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

Ching Wei Tsai, Kari E. North, Adrienne Tin, Karin Haack, Nora Franceschini, V. Saroja Voruganti, Sandy Laston, Ying Zhang, Lyle G. Best, Jean W. MacCluer, Terri L Beaty, Ana Navas Acien, W. H Linda Kao, Barbara V. Howard

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E345-E349
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number2
DOIs
StatePublished - Feb 1 2015

    Fingerprint

Cite this

Tsai, C. W., North, K. E., Tin, A., Haack, K., Franceschini, N., Voruganti, V. S., Laston, S., Zhang, Y., Best, L. G., MacCluer, J. W., Beaty, T. L., Navas Acien, A., Kao, W. H. L., & Howard, B. V. (2015). Both rare and common variants in PCSK9 influence plasma low-density lipoprotein cholesterol level in American Indians. Journal of Clinical Endocrinology and Metabolism, 100(2), E345-E349. https://doi.org/10.1210/jc.2014-3340