Genetic Predictors of Salt Sensitivity of Blood Pressure: The Additive Impact of 2 Hits in the Same Biological Pathway.
Genetic Predictors of Salt Sensitivity of Blood Pressure: The Additive Impact of 2 Hits in the Same Biological Pathway.
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DOI：
10.1161/hypertensionaha.121.18033
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Williams GH
中科院分区：
文献类型：
--
作者：
Haas AV;En Yee L;Yuan YE;Wong YH;Hopkins PN;Jeunemaitre X;Lasky-Su J;Williams JS;Adler GK;Williams GH
Salt sensitivity of blood pressure is associated with increased cardiovascular morbidity and mortality. A diplotype in the β2AR 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 β2AR or ESR2) and a risk allele associated with amplification of aldosterone’s effects (SGK1) would result in more significant SSBP compared to individuals homozygous for a single risk allele. Data was obtained from the HyperPATH cohort where individuals completed 7 days of restricted sodium and liberal sodium diets. We defined 3 genetic combinations: β2AR/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 β2AR/SGK (β= 5.46; p-value < 0.001) and ESR2/SGK (β=4.87; p-value 0.01). Additionally, the number of risk allele pairs was associated with serum aldosterone levels for β2AR/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 β2AR/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. In a general population, individuals that carry the risk alleles of genes associated with the same mechanistic pathway (increased aldosterone (β2AR and ESR2) and increased expression of the final effector of the sodium homeostatic pathway SGK1 (SGK1) have greater salt sensitivity of blood pressure and plasma aldosterone concentrations than risk allele carriers of the individual genes. In contrast, carriers of genes not in the same mechanistic pathway (AGT/SGK) do not show the enhanced phenotype. These studies suggest that the blood pressure of individuals with the genetic combinations of β2AR/SGK1 and ESR2/SGK1 may be particularly responsive to mineralocorticoid blockade. Further prospective clinical studies are warranted.
