BACKGROUND In the European Project on Genes in Hypertension (EPOGH), we investigated to what extent left ventricular mass (LVM) in populations and families relates to the angiotensin-converting enzyme (ACE D/I) and aldosterone synthase (CYP11B2 -344C/T) polymorphisms and urinary sodium excretion. METHODS We recruited 219 nuclear families (382 parents and 436 offspring) randomly in Cracow (Poland), Novosibirsk (Russia) and Mirano (Italy). Echocardiographical LVM was indexed to body surface area, adjusted for covariables, and subjected to multivariate analyses using generalized estimating equations and quantitative transmission disequilibrium tests, in a population-based and family-based approach, respectively. RESULTS We found significant differences between the two Slavic centres and Mirano in left ventricular mass index (LVMI) (94.9 versus 80.3 g/m2), sodium excretion (229 versus 186 mmol/day), and the prevalence of the ACE D allele (52.1 versus 58.5%). There was significant heterogeneity between Slavic and Italian subjects in the phenotype-genotype relationships with the ACE gene, but not with the aldosterone synthase gene. In the two Slavic centres, ACE II homozygosity was significantly associated with higher LVMI, in population-based as well as in family-based analyses. By contrast, in Mirano, LVMI was slightly higher in DD homozygotes (P = 0.05), but only in the population-based approach. LVMI increased with higher sodium excretion in ACE II homozygous offspring of both Slavic and Italian extraction (+4.2 +/- 2.1 g/m2 per 100 mmol; P = 0.04) and in Slavic (+2.6 +/- 1.1 g/m2 per 100 mmol; P = 0.02), but not Italian (-3.3 +/- 3.2 g/m2 per 100 mmol; P = 0.29) D allele carriers. We did not find any association between LVMI and the aldosterone synthase -344C/T polymorphism. CONCLUSIONS The relationship between LVMI and the ACE D/I polymorphism differs across populations, possibly as a consequence of intermediate regulatory mechanisms responsive to varying levels of salt intake.