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

A polymorphism of the α-subunit of adducin, Gly⁴⁶⁰→Trp, may affect membrane ion transport and be associated with human EH (essential hypertension). The α-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 K_m for external sodium was lower in patients with EH than NC. The K_m 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 K_m was lower in patients with EH than NC for any adducin genotype. Thiol alkylation with NEM (N-ethylmaleimide) caused a decrease in K_m in NC, but not in patients with EH. With a Trp allele, NEM lowered K_m 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 V_max in patients with EH but not in NC. With a Trp allele, NEM increased V_max 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 α-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.