|Lai, Chao Qiang|
Submitted to: Diabetes
Publication Type: Review Article
Publication Acceptance Date: 12/19/2007
Publication Date: 4/1/2008
Citation: Lai, C., Tucker, K., Parnell, L.D., Adiconis, X., Garcia-Bailo, B., Griffith, J., Meydani, M., Ordovas, J.M. 2008. PPARGC1A Variations Associated with DNA Damage, Diabetes, and Cardiovascular Diseases: The Boston Puerto Rican Study. Diabetes. 57:809-816.
Technical Abstract: Technical Abstract Type 2 diabetes, a major risk factor for cardiovascular disease (CVD) and other age-related ailments, affects over 200 million people worldwide. Patients with type 2 diabetes exhibit higher levels of oxidative DNA damage measured as 8-OHdG concentration in leukocytes or urine. However, the mechanism underlying the development of type 2 diabetes is not yet understood, nor how that mechanism relates to DNA damage and CVD risk. Peroxisome proliferator-activated receptor-' coactivator-1 alpha (PGC-1a or PPARGC1A) is a master transcriptional regulator of a series of nuclear receptors including HNF4A and PPAR, controlling mitochondrial oxidative phosphorylation and cellular energy metabolism. We examined the relationship between PGC-1a genetic variation, DNA damage, type 2 diabetes, and CVD in 959 participants of the Boston Puerto Rican Health Study. In this population, physical activity and current smoking correlated negatively and positively with DNA damage, respectively. Our results demonstrate that PGC-1a SNPs and haplotypes are significantly associated with urinary 8-OHdG and plasma CRP. Furthermore, two independent PGC-1a variants and their haplotypes associated with a greater prevalence of type 2 diabetes (OR=1.4 and 2.6, P=0.030 and <0.0001). Conversely, two other PGC-1a variants associating with reduced levels of DNA damage and CRP also associated with a lower prevalence of CVD (OR=0.502, P=0.0198). We propose that PGC-1a, via DNA damage, influences development of type 2 diabetes and increases CVD risk for type 2 diabetes patients. Thus, increasing physical activity, which induces expression of PGC-1a, is a potential strategy to slow DNA damage, thereby decreasing the risk of CVD for type 2 diabetics.