Association of the variations in the HSD3 beta gene with primary aldosteronism

Objective:In mice, a lack of cryptochrome results in up-regulation of aldosterone production due to high expression of the 3-hydroxysteroid dehydrogenases (HSD3) gene. The HSD3 pathway might play a pivotal role in aldosterone synthesis. This study aimed to determine the association of HSD3 and HSD32 gene variations with primary aldosteronism in a Taiwanese population.Method:In this case-control cohort, 688 consecutive ethnically matched unrelated individuals including 362 primary aldosteronism and 326 essential hypertension cases were recruited. Nineteen tag single-nucleotide polymorphisms (SNPs) across HSD31, HSD32, and CYP112 were genotyped. Expression of HSD3 mRNA and immunohistochemical stain of HSD3 in the specimens of aldosterone-producing adenoma (APA) was compared with that in nonfunctional incidentaloma.Results:The SNPs of rs12410453 A allele in HSD32 gene [odds ratio (OR) 1.92, 95% confidence interval (CI) 1.13-3.32, P=0.018] and rs6203 C allele in the HSD31 gene (OR 2.21, 95% CI 1.28-3.95, P=0.006) showed significant association with primary aldosteronism, with corresponding population attributable risk of 6.7 and 30.7%, respectively. Primary aldosteronism patients of non-CC in rs6203 and non-GA in rs12401453 had lower plasma aldosterone-to-renin ratio. A haplotype in a linkage disequilibrium block containing rs6203 associated significantly with serum potassium level (OR 1.24, 95% CI 1.02-1.24, P=0.026). The expressions of HSD31 mRNA, HSD32 mRNA and HSD3 protein were increased in APA, as compared to incidentaloma.Conclusion:Risk-conferring genetic variations in the HSD3 gene influenced susceptibility of primary aldosteronism. Concomitant presence of rs6203 CC and rs12410453 GA genotypes synergistically increased aldosterone-to-renin ratio.