GENE-CENTRIC STUDY IDENTIFIES TWO NOVEL GENES, CLCN2 AND KCNAB1, ASSOCIATED WITH BLOOD PRESSURE IN TWO INDEPENDENT IRISH POPULATIONS: PP.21.315

Abstract

Objective: Hypertension is highly heritable. Recent genome-wide association studies identified 13 novel loci associated with BP. However these loci only explain a small proportion of total BP variation. It is recognized that identification of all genetic variants associated with BP will require complementary strategies. Here we report on a targeted candidate gene study with dense SNP coverage of multiple genes involved in electrolyte transport. Design and Method: Using the Illumina GoldenGate platform, we genotyped 1860 SNPs in 81 genes (all known voltage-gated sodium and calcium channels, and a subset of chloride and potassium channels), in 358 healthy bank employees (Population 1) - all participants had undergone seated clinic BP measurements. Only the 35 SNPs, in 21 genes, that were found to be associated with clinic systolic (SBP), diastolic (DBP) and/or pulse pressures (PP) with a P-value ≤ 0.01 in Population 1, were genotyped (Illumina Veracode platform) in a second independent population of 380 healthy bank employees (Population 2) - repeated measures of both ambulatory and clinic BP were available from this population. All association analyses were performed, using additive genetic models, with clinic and ambulatory (daytime and night-time), SBP, DBP and PP as quantitative traits, and adjusting for age and sex. Results: Table 1 summarizes the associations of the top two SNPs with BP. A synonymous (coding) SNP in a voltage-gated chloride channel gene (CLCN2) was associated with both SBP and DBP, while an intronic SNP in a voltage-gated potassium channel gene (KCNAB) was primarily associated with SBP and PP. Conclusions: Variants in CLCN2 and KCNAB have not previously been implicated in the causation of hypertension. These findings provide new insights into the pathophysiology of BP regulation, and may point to novel drug targets for the treatment of hypertension.