Both rare and common variants in PCSK9 influence plasma low-density lipoprotein cholesterol level in American Indians

Context: Elevated LDL cholesterol (LDL-C) is an important risk factor for atherosclerosis and cardiovascular disease. Variants in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene have been associated not only with plasma LDL-C concentration, but also with ischemic heart disease. Little is known about the genetic architecture of PCSK9 and its influence on LDL-C in American Indians. Objective: We aimed to investigate the genetic architecture in the 1p32 region encompassing PCSK9 and its influence on LDL-C in American Indians. Design: The Strong Heart Family Study (SHFS) is a family-based genetic study. Participants: Two thousand four hundred fifty eight American Indians from Arizona, Oklahoma, North Dakota, and South Dakota, who were genotyped by Illumina MetaboChip. Results: We genotyped 486 SNPs in a 3.9 Mb region at chromosome 1p32 encompassing PCSK9 in 2458 American Indians. We examined the association between these SNPs and LDL-C. For common variants (MAF ≥ 1%), meta-analysis across the three geographic regions showed common variants in PCSK9 were significantly associated with higher LDL-C. The most significant SNP rs12067569 (MAF = 1.7 %, β= 16.9 ± 3.7, P = 5.9 × 10^-6) was in complete LD (r² = 1) with a nearby missense SNP, rs505151 (E670G) (β= 15.0 ± 3.6, P = 3.6 × 10^-5). For rare variants (MAF <1%), rs11591147 (R46L, MAF = 0.9%) was associated with lower LDL-C (β= - 31.1 ± 7.1, P = 1.4 × 10^-5). The mean (SD) of LDL-C was 76.9 (7.8) and 107.4(1.0) mg/dL for those with and without the R46L mutation, respectively. One person who was homozygous for R46L had LDL-C levels of 11 mg/dL. In one family, 6 out of 8 members carrying the R46L mutation had LDL-C levels below the lower 10% percentile of LDL-C among all study participants. Conclusions: Both rare and common variants in PCSK9 influence plasma LDL-C levels in American Indians. Follow-up studies may disclose the influence of these mutations on the risk of CVD and responses to cholesterol-lowering medications.