Differential Susceptibility to Hypertension Is Due to Selection during the Out-of-Africa Expansion

Hypertension is a leading cause of stroke, heart disease, and kidney failure. The genetic basis of blood pressure variation is largely unknown but is likely to involve genes that influence renal salt handling and arterial vessel tone. Here we argue that susceptibility to hypertension is ancestral and that differential susceptibility to hypertension is due to differential exposure to selection pressures during the out-of-Africa expansion. The most important selection pressure was climate, which produced a latitudinal cline in heat adaptation and, therefore, hypertension susceptibility. Consistent with this hypothesis, we show that ecological variables, such as latitude, temperature, and rainfall, explain worldwide variation in heat adaptation as defined by seven functional alleles in five genes involved in blood pressure regulation. The latitudinal cline in heat adaptation is consistent worldwide and is largely unmatched by latitudinal clines in short tandem repeat markers, control single nucleotide polymorphisms, or non-functional single nucleotide polymorphisms within the five genes. In addition, we show that latitude and one of these alleles, GNB3 (G protein β3 subunit) 825T, account for a major portion of worldwide variation in blood pressure. These results suggest that the current epidemic of hypertension is due to exposures of the modern period interacting with ancestral susceptibility. Modern populations differ in susceptibility to these new exposures, however, such that those from hot environments are more susceptible to hypertension than populations from cold environments. This differential susceptibility is likely due to our history of adaptation to climate.