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

J Clin Endocrinol Metab. 2015 Feb;100(2):E345-9. doi: 10.1210/jc.2014-3340. Epub 2014 Nov 20.


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 (r(2) = 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Cholesterol, LDL / blood*
  • Female
  • Genetic Variation*
  • Genotype
  • Humans
  • Indians, North American / genetics*
  • Male
  • Middle Aged
  • Mutation
  • Polymorphism, Single Nucleotide
  • Proprotein Convertase 9
  • Proprotein Convertases / genetics*
  • Serine Endopeptidases / genetics*
  • Young Adult


  • Cholesterol, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases