A genome-wide association study identifies a novel association between SDC3 and apparent treatment-resistant hypertension

Abstract

AbstractBackgroundCompared with patients who require fewer antihypertensive agents, those with apparent treatment-resistant hypertension (aTRH) are at increased risk for cardiovascular and all-cause mortality, independent of blood pressure control. However, the etiopathogenesis of aTRH is still poorly elucidated.MethodsWe performed a genome-wide association study (GWAS) in first cohort including 586 aTRHs and 871 healthy controls. Next, expression quantitative trait locus (eQTL) analysis was used to identify genes that are regulated by single nucleotide polymorphisms (SNPs) derived from the GWAS. Then, we verified the genes obtained from the eQTL analysis in the validation cohort including 65 aTRHs, 96 hypertensives, and 100 healthy controls through gene expression profiling analysis and real-time quantitative polymerase chain reaction (RT-qPCR) assay.ResultsThe GWAS in first cohort revealed four suggestive loci (1p35, 4q13.2-21.1, 5q22-23.2, and 15q11.1-q12) represented by 23 SNPs. The 23 significant SNPs were in or nearLAPTM5,SDC3,UGT2A1,FTMT, andNIPA1.eQTL analysis uncovered 14 SNPs in 1p35 locus all had same regulation directions forSDC3andLAPTM5. The disease susceptible alleles of SNPs in 1p35 locus were associated with lower gene expression forSDC3and higher gene expression forLAPTM5.The disease susceptible alleles of SNPs in 4q13.2-21.1 were associated with higher gene expression forUGT2B4. GTEx database did not show any statistically significant eQTLs between the SNPs in 5q22-23.2 and 15q11.1-q12 loci and their influenced genes. Then, gene expression profiling analysis in the validation cohort confirmed lower expression ofSDC3in aTRH but no significant differences onLAPTM5andUGT2B4, when compared with controls and hypertensives, respectively. RT-qPCR assay further verified the lower expression ofSDC3in aTRH.ConclusionsOur study identified a novel association ofSDC3with aTRH, which contributes to the elucidation of its etiopathogenesis and provides a promising therapeutic target.