Investigating the Effect of PCSK9 Variants on Plasma Lipid Profile in African Blacks and U.S. Whites

In the United States, cardiovascular disease (CVD) is the leading cause of death and is a major public health issue. A combination of genetic and environmental factors leads to an increased risk of CVD—specifically, abnormal plasma lipid levels. Familial Hypercholesterolemia (FH) is a genetic condition that greatly increases the risk of CVD due to excess low-density lipoprotein cholesterol (LDL-C) in blood. Autosomal dominant mutations in the LDLR, APOB, and PCSK9 genes cause FH. PCSK9 mutations are the most rare and unique. Studies have found that PCSK9 gain-of-function mutations result in FH, while loss-of-function mutations result in low plasma LDL-C levels. Results from PCSK9 research aided in the creation of PCSK9 inhibitors as a new therapy for FH. In this study, we sought to confirm the relationship between PCSK9 variants and plasma lipid levels in two population-based samples not previously investigated for PCSK9 variants. Study samples are composed of 788 African Blacks from Nigeria and 623 non-Hispanic Whites (NHWs) from the United States. PCSK9 genotyping was completed using genome-wide chip followed by genotype-phenotype association analyses for total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Of the 93 genotyped SNPs in the PCSK9 region, 60 SNPs showed variations in either African Blacks (37), NHWs (4), or both (19). Seven SNPs in African Blacks and two SNPs in NHWs showed significant genotype associations with a least one lipid trait. In African Blacks, two SNPs were associated with TC, two with TG, two with HDL-C, and four with LDL-C. In NHWs, one SNP showed association with HDL-C, and one with TC. One previously identified gain-of-function variant was present in three African Black subjects (Phe216Leu) and one of them had the lipid profile of FH. In conclusion, this study successfully investigated the distribution pattern of PCSK9 allele frequencies and their associations with plasma lipid profile in two previously uncharacterized populations. The relationship between Phe216Leu and abnormal lipid levels in one African Black subject appears to confirm its association with FH