A combination of polymorphisms in HSD11B1 associates with in vivo 11β-HSD1 activity and metabolic syndrome in women with and without polycystic ovary syndrome

Alessandra Gambineri, Federica Tomassoni, Alessandra Munarini, Roland H. Stimson, Roberto Mioni, Uberto Pagotto, Karen E. Chapman, Ruth Andrew, Vilma Mantovani, Renato Pasquali, Brian R. Walker

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Objective: Regeneration of cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) within liver and adipose tissue may be of pathophysiological importance in obesity and the metabolic syndrome. single nucleotide polymorphisms (SNPs) in HSD11B1, the gene encoding 11β-HSD1, have been associated with type 2 diabetes and hypertension in population-based cohort studies, and with hyperandrogenism in patients with the polycystic ovary syndrome (PCOS). However, the functional consequences of these SNPs for in vivo 11β-HSD1 expression and activity are unknown. Methods:We explored associations of well-characterised hormonal and metabolic phenotypes with two common SNPs (rs846910 and rs12086634) in HSD11B1 in 600 women (300 with PCOS) and investigated 11β-HSD1 expression and activity in a nested study of 40 women from this cohort. Results: HSD11B1 genotypes (as single SNPs and as the combination of the two minor allele SNPs) were not associated with PCOS. Women who were heterozygous for rs846910 A and homozygous for rs12086634 T (GA, TT genotype) had a higher risk of metabolic syndrome, regardless of the diagnosis of PCOS (odds ratio in the whole cohort = 2.77 (95% confidence interval (CI) 1.16-6.67), P=0.023). In the nested cohort, women with the GA, TT genotype had higher HSD11B1 mRNA levels in adipose tissue, and higher rates of appearance of cortisol and d3-cortisol (16.1 ± 0.7 nmol/min versus 12.1 ± 1.1, PZ0.044) during 9,11,12,12-2H4-cortisol (d4-cortisol) steady-state infusion. Conclusions: We conclude that, in a population of Southern European Caucasian women with and without PCOS, alleles of HSD11B1 containing the two SNPs rs846910 A and rs12086634 T confer increased 11β-HSD1 expression and activity, which associates with the metabolic syndrome.

Original languageEnglish
Pages (from-to)283-292
Number of pages10
JournalEuropean Journal of Endocrinology
Volume165
Issue number2
DOIs
Publication statusPublished - Aug 2011
Externally publishedYes

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