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.

Highlights

  • Hypertension is currently a major health problem in African Americans (Kramer et al, 2004)

  • We considered the associations of 3 single-nucleotide polymorphisms (SNPs) located near PCSK9 that were reported in prior genome-wide association study (GWAS) of lipid traits [rs11206510 (Schunkert et al, 2011), rs2479409 (Willer et al, 2013), and rs2495478 (Turnbull et al, 2012)] with both systolic blood pressure (SBP) and diastolic blood pressure (DBP)

  • A total of 7700 randomly selected African Americans were recently genotyped with the same Illumina exome chip as HyperGEN

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Summary

Introduction

Hypertension is currently a major health problem in African Americans (Kramer et al, 2004). Data from the National Health and Nutrition Examination Survey (NHANES) in 2008 showed that age-adjusted prevalence of hypertension was 40% in African Americans vs 30% in Caucasians (Egan et al, 2010). For instance stroke risk is twice as high and risk for end-stage renal disease is 4–5 times higher among African Americans (Go et al, 2014). The reason for this disparity is not completely understood, differences in genetic background are hypothesized to play a role (Allison et al, 1994; Kato, 2012). Because dyslipidemia is linked to hypertension, genetic variants associated with lipid levels represent promising candidates for novel hypertension loci (Brown et al, 2000; Sesso et al, 2005; Halperin et al, 2006; Nguyen et al, 2008; Maharjan et al, 2012; Yin et al, 2012)

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