title: 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.
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, 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 11β-HSD1 expression and activity, which associates with the metabolic syndrome.
authors.affiliation: Division of Endocrinology, Department of Clinical Medicine, Centre for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna - Alma Mater Studiorum, Via Massarenti 9, 40138 Bologna, Italy. alessandra.gambineri@aosp.bo.it
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gambineri
authors.forename: Federica
authors.initials: F
authors.lastname: Tomassoni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Munarini
authors.forename: Roland H
authors.initials: RH
authors.lastname: Stimson
authors.forename: Roberto
authors.initials: R
authors.lastname: Mioni
authors.forename: Uberto
authors.initials: U
authors.lastname: Pagotto
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
authors.forename: Ruth
authors.initials: R
authors.lastname: Andrew
authors.forename: Vilma
authors.initials: V
authors.lastname: Mantovani
authors.forename: Renato
authors.initials: R
authors.lastname: Pasquali
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D004789:Enzyme Activation; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis / Q000097:blood / Q000378:metabolism; D024821:Metabolic Syndrome / Q000150:complications / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011085:Polycystic Ovary Syndrome / Q000150:complications / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000502:physiology; D013256:Steroids / Q000652:urine; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D013256:Steroids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D006854:Hydrocortisone