Abstract 21122: Contribution of ABCA1 Genetic Variation to Plasma Lipid Levels in Non-Hispanic White Americans

Introduction: Dyslipidemia [i.e., elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG); decreased level of high-density lipoprotein cholesterol (HDL-C)] is one of the risk factors for cardiovascular disease (CVD). Genetics play an important role in inter-individual variation of lipid levels. ATP-binding cassette A1 (ABCA1), a membrane transporter, mediates cellular phospholipid and cholesterol efflux. Mutations in ABCA1 gene cause Tangier’s disease (OMIM #205400) presented with HDL-C deficiency, as well as, increased risk for developing CVD. In this study, we aimed to identify both common [minor allele frequency (MAF)≥5%] and uncommon (MAF<5%) variants of ABCA1 associated with inter-individual variation in major lipid traits. Methods: We resequenced 50 exons and exon-intron boundaries of ABCA1 in a selected set of 95 individuals with extreme HDL-C levels (≤10 th and ≥90 th %tile), and subsequently genotyped selected variants in the entire sample of 623 US Non-Hispanic Whites. With resequencing, we identified 404 variants, and for genotyping we selected 250 variants (216 from sequencing data, 34 from HapMap-CEU data). A total of 182 successfully genotyped and QC-passed bi-allelic variants were tested for association with plasma lipid levels. Results: Gene-based test showed evidence of association between ABCA1 and TG ( p =0.0108). Single-site association analyses demonstrated 26 common variants nominally associated ( p <0.05) with at least one lipid trait. After multiple testing correction, two variants [rs4743763 with TC levels, p =0.0005; rs2066716 (Thr1427Thr) with TG levels, p =0.0016] remained significant. Furthermore, rs2066716 (Thr1427Thr) was among 11 out of 26 lipid-associated ABCA1 variants for which the replication data were available in an independent sample ( n =744) and it remained significantly associated with TG levels in the meta-analysis (meta- p =0.0088). Rare variant analyses revealed association of multiple sets of rare variants with lipid traits. Conclusions: Our findings support the genetic contribution of ABCA1 , both common and rare variants, to lipid levels in humans.