TY  - BOOK
AU  - Howard, Barbara V
TI  - Both rare and common variants in PCSK9 influence plasma low-density lipoprotein cholesterol level in American Indians
SN  - 0021-972X
KW  - *Cholesterol, LDL/bl [Blood]
KW  - *Genetic Variation
KW  - *Indians, North American/ge [Genetics]
KW  - *Proprotein Convertases/ge [Genetics]
KW  - *Serine Endopeptidases/ge [Genetics]
KW  - Adult
KW  - Female
KW  - Genotype
KW  - Humans
KW  - Male
KW  - Middle Aged
KW  - Mutation
KW  - Polymorphism, Single Nucleotide
KW  - Young Adult
KW  - MedStar Health Research Institute
KW  - Journal Article
KW  - Research Support, N.I.H., Extramural
N1  - Available online through MWHC library: 1999- June 2013, Available in print through MWHC library: 1999 - 2006
N2  - 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; 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; DESIGN: The Strong Heart Family Study (SHFS) is a family-based genetic study; OBJECTIVE: We aimed to investigate the genetic architecture in the 1p32 region encompassing PCSK9 and its influence on LDL-C in American Indians; 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 %, beta = 16.9 +/- 3.7, P = 5.9 x 10(-6)) was in complete LD (r(2) = 1) with a nearby missense SNP, rs505151 (E670G) (beta = 15.0 +/- 3.6, P = 3.6 x 10(-5)). For rare variants (MAF < 1%), rs11591147 (R46L, MAF = 0.9%) was associated with lower LDL-C (beta = - 31.1 +/- 7.1, P = 1.4 x 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
UR  - http://dx.doi.org/10.1210/jc.2014-3340
ER  -