Both rare and common variants in PCSK9 influence plasma low-density lipoprotein cholesterol level in American Indians. J Clin Endocrinol Metab. 2014 Nov 20, Tsai CW1, North KE, Tin A, Haack K, Franceschini N, Saroja Voruganti V (UNC Nutrition Research Institute), Laston S, Zhang Y, Best LG, MacCluer JW, Beaty TH, Navas-Acien A, Linda Kao WH,Howard BV.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD;
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: Strong Heart Family Study (SHFS) is a family-based genetic study. Participants: 2,458 American Indians from Arizona, OK and North 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 2458American 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). Forrare 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.