| Hypertension is a major modifiable cardiovascular risk factor that affects about one third of the adult population worldwide. Because of the disappointing results obtained so far in hypertension genetics in humans, the use of intermediate phenotypes has been advocated as a way to reduce complexity. Given the key role of the kidney in chronic blood pressure control, via sodium and water balance, renal sodium handling represents an ideal intermediate phenotype. The associations between renal sodium handling, measured using the fractional excretion of endogenous lithium (FELi) and the fraction distal sodium reabsorption (FDRNa), with variants located in six hypertension candidate genes---G-protein beta 3 subunit gene (825 C>T GNB3), alpha (460 Gly>Trp AAD), beta (1797 C>T BAD) and gamma (386 A>G GAD) adducin genes, dopamine type 1 receptor gene (48 A>G DRD1) and gamma epithelial sodium channel gene (-173 A>G NACG)---have been analyzed in families randomly selected from the general population of four regions: Hechtel-Eksel (Belgium, Caucasians, n=735), Novosibirsk (Russia, Caucasians, n=253), Krakow (Poland, Caucasians, n=117) and Johannesburg (South Africa, Black Africans, n=222). Heritability estimates for FELi and FDRNa were moderate to high in all centers. Analyses not controlling for population stratification showed a significant interaction (P=0.005) of the 825T allele with sex for its effects on FELi in Belgium. In view of previously published studies, there is a reasonable level of consistency showing that the effects of the 825 C>T GNB3 variant are sex-specific for several cardiovascular traits. The 1797T BAD and 460Trp AAD variants tended to be associated with FDRNa consistently across all four centers. No evidence for an association of the 386 A>G GAD and -48 A>G DRD1 variants with renal sodium handling was found. The -173A NACG allele tended to be associated with FDRNa under conditions of low urinary potassium excretion in Belgium and Poland (P interaction=0.009 for pooled results), which makes sense physiologically. Analyses controlling for population stratification resulted in a more than 50% sample size reduction so that the above-mentioned associations were no longer statistically significant. The lithium clearance technique appears to represent a valuable intermediate phenotype for hypertension genetics in humans. |
