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Association of the variations in the HSD3β gene with primary aldosteronism

Wu, Vin-Centa,*; Wu, Cho-Kaia; Chang, Yi-Chengc; Young, Guang-Huarb; Chen, Shann-Chingd; Yang, Wei-Shiunga; Chen, Chien-Yuana; Wang, Wei-Jiee; Lin, Chien-Yuf; Lin, Yen-Hunga,*; Lin, Shuei-Lionga; Chueh, Shih-Chiehg; Wu, Kwan-DunaTAIPAI study group

doi: 10.1097/HJH.0b013e328360ef3c
ORIGINAL PAPERS: Genetic aspects

Objective: In mice, a lack of cryptochrome results in up-regulation of aldosterone production due to high expression of the 3β-hydroxysteroid dehydrogenases (HSD3β) gene. The HSD3β pathway might play a pivotal role in aldosterone synthesis. This study aimed to determine the association of HSD3β and HSD3β2 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 HSD3β1, HSD3β2, and CYP11β2 were genotyped. Expression of HSD3β mRNA and immunohistochemical stain of HSD3β in the specimens of aldosterone-producing adenoma (APA) was compared with that in nonfunctional incidentaloma.

Results: The SNPs of rs12410453 A allele in HSD3β2 gene [odds ratio (OR) 1.92, 95% confidence interval (CI) 1.13–3.32, P = 0.018] and rs6203 C allele in the HSD3β1 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 HSD3β1 mRNA, HSD3β2 mRNA and HSD3β protein were increased in APA, as compared to incidentaloma.

Conclusion: Risk-conferring genetic variations in the HSD3β gene influenced susceptibility of primary aldosteronism. Concomitant presence of rs6203 CC and rs12410453 GA genotypes synergistically increased aldosterone-to-renin ratio.

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aDepartment of Internal Medicine

bDepartment of Surgery, National Taiwan University Hospital, Taipei, Taiwan

cGenomics Research Center, Academia Sinica, Taipei, Taiwan

dDepartment of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

eDepartment of Internal Medicine, Tao-Yuan General Hospital, Tao-Yuan County

fDepartment of Internal Medicine, En- Chu- Kong Hospital, Taipei County, Taiwan

gCleveland Clinic Glickman Urological and Kidney Institute, Cleveland, Ohio, USA

hTAIPAI, the Taiwan Primary Aldosteronism Investigation, Taiwan

*Vin-Cent Wu and Yen-Hung Lin contributed equally to this study.

Correspondence to Kwan-Dun Wu, MD, PhD, Room 1419, Clinical Research Building, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. Tel: +886 2 2356 2082; fax: +886 2 2393 4176; e-mail:

Abbreviations: APA, aldosterone-producing adenoma; IHA, idiopathic hyperaldosteronism; PAC, plasma aldosterone concentration; PRA, plasma renin activity; SNP, single-nucleotide polymorphism; TAIPAI, Taiwan Primary Aldosteronism Investigation

Received 12 December, 2012

Revised 7 February, 2013

Accepted 5 March, 2013

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