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

作者：Gambineri Alessandra^*; Tomassoni Federica; Munarini Alessandra; Stimson Roland H; Mioni Roberto; Pagotto Uberto; Chapman Karen E; Andrew Ruth; Mantovani Vilma; Pasquali Renato; RWalker Brian

来源：European Journal of Endocrinology, 2011, 165(2): 283-292.

DOI：10.1530/EJE-11-0091

Objective: Regeneration of cortisol by 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-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 11b-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 11 beta-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 11 beta-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, P=0.044) 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 11 beta-HSD1 expression and activity, which associates with the metabolic syndrome.

• 出版日期2011-8