Genetic Predictors of Salt Sensitivity of Blood Pressure: The Additive Impact of 2 Hits in the Same Biological Pathway

Salt sensitivity of blood pressure is associated with increased cardiovascular morbidity and mortality. A diplotype in the beta 2AR gene (rs1042713, rs1042714) and single nucleotide polymorphisms in ESR2 (rs10144225), SGK1 (rs2758151), and AGT (rs2493134) genes are all independently associated with salt sensitivity of blood pressure and all but AGT are associated with increased aldosterone levels and/or activity. We sought to determine whether individuals who carried a double hit risk phenotype-a risk allele associated with increased aldosterone secretion (either beta 2AR or ESR2) and a risk allele associated with amplification of aldosterone's effects (SGK1) would result in more significant SSBP compared with individuals homozygous for a single risk allele. Data were obtained from the Hypertension Pathotypes cohort where individuals completed 7 days of restricted sodium and liberal sodium diets. We defined 3 genetic combinations: beta 2AR/SGK, ESR2/SGK, and AGT/SGK. Multivariate regression analyses found a significantly higher salt sensitivity of blood pressure as the number of risk allele pairs increased in both the beta 2AR/SGK (beta=5.46; P<0.001) and ESR2/SGK (beta=4.87; P 0.01). In addition, the number of risk allele pairs was associated with serum aldosterone levels for beta 2AR/SGK and ESR2/SGK. On the other hand, there was no association between the number of risk allele pairs with salt sensitivity of blood pressure nor aldosterone levels in the AGT/SGK combination. In conclusion, genetic combinations of beta 2AR/SGK1 and ESR2/SGK1 are associated with greater salt sensitivity of blood pressure and plasma aldosterone concentrations. Hypertensive combination risk homozygotes may be candidates for mineralocorticoid receptor antagonist therapy-gene-driven, personalized medicine.