The genetics of obesity-related traits and lipoproteins in Filipino women

The underlying genetic component of risk factors for cardiovascular disease (CVD) is not well understood. Recently, advances in high-throughput genotyping, single nucleotide polymorphism (SNP) discovery, and the development of databases such as the International Haplotype Map (HapMap) have provided scientists with tools to complete a genetic analysis of complex diseases such as CVD. Research presented in this dissertation aims to further understand the genetics of obesity-related traits and lipoprotein levels and identify variants that are associated with these traits in a cohort of adult women from metro Cebu, Philippines, who participated in the Cebu Longitudinal Health and Nutrition Survey (CLHNS). Initially I assess the transferability of tag SNPs chosen from HapMap panels to the CLHNS. I show that the Asian HapMap samples are an effective resource for studies in the CLHNS. I then investigate the association between 19 candidate variants in 10 genes previously reported to be associated with obesity-related traits with similar traits in the CLHNS. We observe evidence for association with the A-allele of rs9939609 of FTO and ADRB3 Trp64-allele with obesity traits. I perform a genome-wide association study for HDL-C, triglycerides, LDL-C, and total cholesterol. Among ~2 million SNPs analyzed, we observe evidence of association for 11 loci previously described. We observe suggestive evidence of trait association (P <10-5) for Tankyrase (TNKS) with LDL-C and Collecting-12 (COLEC12) with total cholesterol. In a separate study, I investigate an HDL-C associated locus, GALNT2, to identify functional variants responsible for the association signal. I identify variants in moderate linkage disequilibrium (r2 >.5) with HDL-C associated SNPs, clone regions that have suggestive regulatory function into a luciferase reporter vector, and measure transcriptional activity in HepG2 cells. The results suggest that a 21 bp deletion, rs4849913, and/or rs2144300 may act to increase the transcriptional activity of GALNT2 or an unknown novel intronic transcript to increase HDL-C. These studies present the first genetic study of CVD traits in the CLHNS and a molecular study of a gene that is associated with HDL-C. Together this research provides a solid foundation for one day identifying the molecular mechanism underlying complex diseases.