oa Estrogen receptor α gene and vitamin K epoxide reductase (VKORC1) gene haplotypes and low BMD in Palestinian postmenopausal women

Background Osteoporosis is a common skeletal disorder characterized by low bone mass and microarchetectual deterioration of bone tissue with increased susceptibility to fractures. Osteoporosis is considered a multifactorial polygenic disease. The prevalence of postmenopausal osteoporosis in Palestine, based on of BMD at femoral neck, total hip and spine was 24%, 14% and 29.7% respectively. Previous studies on the effect of genetic polymorphisms on bone mineral density (BMD) showed significant correlation between various haplotypes and mutations in the VDR and MTHFR and low bone mineral density [BMD] among Palestinian postmenopausal subjects. Estrogens are known to play an important role in regulating bone homeostasis. Estrogen act through binding to Estrogen Receptor α (ERα) which is a member of the nuclear receptor superfamily of ligand activated transcription factors. Vitamin K hydrochinon is an important cofactor for gamma carboxylation of osteocalcin, a major bone matrix protein . The reduction of vitamin K to vitamin K hydrochinon depends on the vitamin K epoxide reductase complex subunit 1 (VKORC1). Aim In the present study, correlation between specific XbaI and PvuII polymorphisms in the ERα gene and selected polymorphisms in the VKORC1 gene with low BMD and fractures risk were investigated in 345 postmenopausal Palestinian women including 165 osteoporotic, 93 osteopenic and 86 normal subjects using allele-specific polymerase chain reaction (PCR) and RFLP-PCR technology. Results The data showed significance association between the XX haplotype of the XbaI in ERα gene and lower BMD at the hip (P=0.012). Similarly the PP haplotype of PvuII ER α gene was significantly associated with lower hip BMD ( P=0.03). In addition, the 9041G allele [GG and GA] was significantly more frequent in patients with low BMD (P = 0.012). In our cohort, a genetic variation in the 3'-region of the VKORC1 gene (9041 AG and GG) was significantly associated with low BMD. The data also revealed the +2255 TT haplotype which is linked to lower activity of the enzyme was associated with low BMD while the presence of the C allele [CC or CT], linked to higher activity at this locus, was associated with normal BMD levels [P=0.02]. Conclusions These findings indicate that specific polymorphisms in the ERα gene and VKORC1 gene are correlated with variation in BMD levels among our subjects. These results along with previous data with the VDR and MTHFR genes provide evidence for the strong correlation between genetics and osteoporosis in our population may be significant for treatment decisions and screening of osteoporotic patients. The involvement of other genes variation like the osteoprotegrin and TNF superfamily member genes are underway. The overall data will eventialy be employed for direct correlation and evaluation between the genetic background of patients and the efficacy of selected specific drugs used to treat osteoporosis.