator-1 • ROS, reactive oxygen species • SNP, single nucleotide polymorphism • SOD2, superoxide dismutase 2

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- coactivator-1 (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, and PPARGC1A haplotypes exhibited significant association after correction for multiple testing. Two independent PPARGC1A variants associated significantly with type 2 diabetes (odds ratios [ORs] 1.35 and 2.46; P = 0.045 and <0.001). Carriers of minor alleles of two other PPARGC1A variants, both in strong linkage disequilibrium and associated with lower DNA damage, showed lower prevalence of CVD (ORs 0.53 and 0.65; P = 0.030 and 0.175). Moreover, we found that physical activity correlated negatively with DNA damage.

CONCLUSIONS—It is plausible that low physical activity combined with risk haplotyes contribute to 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.

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