Genome-wide association studies categorized by class of anti-hypertensive drugs reveal complex pathogenesis of hypertension with drug resistance.

Abstract

Resistant hypertension is defined as uncontrolled blood pressure despite the use of three or more anti-hypertensive drugs of different classes. Though 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 seven classes of anti-hypertensive drugs and performed genome-wide association studies. Our genome-wide association studies identified four loci with significant association (P < 5×10-8 ): rs6445583 in CACNA1D and rs12308051 in the intergenic region on chromosome 12 for ARBs, rs35497065 in FOXA3 for CCBs, and rs11066280 in HECTD4 for α-blockers. Since these loci are known to be susceptibility loci for hypertension and/or blood pressure, our results indicate that resistant hypertension is caused by a combination of excessive blood pressure and drug resistance to each anti-hypertensive pharmacological class. Furthermore, to investigate the genetic difference between BP traits and the treatment effectiveness of anti-hypertensive drugs, we performed gene-set analysis and calculated the genetic correlation continuously. Most of the genetic factors were in common between BP traits and anti-hypertensive effectiveness, but it seems that the genetic architecture of the drug response to anti-hypertensive 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 anti-hypertensive drugs.