Peroxisome Proliferator-Activated Receptor-γ Coactivator 1-α (PPARGC1A) Genetic Associations with Type 2 Diabetes in Three Ethnicities

Genetic heterogeneity, lifestyle factors, gene-gene or gene-environment interactions are the determinants of T2D which puts Hispanics and populations with African ancestry at higher risk of developing T2D. In this dissertation, the genetic associations of PPARGC1A polymorphisms with T2D and its related phenotypes (metabolic markers) in Haitian Americans (cases=110, controls=116), African Americans (cases=120, controls=124) and Cuban Americans (cases=160, controls=181) of South Florida were explored. Five single nucleotide polymorphisms of gene PPARGC1A were evaluated in each ethnicity for their disease association. In Haitian Americans, rs7656250 (OR= 0.22, pp=0.03) had significant protective association with T2D but had risk association in African Americans for rs7656250 (OR=1.02, p=0.96) and rs4235308 (OR=2.53, p=0.03). We found that in Haitian American females, both rs7656250 (OR=0.23, pp=0.03) had protective association with T2D. In African American females, rs7656250 (OR=1.14, p=0.78) had risk association whereas in males, it had significant protective effect (OR=0.37, p=0.04). However, the risk association exhibited by rs4235308 was stronger in African American females (OR=2.69, p=0.03) than males (OR=1.16, p=0.72). In Cuban Americans, only rs7656250 showed significant risk association with T2D (OR=6.87, p=0.02) which was stronger in females alone (OR=7.67, p=0.01). We also observed significant differences among correlations of PPARGC1A SNPs and T2D phenotypes. Positive correlation was observed for log Hs-CRP with rs3774907 (pp=0.03) in Cuban Americans respectively. Correlation of log A1C with rs7656250 (p=0.02) was positive in Cuban Americans while it was negative for rs3774907 in Haitian Americans (ppPPARGC1A correlations with T2D and its phenotypes among the three ethnicities studied (ii) the associations of PPARGC1A SNPs showed significant effect modification by sex. The findings suggest that variations in effects of PPARGC1A gene polymorphisms among three ethnicities and between sexes may have biomedical implications for the development of T2D as well as the phenotypes related to T2D.

The relationship among serum levels of manganese superoxide dismutase and mtDNA 8-hydroxy-2'-deoxyguanosine, and dietary antioxidants intake in Type 2 Diabetes

Oxidative stress plays a key role in the development of Type 2 Diabetes (T2D). This cross-sectional study examined the relationship among serum levels of manganese superoxide dismutase (MnSOD), 8-hydroxy-2’-deoxyguanosine (8OHdG), dietary antioxidant intakes and glycemic control in African Americans (n=209) and Haitian Americans (n=234) with and without T2D. African Americans had higher BMI (32.8 vs. 29.3 kg/m2), higher energy intake (2148 vs. 1770 kcal), and were more educated as compared to Haitian Americans; all variables were significant at p < .001. Serum levels of 8OHdG and MnSOD for African Americans (1691.0 ± 225.1 pg/ml, 2538.0 ± 1091.8 pg/ml; respectively) were significantly higher than for Haitian Americans (1626.2 ± 222.9, 2015.8 ± 656.3 pg/ml; respectively). 8OHdG was negatively correlated with MnSOD (r = -.167, p < .001) in T2D. Having T2D was negatively correlated with MnSOD (r = -.337; p < .01) and positively correlated with 8OHdG (r = .500; p < .01). African Americans and Haitian Americans with T2D had fasting plasma glucose (FPG) levels of 143.0 ± 61.0 mg/dl and 157.6 ± 65.5 mg/dl, and A1C of 7.5 ± 1.8 % and 8.4 ± 2.4 %, respectively. African Americans and Haitian Americans without T2D had FPG levels of 95.8 ± 13.2 mg/dl and 98.7 ± 16.9 mg/dl, and A1C of 5.9 ± 0.4% and 6.0 ± 0.5%, respectively. Dietary intakes of vitamin C and vitamin D were negatively correlated with FPG (r = -.21; r = -.19, p < .05) respectively. Carotenoids negatively correlated with A1C (r = -.19, p < .05). Lower levels of MnSOD were associated with lower levels of zinc, r = .10, p < .05, and higher levels of carotenoids r = -.10, p < .05. Higher levels of 8OHdG were associated with lower levels of Vitamin D, r = -.14, p < .01, and carotenoids, r = -.09, p < .05. The results demonstrate greater oxidative mtDNA damage in persons with T2D compared to those without T2D and in African Americans compared with Haitian Americans. The inverse relationship between dietary intake of antioxidants and oxidative stress implies a potential to reduce oxidative stress with diet. African Americans were significantly younger (53.3 vs. 55.6 years), had higher BMI (32.8 vs. 29.3 kg/m2), higher energy intake (2148 vs. 1770 kcal), and were more educated as compared to Haitian Americans; all variables were significant at p < .001. Serum levels of 8OHdG and MnSOD for African Americans (1691.0 ± 225.1 pg/ml, 2538.0 ± 1091.8 pg/ml; respectively) were significantly higher than for Haitian Americans (1626.2 ± 222.9, 2015.8 ± 656.3 pg/ml; respectively). 8OHdG was negatively correlated with MnSOD (r = -.167, p < .001) in T2D. Having T2D was negatively correlated with MnSOD (r = -.337; p < .01) and positively correlated with 8OHdG (r = .500; p < .01). African Americans and Haitian Americans with T2D had fasting plasma glucose (FPG) levels of 143.0 ± 61.0 mg/dl and 157.6 ± 65.5 mg/dl, and A1C of 7.5 ± 1.8 % and 8.4 ± 2.4 %, respectively. African Americans and Haitian Americans without T2D had FPG levels of 95.8 ± 13.2 mg/dl and 98.7 ± 16.9 mg/dl, and A1C of 5.9 ± 0.4% and 6.0 ± 0.5%, respectively. Dietary intakes of vitamin C and vitamin D were negatively correlated with FPG (r = -.21; r = -.19, p < .05) respectively. Carotenoids negatively correlated with A1C (r = -.19, p < .05). Lower levels of MnSOD were associated with lower levels of zinc, r = .10, p < .05, and higher levels of carotenoids r = -.10, p < .05. Higher levels of 8OHdG were associated with lower levels of Vitamin D, r = -.14, p < .01, and carotenoids, r = -.09, p < .05. The results demonstrate greater oxidative mtDNA damage in persons with T2D compared to those without T2D and in African Americans compared with Haitian Americans. The inverse relationship between dietary intake of antioxidants and oxidative stress implies a potential to reduce oxidative stress with diet.