Abstract 13186: Rare and Low Frequency Variants Associated With Hypertension and Systolic Blood Pressure in Taiwan Chinese Families

Abstract

Introduction: Hypertension (HTN) and related disorders constitute a major public-health burden. While genome-wide association studies have identified common variants for HTN, <2.5% of blood pressure (BP) variance has been explained. Hypothesis: Exome sequencing in families highly enriched for HTN will identify novel rare and low frequency variants associated with HTN and systolic blood pressure (SBP) with larger effect sizes. Methods: Exome sequencing in 150 hypertensive sib-pairs (300 subjects) and 300 unrelated controls identified 6,000 top variants which were then genotyped in SAPPHIRe families (N=1,100) and 1,100 unrelated matched controls. Single-variant analysis and four gene-based association tests (burden and SKAT tests using minor allele frequency thresholds of 1% [T1] and 5% [T5]) were performed for HTN and SBP. Bonferroni-adjusted significance level (5.4•10 -5 ) was used. Results: Novel rare and low frequency variants with significant/suggestive association and biologic plausibility for roles in BP regulation were identified: PLA2G4B-SPTBN5 (7 variants, burden T1 p-value 1.3•10 -6 for SBP and burden T1 p-value 4.2•10 -5 for HTN); RGS2 (1 variant, burden T1 p-value 1.4•10 -5 for SBP and burden T1 p-value 8.9•10 -4 for HTN); BCHE (4 variants, burden T1 p-value 3.4•10 -5 for SBP and burden T1 p-value 5.6•10 -4 for HTN); STRADA (5 variants, burden T1 p-value 5.8•10 -5 for HTN); DYNC2LI1 (8 variants, SKAT T1 p-value 9.9•10 -5 for SBP); TNK1-PLSCR3 (8 variants, SKAT T5 p-value 3.5•10 -4 for SBP). PLAG4B , BCHE and RGS2, identified by both SBP and HTN analyses, are notable for roles played in the synthesis and signal transduction of vasomodulatory peptides in the vascular endothelium and vascular smooth muscle. DYNC2LI1 and STRADA play roles in the regulation of renal water and salt handling via aquaporin and sodium-chloride cotransporters, respectively. Murine PLSCR3 knock-out models lead to a metabolic syndrome phenotype in mice. Conclusions: Several significant and promising rare and low frequency variants associated with HTN and SBP were identified. Studies are underway to replicate the most promising loci. Identification of the causal variants for HTN may lead to novel drug targets and interventions.