Genetic polymorphisms in 11β-hydroxysteroid dehydrogenase type 1 correlate with the postdexamethasone cortisol levels and bone mineral density in patients evaluated for osteoporosis.

Higher physiological cortisol levels may increase the risk of age-related osteoporosis. We hypothesized that common polymorphisms in the cortisol synthesis enzyme 11β-hydroxysteroid dehydrogenase (HSD11B) may cause interindividual variations in cortisol levels and age-related bone loss. We performed a retrospective study in a cohort of 452 ambulatory patients under evaluation for osteoporosis. We investigated the associations of 16 single-nucleotide polymorphisms (in the HSD11B1 and HSD11B2 genes with a postdexamethasone cortisol (PDC) level and bone mineral density (BMD; primary end points) and fracture risk (secondary end point) in a subgroup of 304 patients. The observed associations with BMD were validated in a subgroup of 148 patients. The PDC level increased with age (R = 0.274, P < 10(-5), n = 287) and was negatively correlated with BMD at the femoral neck (R = -0.278, P < 10(-5), n = 258). Three genetically linked single-nucleotide polymorphisms (in intron 5 of HSD11B1), rs1000283, rs932335, and rs11811440, were significantly associated with BMD, with rs11811440 having the strongest association. The presence of the minor rs11811440 A allele was correlated with a lower PDC level (R = -0.128, P = .03, n = 304). The A allele was also consistently correlated with a higher spinal BMD in both patient subgroups (R = 0.17, Bonferroni corrected P = .006, n = 452). The correlation with BMD remained significant after adjustment for age, gender, body mass index, and type of osteoporosis and was stronger in patients older than 65 years. Genetic variations in HSD11B1 may affect the physiological cortisol levels and the severity of age-related osteoporosis. Underlying functional mechanisms remain to be elucidated.