Genome‐wide Association Studies Categorized by Class of Antihypertensive Drugs Reveal Complex Pathogenesis of Hypertension with Drug Resistance

Abstract

Resistant hypertension is defined as uncontrolled blood pressure (BP) despite the use of three or more antihypertensive drugs of different classes. Although genetic factors may greatly contribute to hypertension with resistance to multiple drug classes, more than for general hypertension, its pathogenesis remains unknown. To reveal the genetic background of resistant hypertension, we categorized 32,239 patients whose data were obtained from the BioBank Japan Project, by prescription of 7 classes of antihypertensive drugs and performed genome-wide association studies (GWAS). Our GWAS identified four loci with significant association (P < 5 × 10 −8 ): rs6445583 in CACNA1D and rs12308051 in the intergenic region on chromosome 12 for angiotensin II receptor blockers, rs35497065 in FOXA3 for calcium channel blockers, and rs11066280 in HECTD4 for αβ-blockers. Because these loci are known to be susceptibility loci for hypertension and/or BP, our results indicate that resistant hypertension is caused by a combination of excessive BP and drug resistance to each antihypertensive pharmacological class. Furthermore, to investigate the genetic difference between BP traits and the treatment effectiveness of antihypertensive drugs, we performed gene-set analysis and calculated the genetic correlation continuously. Most of the genetic factors were in common between BP traits and antihypertensive effectiveness, but it seems that the genetic architecture of the drug response to antihypertensive treatment is more complicated than BP traits. This corresponds to the well-known mosaic theory of hypertension. Our findings reveal the complex pathogenesis of hypertension with resistance to multiple classes of antihypertensive drugs.

Association study between biomarkers of metabolites and its relevance genes for hypertension in Korean adults

“…The effects of these genotypes on HTN were analyzed, and among them, rs11066280 of the HECTD4 gene was found to be related to HTN (p = 0.03). The HECTD4 gene is known to enable ubiquitin-protein transferase activity and is believed to be involved in glucose homeostasis and blood pressure regulation [27,28]. Vascular endothelial cells (VECs) regulate blood pressure by secreting nitric oxide (NO), a vasodilator, and it has been demonstrated that ablation of endothelial nitric oxide synthase (eNOS) elicits signi cant elevations in blood pressure [29,30].…”