Related Experiment Video
Updated: Apr 20, 2026

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Both rare and common variants in PCSK9 influence plasma low-density lipoprotein cholesterol level in American Indians
Ching-Wei Tsai1, Kari E North, Adrienne Tin
1Departments 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.
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.
More Related Videos
Related Concept Videos
Principles of Pharmacogenetics: Types of Genetic Variants
Pharmacogenomics: Identification of New Drug Targets
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters
Comparing Copy Number Variations and SNPs
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...
Coronary Artery Disease IV: Preventive Measures

