AUTHOR=Tran Ngan T. , Aslibekyan Stella , Tiwari Hemant K. , Zhi Degui , Sung Yun Ju , Hunt Steven C. , Rao DC , Broeckel Ulrich , Judd Suzanne E. , Muntner Paul , Kent Shia T. , Arnett Donna K. , Irvin Marguerite R. 

TITLE=PCSK9 variation and association with blood pressure in African Americans: preliminary findings from the HyperGEN and REGARDS studies

JOURNAL=Frontiers in Genetics

VOLUME=6

YEAR=2015

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2015.00136

DOI=10.3389/fgene.2015.00136

ISSN=1664-8021

ABSTRACT=<p>Proprotein convertase subtilisin/kexin type 9 (encoded by <italic>PCSK9</italic>) plays a well-known role in the regulation of low-density lipoprotein (LDL) receptors, and an inhibitor of this enzyme is a promising new therapeutic for hyperlipidemia. Recently, animal and human studies also implicate <italic>PCSK9</italic> genetic variation in the regulation of blood pressure. The goal of this study was to examine if common and rare polymorphisms in <italic>PCSK9</italic> are associated with blood pressure in an African-American population at high risk for cardiovascular disease. Using genomic data assayed on the Affymetrix 6.0 array (<italic>n</italic> = 1199) and the Illumina HumanExome Beadchip (<italic>n</italic> = 1966) from the Hypertension Genetic Epidemiology Network (HyperGEN), we tested the association of <italic>PCSK9</italic> polymorphisms with blood pressure. We used linear mixed models and the sequence kernel association test (SKAT) to assess the association of 31 common and 19 rare variants with blood pressure. The models were adjusted for age, sex, center, smoking status, principal components for ancestry and diabetes as fixed effects and family as a random effect. The results showed a marginally significant effect of two genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) (rs12048828: β = 1.8, <italic>P</italic> = 0.05 and rs9730100: β = 1.0, <italic>P</italic> = 0.05) with diastolic blood pressure (DBP); however these results were not significant after correction for multiple testing. Rare variants were cumulatively associated with DBP (<italic>P</italic> = 0.04), an effect that was strengthened by restriction to non-synonymous or stop-gain SNPs (<italic>P</italic> = 0.02). While gene-based results for DBP did not replicate (<italic>P</italic> = 0.36), we found an association with SBP (<italic>P</italic> = 0.04) in the Reasons for Geographic And Racial Differences in Stroke study (REGARDS). The findings here suggest rare variants in <italic>PCSK9</italic> may influence blood pressure among African Americans, laying the ground work for further validation studies.</p>