|Institution:||University of Michigan|
|Keywords:||genetics; epigenetics; Genetics; Public Health; Health Sciences; Science|
|Full text PDF:||http://hdl.handle.net/2027.42/111569|
Complex diseases, such as cardiovascular disease (CVD), are caused by combination and interaction of various factors. The goal of this dissertation is to provide insight into the mechanisms of CVD by combining information of genetic, epigenetic, and environmental factors. Aim 1 examines the effect modification by vitamin D receptor (VDR) genetic polymorphisms in the association between bone lead levels and pulse pressure in older unrelated non-Hispanic White men (Normative Aging Study). Aim 2 studies the mediating effect of DNA methylation in the association between cigarette smoking and inflammation in older African American siblings (Genetic Epidemiology Network of Arteriopathy (GENOA)) using two-step epigenetic Mendelian randomization (MR) approaches. Aim 3 investigates the role of DNA methylation in cigarette smoking, inflammation, and subclinical markers of CVD in older African American siblings (GENOA) using network MR approaches. In Aim 1, we found that subjects with the minor frequency alleles of VDR Bsm1 or Taq1 may be more susceptible to cumulative lead exposure-related elevated pulse pressure. Adjusting for potential confounders, pulse pressure was 2.5 mmHg (95% CI: 0.4-4.7) and 1.9 mmHg (95% CI: 0.1-3.8) greater per interquartile range increase in tibia lead (15??g/g) and patella lead (20 ??g/g), respectively, in those with at least one minor frequency allele in Bsm1 compared with the others. In Aim 2, we identified that the odds ratio for current smoking was 1.96 for a one-unit increase in rs4887071 which results in 0.44 decrease in M-values of cg03636183 on F2RL3 gene, and a 5% increase in interleukin-18 (IL-18) levels (pg/ml), and results in 0.09 decrease in M-values of cg13500388 on CBFB gene and a 3% increase in C-reactive protein (CRP) levels (mg/L). In Aim 3, we found that the indirect effect from smoking to log(IL-18) levels mediated by cg03636183 on F2RL3 gene. The indirect path had a significant effect on left ventricular mass index (LVMI). In summary, results suggest that VDR-related calcium metabolism pathways and DNA methylation play a role in adverse effects of cumulative lead exposure and cigarette smoking, respectively, on CVD. These findings together expand our understanding of mechanisms behind CVD development and can inform future studies.