Sodium–lithium countertransport and the Gly460→Trp α-adducin polymorphism in essential hypertension

Abstract

A polymorphism of the alpha-subunit of adducin, Gly460-->Trp, may affect membrane ion transport and be associated with human EH (essential hypertension). The alpha-adducin Gly460-->Trp polymorphism was determined in 242 NC (normal controls) and 73 patients with EH and was related to the membrane ion transport marker in EH, erythrocyte Na/LiCT (sodium-lithium countertransport), in a subgroup of these subjects. The Km for external sodium was lower in patients with EH than NC. The Km of the Trp allele was lower than with the Gly/Gly genotype [NC, 105+/-6 compared with 88+/-5 mmol Na/l respectively (P=0.05); patients with EH, 76+/-5 compared with 64+/-4 mmol Na/l respectively (P=0.06)]. The Km was lower in patients with EH than NC for any adducin genotype. Thiol alkylation with NEM (N-ethylmaleimide) caused a decrease in Km in NC, but not in patients with EH. With a Trp allele, NEM lowered Km less in NC (-20 compared with -35) and increased it in patients with EH (+24 compared with +3; P=0.007 for genotype effect). Thiol alkylation with NEM caused an increase in Vmax in patients with EH but not in NC. With a Trp allele, NEM increased Vmax substantially in patients with EH (+0.12 compared with +0.03) but did not cause a decrease in NC (+0.02 compared with -0.06; P=0.007 for genotype effect). In conclusion, the Gly460-->Trp polymorphism of alpha-adducin modifies the kinetics of Na/LiCT. The effect of this genotype is different in patients with EH compared with NC and it does not explain the abnormal kinetics in patients with EH. The Trp allele was not associated with disease in the population studied. Several cytoskeletal proteins may interact with adducin in the overall phenotype of EH.

Gly460Trp polymorphism of the ADD1 gene and essential hypertension in an Indian population: A meta-analysis on hypertension risk

“…A meta-analysis was conducted on Gly460Trp polymorphism of the ADD1 gene comprising 45 studies[9–1113–2224–55] among different populations. In addition to the overall analysis, subgroup analysis for each ethnicity was also performed to find out the allelic prevalence.…”

“…Further, we also analyzed the association between ADD1 Gly460Trp polymorphism and essential hypertension by combining 15 case-control studies, involving 3187 cases and 3720 controls[913–2224–27] as shown in Table 4. Surprisingly, the overall prevalence of 460Trp allele was higher in control subjects that amounted to 34.7% as compared to 32% in cases.…”

“…Some studies implicated the positive association of the Gly460Trp polymorphism,[12–15] whereas other studies reported negative association. [16–22]…”

Alpha-Adducin Gly460Trp Polymorphism and Hypertension Risk: A Meta-Analysis of 22 Studies Including 14303 Cases and 15961 Controls

“…Population-based and hospital-based studies were all included in our meta-analysis. Twelve studies were population-based [9], [13], [20], [22], [23], [25]–[28], [30]–[32], and ten were hospital-based studies [6]–[8], [10]–[12], [21], [24], [29], [33]. Populations among these studies were as following: ten studies were Caucasians or European descent (7632 cases and 8588 controls), nine studies were East Asians (5957 cases and 6770 controls) and three studies were others (one study recruited South African Negro subjects and the other two studies recruited African-American subjects) involving 714 cases and 603 controls.…”

The Association between Gly460Trp-Polymorphism of Alpha-Adducin 1 Gene (ADD1) and Arterial Hypertension Development in Ukrainian Population

“…In vivo adducin is a substrate for PKC, PKA, and Rho-associated kinase [ 28 ] and is involved in cell signal transduction. Besides, adducin interacts with other membrane skeleton components and membrane proteins to influence ion transport, particularly, Na + transport (Na + channels, Na + -H + exchange, Na + -Li + countertransport, and Na + -K + -Cl − cotransport) [ 33 , 34 ]. α - or β -adducin point mutations can lead to hypertension, as the phosphorylation pattern changes from tyrosine kinase to the PKA site.…”