Genetic Association of the Renin-Angiotensin-Aldosterone System with hypertension among the Malays and their adaptation to climate change

Hypertension (HT) is a ‘by-product’ to the forces of natural selection against environmental drift and salt availability, therefore contributed to differential HT susceptibility. This study provides further supporting evidence through: (i) associating three salt-sensitive related candidate gene variants, to the susceptibility of HT among the Malays from Peninsular Malaysia with a detail genotype-phenotype evaluation; (ii) comparing the blood pressure and the frequency spectrums of these variants across global populations; (iii) correlating them with the geographical coordinates and BP of the respective populations, and evaluating the presence of local adaptation in these candidate variants. We tested the genetic association of six SNPs underlying CYP11B2 , AGT and ADRB2 in 918 normotensives and hypertensives Malays, men and women. CYP11B2 and ADRB2 were associated with elevated BP in males and females, respectively. Evaluation of these gene variations across 38 populations residing in different latitudinal clines revealed strong correlations between CYP11B2 , AGT and latitudinal coordinates; whilst ADRB2 to a weaker extent. Tajima’s D analyses suggested a non-neutral evolution on CYP11B2 , which suggested a modest putative signals of local adaptation. In summary, we complement the notion that effective pharmacogenetic marker(s) to predict responsiveness of anti-HT medication requires comprehensive characterization of population genetics and HT phenotypes.