Sodium-potassium adenosine triphosphatase and individual susceptibility to the effect of lead on blood pressure

Abstract

Problem. Over one-third of coronary heart disease mortality in the United States may be attributable to above optimal blood pressure. Several factors may contribute to high blood pressure including exposure to lead. Elevated blood pressure is associated with blood lead and may be related to Na⁺-K⁺ ATPase inhibition. Genetic differences in Na⁺-K⁺ ATPase, a membrane protein that regulates cellular sodium and potassium concentration, may influence susceptibility to elevated blood pressure associated with lead dose.

Methods. In a cross-sectional study the relation of lead dose with blood pressure, hypertension prevalence, polymorphisms, in the α2 Na⁺-K⁺ ATPase gene (ATP1A2), and enzyme activity in erythrocytes was studied in 226 former organolead manufacturing workers. Subjects had not been exposed to lead occupationally for an average of 14.5 ± 10.8 years.

Results. Mean age (±SD) of study participants was 58.0 (±7.4) years. Blood lead averaged 5.2 (±3.1) μg/dL and ranged from 1 to 20 μg/dL. Subjects were genotyped for a restriction fragment length polymorphism on the α2 Na⁺-K⁺ ATPase gene. The prevalence of the less common allele (10.5 kilobases (kb)) was 24.5%. Blood lead was significantly related to systolic blood pressure among individuals with the 10.5/10.5 genotype and among subjects with low Na⁺-K⁺ ATPase activity. The 10.5/10.5 genotype was also associated with hypertension (adjusted odds ratio [95% confidence interval], 7.7 [1.9–31.4]). Finally, the 10.5 allele was 1.8 times more common among African Americans than among Caucasians. Na ⁺-K⁺ ATPase activity in erythrocyte membranes was not associated with blood lead or blood pressure.

Conclusions. Blood lead is associated with systolic blood pressure in this population, but the mechanism does not appear to involve inhibition of Na⁺-K⁺ ATPase activity. This is the first study to evaluate effect modification by a genetic polymorphism on the relation between lead dose and blood pressure. ATP1A2 genotype or low Na⁺-K⁺ ATPase activity in erythrocytes identifies individuals susceptible to the effect of blood lead on systolic blood pressure. Moreover, the α2 gene may be involved in the pathophysiology of hypertension and may explain some of the racial differences in the prevalence of hypertension.