Context: Variation in the region of chromosome 8 including the genes steroid 11- hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) influences mineralocorticoid and glucocorticoid metabolism. However, the relative importance of polymorphisms in CYP11B1 and CYP11B2 in determining these phenotypes is unknown.

Objective: To investigate genetic influences of the CYP11B1 and CYP11B2 genes on mineralocorticoid metabolism.

Design: We measured 24-hour urinary excretion of the key metabolites of the principal mineralocortoids, glucocorticoids and androgens secreted by the adrenal cortex. We genotyped polymorphisms spanning the CYP11B1 and CYP11B2 genes which together capture all common variation at the locus.

Participants: 573 members of 105 British Caucasian families ascertained on a hypertensive proband.

Main outcome measures: Heritability of urinary tetrahydroaldosterone (THAldo) excretion; association of THAldo excretion with genotype.

Results: The heritability of THAldo excretion was 52% (P < 10^-6). There was significant association between THAldo and genotype at several of the CYP11B1/B2 polymorphisms. The strongest association was observed at the rs6387 (2803A/G) polymorphism in intron 3 of CYP11B1 (P = 0.0004). Association followed a codominant model with a 21% higher THAldo excretion per G allele. Genotype at rs6387 accounted for 2.1% of the total population variability of THAldo. We found significant association between THAldo excretion and urinary total androgen excretion, urinary tetrahydrodeoxycortisol level, and urinary Cortisol metabolites (all P < 0.001).

Conclusions: Aldosterone synthesis is highly heritable, and is affected by genotype at CYP11B1. Our findings support the hypothesis that genetically determined differences in 11-hydroxylation efficiency can have downstream effects on mineralocorticoid synthesis. Such effects may be of relevance to the development of low renin essential hypertension.