TY - JOUR
T1 - A combination of polymorphisms in HSD11B1 associates with in vivo 11β-HSD1 activity and metabolic syndrome in women with and without polycystic ovary syndrome
AU - Gambineri, Alessandra
AU - Tomassoni, Federica
AU - Munarini, Alessandra
AU - Stimson, Roland H.
AU - Mioni, Roberto
AU - Pagotto, Uberto
AU - Chapman, Karen E.
AU - Andrew, Ruth
AU - Mantovani, Vilma
AU - Pasquali, Renato
AU - Walker, Brian R.
PY - 2011/8
Y1 - 2011/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79960167562&partnerID=8YFLogxK
U2 - 10.1530/EJE-11-0091
DO - 10.1530/EJE-11-0091
M3 - Article
C2 - 21622477
AN - SCOPUS:79960167562
VL - 165
SP - 283
EP - 292
JO - European Journal of Endocrinology,
JF - European Journal of Endocrinology,
SN - 0804-4643
IS - 2
ER -