title: PCSK9 variation and association with blood pressure in African Americans: preliminary findings from the HyperGEN and REGARDS studies.
abstract: Proprotein convertase subtilisin/kexin type 9 (encoded by PCSK9) 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 PCSK9 genetic variation in the regulation of blood pressure. The goal of this study was to examine if common and rare polymorphisms in PCSK9 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 (n = 1199) and the Illumina HumanExome Beadchip (n = 1966) from the Hypertension Genetic Epidemiology Network (HyperGEN), we tested the association of PCSK9 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, P = 0.05 and rs9730100: β = 1.0, P = 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 (P = 0.04), an effect that was strengthened by restriction to non-synonymous or stop-gain SNPs (P = 0.02). While gene-based results for DBP did not replicate (P = 0.36), we found an association with SBP (P = 0.04) in the Reasons for Geographic And Racial Differences in Stroke study (REGARDS). The findings here suggest rare variants in PCSK9 may influence blood pressure among African Americans, laying the ground work for further validation studies.
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Ngan T
authors.initials: NT
authors.lastname: Tran
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Degui
authors.initials: D
authors.lastname: Zhi
authors.affiliation: Department of Biostatistics, Washington University in St. Louis St. Louis, MO, USA.
authors.forename: Yun Ju
authors.initials: YJ
authors.lastname: Sung
authors.affiliation: Department of Internal Medicine, University of Utah Salt Lake City, UT, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.affiliation: Department of Biostatistics, Washington University in St. Louis St. Louis, MO, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Rao
authors.affiliation: Department of Medicine, Human and Molecular Genetics Center, Medical College of Wisconsin Milwaukee, WI, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Broeckel
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Judd
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Muntner
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Shia T
authors.initials: ST
authors.lastname: Kent
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Marguerite R
authors.initials: MR
authors.lastname: Irvin
keywords: PCSK9; blood pressure; dyslipidemia; hypertension; low-density lipoprotein cholesterol