TY - JOUR
T1 - Both rare and common variants in PCSK9 influence plasma low-density lipoprotein cholesterol level in American Indians
AU - Tsai, Ching Wei
AU - North, Kari E.
AU - Tin, Adrienne
AU - Haack, Karin
AU - Franceschini, Nora
AU - Voruganti, V. Saroja
AU - Laston, Sandy
AU - Zhang, Ying
AU - Best, Lyle G.
AU - MacCluer, Jean W.
AU - Beaty, Terri H.
AU - Navas-Acien, Ana
AU - Kao, W. H.Linda
AU - Howard, Barbara V.
N1 - Publisher Copyright:
Copyright © 2015 by the Endocrine Society.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - 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.
AB - 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.
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U2 - 10.1210/jc.2014-3340
DO - 10.1210/jc.2014-3340
M3 - Article
C2 - 25412415
AN - SCOPUS:84928332471
VL - 100
SP - E345-E349
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 2
ER -