Ching-Wei Tsai1, Kari E North, Adrienne Tin, Karin Haack, Nora Franceschini, V Saroja Voruganti, Sandy Laston, Ying Zhang, Lyle G Best, Jean W MacCluer, Terri H Beaty, Ana Navas-Acien, W H Linda Kao, Barbara V Howard. 1. Departments of Epidemiology (C.-W.T., A.T., T.H.B., A.N.-A., W.H.L.K.) and Environmental Health Sciences (A.N.-A.), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Department of Epidemiology (K.E.N., N.F.), University of North Carolina, Chapel Hill, North Carolina; Department of Genetics (K.H., S.L., J.W.M.), Texas Biomedical Research Institute, San Antonio, Texas; Department of Nutrition and University of North Carolina Nutrition Research Institute (V.S.V.), University of North Carolina at Chapel Hill, Kannapolis, North Carolina; Center for American Indian Health Research (Y.Z.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Missouri Breaks Industries Research, Inc. (L.G.B.), Timber Lake, South Dakota; The Welch Center for Prevention (A.N.-A., W.H.L.K.), Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland; MedStar Health Research Institute (B.V.H.), Hyattsville, Maryland; Georgetown and Howard Universities Center for Clinical and Translational Science (B.V.H.), Washington, D.C.; Kidney Institute and Division of Nephrology, Department of Internal Medicine (C.-W.T.), China Medical University Hospital, Taichung, Taiwan.
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 (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.
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.
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