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- Title
A combination of polymorphisms in HSD11B1 associates with in vivo 11Β-HSD1 activity and metabolic syndrome in women with and without polycystic ovary syndrome.
- Authors
Gambineri, Alessandra; Tomassoni, Federica; Munarini, Alessandra; Stimson, Roland H.; Mioni, Roberto; Pagotto, Uberto; Chapman, Karen E.; Andrew, Ruth; Mantovani, Vilma; Pasquali, Renato; Walker, Brian R.
- Abstract
Objective: Regeneration of cortisol by 11b-hydroxysteroid dehydrogenase type 1 (11b-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 11b-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 11b-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 cohortZ2.77 (95% confidence interval (CI) 1.16-6.67), PZ0.023). 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 (16.1G0.7 nmol/min versus 12.1G1.1, 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 11b-HSD1 expression and activity, which associates with the metabolic syndrome
- Subjects
GENETIC polymorphisms; HYDROXYSTEROID dehydrogenases; REGENERATION (Biology); HYDROCORTISONE; METABOLIC syndrome; POLYCYSTIC ovary syndrome; HYPERTENSION; NUCLEOTIDES
- Publication
European Journal of Endocrinology, 2011, Vol 165, Issue 2, p283
- ISSN
0804-4643
- Publication type
Article
- DOI
10.1530/EJE-11-0091