Abstract
Polymorphic genetic markers of estrogen-receptor-α (ERα) gene studied so far in osteoporosis reside in non-coding region with uncertain functional significance. The purpose of the present study was to search for nucleotides changes in the exon 1 and 5′ regulatory region of ERα gene, to study the nature of their linkages to the previously reported Pvull polymorphism in intron 1 and their functional significance in post-menopausal osteoporosis. Direct sequencing of exon 1 and promotor region of ERα gene revealed a synonymous nucleotide substitution from T to C at position 262, 29 nucleotides downstream from the putative start codon. No nucleotide change was found in the promotor region. Linkage disequilibrium between the T262C polymorphism and the Pvull polymorphism in intron 1 of ERα gene was demonstrated in 129 post-menopausal women (p<0.001). After treating 96 post-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 T262C genotype. However, with regard to femoral neck BMD, only those subjects that were homozygous for the T262C polymorphism had an increase in femoral BMD (+5.9±1.4%, mean±SE; p<0.0001). Using analysis of covariance to assess the effects of the T262C polymorphism, the intronic Pvull polymorphism, doses of CEE and the corresponding baseline BMD on the changes in vertebral or femoral BMD after treatments, it was found that the change in vertebral BMD was related only to the baseline BMD (p<0.05). The change in femoral BMD was independently related to the T262C polymorphism (p<0.01) and the baseline femoral BMD (p<0.01). No effect of the Pvull polymorphism or the doses of CEE on femoral BMD was demonstrated. We concluded that the previously described intronic Pvull polymorphism of ERα gene is in linkage disequilibrium with a T262C polymorphism in exon 1. This T262C polymorphism appears to be more directly related to the skeletal response after long-term treatment with estrogen.
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Sano M., Inoue S., Hosoi T., Ouchi Y., Emi M., Shiraki M., Orimo H. Association of estrogen receptor dinucleotide repeat polymorphism with osteoporosis. Biochem. Biophys. Res. Commun. 1995, 217: 378–383.
Kobayashi S., Inoue S., Hosoi T., Ouchi Y., Shiraki M., Orimo H. Association of bone mineral density with polymorphism of the estrogen receptor gene. J. Bone Miner. Res. 1996, 11: 306–311.
Mizunuma H., Hosoi T., Okano H., Soda M., Tokizawa T., Kagami I., Miyamoto S., Ibuki Y., Inoue S., Shiraki M., Ouchi Y. Estrogen receptor gene polymorphism and bone mineral density at the lumbar spine of pre- and post-menopausal women. Bone 1997, 21: 379–383.
Ongphiphadhanakul B., Rajatanavin R., Chanprasertyothin S., Piaseu N., Chailurkit L., Sirisriro R., Komindr S. Estrogen receptor gene polymorphism is associated with bone mineral density in premenopausal women but not in postmenopausal women. J. Endocrinol. Invest. 1998, 21: 487–493.
Han K., Choi J., Moon I., Yoon H., Han I., Min H., Kim Y., Choi Y. Non-association of estrogen receptor genotypes with bone mineral density and bone turnover in Korean pre-, peri-, and postmenopausal women. Osteoporos. Int. 1999, 9: 290–295.
Vandevyver C., Vanhoof J., Declerck K., Stinissen P., Vandervorst C., Michiels L., Cassiman J.J., Boonen S., Raus J., Geusens P. Lack of association between estrogen receptor genotypes and bone mineral density, fracture history, or muscle strength in elderly women. J. Bone Miner. Res. 1999, 14: 1576–1582.
Willing M., Sowers M., Aron D., Clark M.K., Burns T., Bunten C., Crutchfield M., D’Agostino D., Jannausch M. Bone mineral density and its change in white women: estrogen and vitamin D receptor genotypes and their interaction. J. Bone Miner. Res. 1998, 13: 695–705.
Gennari L., Becherini L., Masi L., Mansani R., Gonnelli S., Cepollaro C., Martini S., Montagnani A., Lentini G., Becorpi A.M., Brandi M.L. Vitamin D and estrogen receptor allelic variants in Italian postmenopausal women: evidence of multiple gene contribution to bone mineral density. J. Clin. Endocrinol. Metab. 1998, 83: 939–944.
Han K.O., Moon I.G., Kang Y.S., Chung H.Y., Min H.K., Han I.K. Nonassociation of estrogen receptor genotypes with bone mineral density and estrogen responsiveness to hormone replacement therapy in Korean post-menopausal women. J. Clin. Endocrinol. Metab. 1997, 82: 991–995.
Yaich L., Dupont W.D., Cavener D.R., Parl F.F. Analysis of the Pvull restriction fragment-length polymorphism and exon structure of the estrogen receptor gene in breast cancer and peripheral blood. Cancer Res. 1992, 52: 77–83.
Ettinger B., Genant H.K., Cann C.E. Postmenopausal bone loss is prevented by treatment with low-dosage estrogen with calcium. Ann. Intern. Med. 1987, 106: 40–45.
Genant H.K., Lucas J., Weiss S., Akin M., Emkey R., McNaney-Flint H., Downs R., Mortola J., Watts N., Yang H.M., Banav N., Brennan J.J., Nolan J.C. Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group. Arch. Intern. Med. 1997, 157: 2609–2615.
Morrison N.A., Qi J.C., Tokita A., Kelly P.J., Crofts L., Nguyen T.V., Sambrook P.N., Eisman J.A. Prediction of bone density from vitamin D receptor alleles. Nature 1994, 367: 284–287.
Gennari L., Becherini L., Mansani R., Masi L., Falchetti A., Morelli A., Colli E., Gonnelli S., Cepollaro C., Brandi M.L. FokI polymorphism at translation initiation site of the vitamin D receptor gene predicts bone mineral density and vertebral fractures in postmenopausal Italian women. J. Bone Miner. Res. 1999, 14: 1379–1386.
Eccleshall T.R., Garnero P., Gross C., Delmas P.D., Feldman D. Lack of correlation between start codon polymorphism of the vitamin D receptor gene and bone mineral density in premenopausal French women: the OFELY study. J. Bone Miner. Res. 1998, 13: 31–35.
Arai H., Miyamoto K., Taketani Y., Yamamoto H., Lemori Y., Morita K., Tonai T., Nishisho T., Mori S., Takeda E. A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J. Bone Miner. Res. 1997, 12: 915–921.
Uitterlinden A.G., Pols H.A., Burger H., Huang Q., Van Daele P.L., Van Duijn C.M., Hofman A., Birkenhager J.C., Van Leeuwen J.P. A large-scale population-based study of the association of vitamin D receptor gene polymorphisms with bone mineral density. J. Bone Miner. Res. 1996, 11: 1241–1248.
Lim S.K., Park Y.S., Park J.M., Song Y.D., Lee E.J., Kim K.R., Lee H.C., Huh K.B. Lack of association between vitamin D receptor genotypes and osteoporosis in Koreans. J. Clin. Endocrinol. Metab. 1995, 80: 3677–3681.
Ames S.K., Ellis K.J., Gunn S.K., Copeland K.C., Abrams S.A. Vitamin D receptor gene Fok1 polymorphism predicts calcium absorption and bone mineral density in children. J. Bone Miner. Res. 1999, 14: 740–746.
Gennari L., Becherini L., Masi L., Gonnelli S., Cepollaro C., Martini S., Mansani R., Brandi M.L. Vitamin D receptor genotypes and intestinal calcium absorption in postmenopausal women. Calcif. Tissue Int. 1997, 61: 460–463.
Dawson-Hughes B., Harris S.S., Finneran S. Calcium absorption on high and low calcium intakes in relation to vitamin D receptor genotype. J. Clin. Endocrinol. Metab. 1995, 80: 3657–3661.
Deng H.W., Li J., Li J.L., Johnson M., Gong G., Davis K.M., Recker R.R. Change of bone mass in postmenopausal Caucasian women with and without hormone replacement therapy is associated with vitamin D receptor and estrogen receptor genotypes. Hum. Genet. 1998, 103: 576–585.
Moutsatsou P., Fountas L., Coulocheri S., Kassi E., Sekeris C.E. The oestrogen receptor codon 10 polymorphism detected in breast cancer is also present in non-malignant cells. J. Cancer Res. Clin. Oncol. 1999, 125: 214–218.
Roper R.J., Griffith J.S., Lyttle C.R., Doerge R.W., McNabb A.W., Broadbent R.E., Teuscher C. Interacting quantitative trait loci control pheno-typic variation in murine estradiol-regulated response. Endocrinology 1999, 140: 556–561.
Kozak M. Initiation of translation in prokaryotes and eukaryotes. Gene 1999, 234: 187–208.
Afshar-Kharghan V., Li C.Q., Khoshnevis-Asl M., Lopez J.A. Kozak sequence polymorphism of the glycoprotein (GP) Ibalpha gene is a major determinant of the plasma membrane levels of the platelet GP Ib-IX-V complex. Blood 1999, 94: 186–191.
Lufkin E.G., Wahner H.W., O’Fallon W.M., Hodgson S.F., Kotowicz M.A., Lane A.W., Judd H.L., Caplan R.H., Riggs B.L. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann. Intern. Med. 1992, 117: 1–9.
The Writing Group for the PEPI. Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA 1996, 276: 1389–1396.
Grey A.B., Cundy T.F., Reid I.R. Continuous combined oestrogen/progestin therapy is well tolerated and increases bone density at the hip and spine in post-menopausal osteoporosis. Clin. Endocrinol. (Oxf). 1994, 40: 671–677.
Kohrt W.M., Birge S.J. Jr. Differential effects of estrogen treatment on bone mineral density of the spine, hip, wrist and total body in late postmenopausal women. Osteoporos. Int. 1995, 5: 150–155.
Duan Y., Tabensky A., DeLuca V., Seeman E. The benefit of hormone replacement therapy on bone mass is greater at the vertebral body than posterior processes or proximal femur. Bone 1997, 21: 447–451.
Ettinger B., Black D.M., Mitlak B.H., Knickerbocker R.K., Nickelsen T., Genant H.K., Christiansen C., Delmas P.D., Zanchetta J.R., Stakkestad J., Gluer C.C., Krueger K., Cohen F.J., Eckert S., Ensrud K.E., Avioli L.V., Lips P., Cummings S.R. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999, 282: 637–645.
Liberman U.A., Weiss S.R., Broll J., Minne H.W., Quan H., Bell N.H., Rodriguez-Portales J., Downs R.W. Jr., Dequeker J., Favus M. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N. Engl. J. Med. 1995, 333: 1437–1443.
Black D.M., Cummings S.R., Karpf D.B., Cauley J.A., Thompson D.E., Nevitt M.C., Bauer D.C., Genant H.K., Haskell W.L., Marcus R., Ott S.M., Torner J.C., Quandt S.A., Reiss T.F., Ensrud K.E. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996, 348: 1535–1541.
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Ongphiphadhanakul, B., Chanprasertyothin, S., Payattikul, P. et al. Association of a T262C transition in exon 1 of estrogen-receptor-α gene with skeletal responsiveness to estrogen in post-menopausal women. J Endocrinol Invest 24, 749–755 (2001). https://doi.org/10.1007/BF03343923
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DOI: https://doi.org/10.1007/BF03343923