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Sequence Variations in the Osteoprotegerin Gene Promoter in Patients with Postmenopausal Osteoporosis

B. Arko, J. Preelj, R. Komel, A. Kocijani, P. Hudler and J. Marc

Department of Clinical Biochemistry (B.A., J.M.), Faculty of Pharmacy; Department of Endocrinology and Metabolic Diseases (J.P., A.K.), Clinical Centre; and Medical Centre for Molecular Biology (R.K., P.H.), Institute of Biochemistry, Faculty of Medicine, SI-1000 Ljubljana, Slovenia

Address all correspondence and requests for reprints to: Janja Marc, Ph.D., Faculty of Pharmacy, Department of Clinical Biochemistry, Akereva 7, SI-1000 Ljubljana, Slovenia. E-mail: . janja.marc{at}ffa.uni-lj.si

Abstract

Osteoprotegerin (OPG) is a recently discovered member of the TNF receptor superfamily that acts as an important paracrine regulator of bone remodeling. OPG knockout mice develop severe osteoporosis, whereas administration of OPG can prevent ovariectomy-induced bone loss. These findings implicate a role for OPG in the development of osteoporosis.

In the present study, we screened the OPG gene promoter for sequence variations and examined their association with bone mineral density (BMD) in 103 osteoporotic postmenopausal women. Single-strand conformation polymorphism analysis followed by DNA sequencing revealed a presence of four nucleotide substitutions: 209 GA, 245 TG, 889 CT, and 950 TC.

The frequencies of genotypes were as follows: GG (89.3%), GA (10.7%) for 209 GA polymorphism; TT (89.3%), TG (10.7%) for 245 TG polymorphism; and TT (25.2%), TC (53.4%), CC (21.4%) for 950 TC polymorphism. Substitution 889 CT was found in only two patients.

Statistically significant association of genotypes with BMD at the lumbar spine (P = 0.005) was observed for 209 GA and 245 TG polymorphisms. Haplotype GATG was associated with lower BMD as compared with GGTT haplotype.

Our results suggest that 209 GA and 245 TG polymorphisms in the OPG gene promoter may contribute to the genetic regulation of BMD.

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