Homozygosity for an Alpha-Adducin Polymorphism (460TRP) Is Associated with Salt-Sensitivity and Low-Renin Hypertension in Humans
Single nucleotide polymorphisms of the adducin genes have been associated with the development of elevated blood pressure in the rat. However, previous studies of the 460Trp polymorphism of human alpha-adducin have not clearly identified an association with the development of human hypertension. In this study, 281 hypertensive subjects were subgrouped by the intermediate phenotypes of plasma renin status and sensitivity of systolic blood pressure to dietary sodium. The frequency of the 460Trp allele was 19% and 9 of 281 subjects (3.2%) were homozygous (TT) for the 460Trp allele. The systolic blood pressure response to changes in dietary sodium (>150 meq/d vs. ≤30 meq/d) was significantly (p < 0.05) greater in TT subjects (25 ± 2 mmHg) compared to those heterozygous (GT) for the 460Trp allele (12 ± 2 mmHg) or homozygous (GG) for the 460Gly allele (14 ± 1 mmHg). There was a significant (p < 0.005) association between homozygosity for the 460Trp allele and low-renin hypertension. Six of 67 (9%) low-renin subjects, but only 3 of 214 (1.4%) normal- renin subjects had the TT genotype. Heterozygous (GT) subjects did not have increased salt-sensitivity of systolic blood pressure and did not have an increased frequency of low-renin hypertension. Erythrocyte sodium content was significantly (p < 0.01) less in subjects with the TT genotype (24.5 ± 1.0 mmol/kgHgb) compared to all subjects (33.2 ± 0.4 mmol/kgHgb). Subjects with the TT genotype had a significantly (p < 0.05) lower sodium-lithium countertransport (SLC) (0.16 ± 0.04 mmol/l/h) than other subjects (0.28 ± 0.01 mmol/l/h). However, the mean SLC of all low-renin hypertensive subjects (0.25 ± 0.02 mmol/l/h) was not significantly different than the mean SLC of normal-renin hypertensive subjects (0.26 ± 0.01 mmol/l/h). Thus, a decreased SLC is associated with the TT genotype and is not a characteristic of all individuals with low-renin hypertension. These findings suggest that homozygous expression of the 460Trp polymorphism of the alpha-adducin gene alters sodium handling in humans and may be an important contributor to the development of low-renin hypertension in some individuals.