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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 78; no. 6; pp. 1809 - 1817
• Main Authors: Haas, Andrea V., Yee, Li En, Yuan, Yan E., Wong, Yin H., Hopkins, Paul N., Jeunemaitre, Xavier, Lasky-Su, Jessica, Williams, Jonathan S., Adler, Gail K, Williams, Gordon H
• Format: Journal Article
• Language: English
• Published: 10-11-2021
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.121.18033

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.