Genetic influence of sequence variants in SCARB1 and ABCA1 genes on major lipid traits: a candidate gene association study

Background: Abnormal lipid-lipoprotein levels are associated with the risk of coronary heart disease (CHD), a major public health problem worldwide. Scavenger receptor class B type 1 (SCARB1) and ATP-binding cassette transporter A1 (ABCA1) play important roles in the reverse cholesterol transport. We aimed to identify genetic variants in two lipid genes, SCARB1 and ABCA1, and elucidated their contribution to major lipid traits in two populations; Non-Hispanic Whites (NHWs) and African Blacks (ABs). Methods: We resequenced mainly the exons and exon-intron boundaries of SCARB1 and ABCA1 genes in 190 individuals (95 NHWs; 95 ABs) with extreme high-density lipoprotein cholesterol (HDL-C) levels, followed by genotyping of selected variants in the entire sample (623 NHWs; 788 ABs). Lipid associations were evaluated by multiple analyses. Results: Initial sequencing identified 105 SCARB1 (44/NHWs; 83/ABs) and 404 ABCA1 variants, including 58 novel ones (21 SCARB1; 37 ABCA1). Among genotyped variants, 159 SCARB1 (69/NHWs; 137/ABs) and 182 ABCA1 variants passed quality controls and were tested for associations. Gene-based tests revealed associations (P <0.05) of SCARB1 with HDL-C and apolipoprotein B (apoB), while ABCA1 demonstrated association with triglycerides (TG). Eleven common SCARB1 variants were nominally associated (P <0.05) with HDL-C or apoB in single-site analyses, and four of them (3/apoB/NHWs; 1/HDL-C/ABs) survived after multiple testing correction. The best signal of SCARB1 was rs4765615 (apoB/P = 0.0059) in NHWs and rs11057851 (HDL-C/P = 0.0043) in ABs. Twenty-one common ABCA1 variants were nominally associated with TG, and 16 remained significant after multiple testing correction. The best signal of ABCA1 with TG was rs2066716 (p.Thr14217Thr; P = 0.0016) in NHWs. A group of rare SCARB1 variants (frequency ≤1%) were associated with apoB (P = 0.0284) in NHWs, and HDL-C (P = 0.0478) in ABs. Several haplotypes and regions of SCARB1 and ABCA1 genes showed associations (global P