HSD11B1 polymorphisms predicted bone mineral density and fracture risk in postmenopausal women without a clinically apparent hypercortisolemia
Received 26 May 2009; received in revised form 16 July 2009; accepted 28 July 2009. published online 01 September 2009.
Abstract
Introduction
Endogenous glucocorticoid (GC) may participate in bone physiology, even in subjects with no glucocorticoid excess. 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) is a primary regulator catalyzing the reduction of inactive cortisone to active cortisol. To elucidate genetic relevance of HSD11B1 variants to vertebral fracture and osteoporosis, we investigated the potential involvement of six HSD11B1 SNPs in postmenopausal women.
Methods
All exons, their boundaries and the promoter region (approximately 1.5 kb) were directly sequenced in 24 individuals. Six polymorphisms were selected and genotyped in all study participants (n=1329). BMD was measured using dual-energy X-ray absorptiometry.
Results
HSD11B1 +16374C>T and +27447G>C were associated with reduced vertebral fracture risk (p=0.016 and 0.032, respectively). Two of these (LD block2) in intron 5 (rs1000283 and rs932335) were significantly associated with bone mineral density (BMD) at the femoral neck (p=0.00005 and 0.0002, respectively). Specifically, HSD11B1 +16374C>T and +27447G>C polymorphisms were associated with higher BMD values of the femoral neck in multiple comparison (p=0.0002 and 0.0004, respectively) and Bonferroni corrected significance level (97% power). Consistent with these results, HSD11B1-ht21 and -ht22 comprising both SNPs also showed the evidence of association with BMD values of the femoral neck (pdomiant=0.0002 and precessive=0.00005, respectively).
Conclusion
Our results provide preliminary evidence supporting an association of HSD11B1 with osteoporosis in postmenopausal women. Also, these findings demonstrate that +16374C>T polymorphism may be useful genetic markers for bone metabolism.
aThe Center for Genome Science, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul, 122-701, Republic of Korea
bSkeletal Diseases Genome Research Center, Kyungpook National University Hospital, 44-2, Samduk 2-ga, Jung-gu, Daegu, 700-412, Republic of Korea
cDepartment of Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University, 188-1, Samduk 2-ga, Jung-gu, Daegu, 700-412, Republic of Korea
dDivision of Endocrinology and Metabolism, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 138-736, Republic of Korea
eDepartment of Orthopedic Surgery, School of Medicine, Kyungpook National University, 50, Samduk 2-ga, Jung-gu, Daegu, 700-412, Republic of Korea
Corresponding authors. S.-Y. Kim is to be contacted at fax: +82 2 422 6605. J.-Y. Lee, fax: +82 2 354 1063.
ABSTRACT