Association of a T262C transition in exon 1 of estrogen-receptor-alpha gene with skeletal responsiveness to estrogen in post-menopausal women

Polymorphic genetic markers of estrogen-receptor-alpha (ER alpha) gene stud ied so far in osteoporosis reside in non-coding region with uncertain funct ional significance. The purpose of the present study was to search for nucl eotides changes in the exon 1 and 5' regulatory region of ER alpha gene, to study the nature of their linkages to the previously reported Pvull polymo rphism in intron 1 and their functional significance in postmenopausal oste oporosis. Direct sequencing of exon 1 and promotor region of ER alpha gene revealed a synonymous nucleotide substitution from T to C at position 262, 29 nucleotides downstream from the putative start codon. No nucleotide chan ge was found in the promotor region. Linkage disequilibrium between the T26 2C polymorphism and the Pvull polymorphism in intron 1 of ER alpha gene was demonstrated in 129 post-menopausal women (p <0.001). After treating 96 po st-menopausal with 0.3 mg or 0.625 mg conjugated equine estrogen (CEE) for 2 yr, vertebral bone mineral density (BMD) increased regardless of the T262 C genotype. However, with regard to femoral neck BMD, only those subjects t hat were homozygous for the T262C polymorphism had an increase in femoral B MD (+5.9 +/-1.4%, mean +/- SE; p <0.0001). Using analysis of covariance to assess the effects of the T262C polymorphism, the intronic Pvull polymorphi sm, doses of CEE and the corresponding baseline BMD on the changes in verte bral or femoral BMD after treatments, it was found that the change in verte bral BMD was related only to the baseline BMD (p <0.05). The change in femo ral BMD was independently related to the T262C polymorphism (p <0.01) and t he baseline femoral BMD (p <0.01). No effect of the Pvull polymorphism or t he doses of CEE on femoral BMD was demonstrated. We concluded that the prev iously described intronic Pvull polymorphism of ER alpha gene is in linkage disequilibrium with a T262C polymorphism in exon 1. This T262C polymorphis m appears to be more directly related to the skeletal response after long-t erm treatment with estrogen. (C) 2001, Editrice Kurtis.