Abstract
Variation in drug response to hormone replacement therapy (HRT) may reflect genetic heterogeneity in the estrogen-related genes, possibly including estrogen receptor alpha (ERα) gene. However, only a few association studies of the drug response to HRT have been reported, focusing mainly on the intronic polymorphisms of the ERα gene. We therefore examined 284 postmenopausal women (mean age, 52.2 ± 5.0 years) for the microsatellite thymine–adenine (TA) repeat polymorphism in the promoter of the ERα gene and its relationship to drug response by measuring changes in bone mineral density (BMD) after 1 year of HRT. In our study population, the most common number of TA repeats was 14, with a range of values between 11 and 27. At baseline, the number of TA repeats was neither associated with measured lumbar spine or femoral neck BMD nor with bone markers. When we categorized the subjects by the TA repeat numbers into an L group (n = 142), with a low mean number of repeats (TA < 16), and an H group (n = 142), with a high mean number of repeats (TA ≥ 16), no significant genotypic differences were noted in spinal or femoral neck BMD or in bone markers. However, the drug response on lumbar spine BMD after 1 year of HRT correlated with the mean number of TA repeats (r = −0.131, P = 0.035) after adjustment for confounding factors such as body mass index and years since menopause. This correlation was also seen with the number of TA repeats on the shorter allele (r = −0.159, P = 0.012), which was defined as the allele with the lower number of TA repeats. However, this genotypic association was not found in the femoral neck BMD (r = 0.053, P = 0.396). When we defined the nonresponder group as women who had lost BMD even with HRT, 15.9% of the subjects were included, and this group was significantly younger and had higher initial BMD than the responder group. After further adjustment for age and initial BMD, the number of TA repeats on the shorter allele remained significantly associated with drug responsiveness (P = 0.005). These data indicate significant effects of the ERα TA repeat polymorphism on the estrogen responsiveness of lumbar spine BMD after 1 year of HRT in Korean women.
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References
BL Riggs LJ Melton (1986) ArticleTitleInvolutional osteoporosis N Engl J Med 314 1676–1686 Occurrence Handle3520321
GA Rodan TJ Martin (2000) ArticleTitleTherapeutic approaches to bone diseases Science 289 1508–1514 Occurrence Handle10.1126/science.289.5484.1508 Occurrence Handle10968781
JA Cauley J Robbins Z Chen SR Cummings RD Jackson et al. (2003) ArticleTitleWomen’s Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial JAMA 290 1729–1738 Occurrence Handle10.1001/jama.290.13.1729 Occurrence Handle14519707
C Hassager SB Jensen C Christiansen (1994) ArticleTitleNon-responders to hormone replacement therapy for the prevention of postmenopausal bone loss: do they exist? Osteoporos Int 4 36–41 Occurrence Handle10.1007/BF01622196 Occurrence Handle8148570
M Komulainen H Kroger MT Tuppurainen AM Heikkinen R Honkanen et al. (2000) ArticleTitleIdentification of early postmenopausal women with no bone response to HRT: results of a five-year clinical trial Osteoporos Int 11 211–218 Occurrence Handle10.1007/s001980050283 Occurrence Handle10824236
KO Han IG Moon YS Kang HY Chung HK Min et al. (1997) ArticleTitleNonassociation of estrogen receptor genotypes with bone mineral density and estrogen responsiveness to hormone replacement therapy in Korean postmenopausal women J Clin Endocrinol Metab 82 991–995 Occurrence Handle10.1210/jc.82.4.991 Occurrence Handle9100562
S Kobayashi S Inoue T Hosoi Y Ouchi M Shiraki et al. (1996) ArticleTitleAssociation of bone mineral density with polymorphism of the estrogen receptor gene J Bone Miner Res 11 306–311 Occurrence Handle8852941
M Sano S Inoue T Hosoi Y Ouchi M Emi et al. (1995) ArticleTitleAssociation of estrogen receptor dinucleotide repeat polymorphism with osteoporosis Biochem Biophys Res Commun 217 378–383 Occurrence Handle10.1006/bbrc.1995.2787 Occurrence Handle8526937
L Becherini L Gennari L Masi R Mansani F Massart et al. (2000) ArticleTitleEvidence of a linkage disequilibrium between polymorphisms in the human estrogen receptor alpha gene and their relationship to bone mass variation in postmenopausal Italian women Hum Mol Genet 9 2043–2050 Occurrence Handle10.1093/hmg/9.13.2043 Occurrence Handle10942433
WE Evans HL McLeod (2003) ArticleTitlePharmacogenomics – drug disposition, drug targets, and side effects N Engl J Med 348 538–549 Occurrence Handle10.1056/NEJMra020526 Occurrence Handle12571262
N Kobayashi T Fujino T Shirogane I Furuta Y Kobamatsu et al. (2002) ArticleTitleEstrogen receptor alpha polymorphism as a genetic marker for bone loss, vertebral fractures and susceptibility to estrogen Maturitas 41 193–201 Occurrence Handle10.1016/S0378-5122(01)00287-0 Occurrence Handle11886765
L del Senno GL Aguiari R Piva (1992) ArticleTitleDinucleotide repeat polymorphism in the human estrogen receptor (ESR) gene Hum Mol Genet 1 354
WC Chen HC Wu WC Lin MC Wu CD Hsu et al. (2001) ArticleTitleThe association of androgen- and oestrogen-receptor gene polymorphisms with urolithiasis in men BJU Int 88 432–436 Occurrence Handle10.1046/j.1464-410X.2001.02319.x Occurrence Handle11564035
M Syrrou I Georgiou PC Patsalis I Bouba G Adonakis et al. (1999) ArticleTitleFragile X premutations and (TA)n estrogen receptor polymorphism in women with ovarian dysfunction Am J Med Genet 84 306–308 Occurrence Handle10.1002/(SICI)1096-8628(19990528)84:3<306::AID-AJMG29>3.0.CO;2-I Occurrence Handle10331614
E Weiderpass I Persson H Melhus S Wedren A Kindmark et al. (2000) ArticleTitleEstrogen receptor alpha gene polymorphisms and endometrial cancer risk Carcinogenesis 21 623–627 Occurrence Handle10.1093/carcin/21.4.623 Occurrence Handle10753195
EA Krall B Dawson-Hughes (1993) ArticleTitleHeritable and lifestyle determinants of bone mineral density J Bone Miner Res 8 1–9 Occurrence Handle8427042
EP Smith J Boyd GR Frank H Takahashi RM Cohen et al. (1994) ArticleTitleEstrogen resistance caused by a mutation in the estrogen receptor gene in a man N Engl J Med 331 1056–1061 Occurrence Handle10.1056/NEJM199410203311604 Occurrence Handle8090165
KS Korach (1994) ArticleTitleInsights from the study of animals lacking functional estrogen receptor Science 266 1524–1527 Occurrence Handle7985022
BL Langdahl E Lokke M Carstens LL Stenkjaer EF Eriksen (2000) ArticleTitleA TA repeat polymorphism in the estrogen receptor gene is associated with osteoporotic fractures but polymorphisms in the first exon and intron are not J Bone Miner Res 15 2222–2230 Occurrence Handle11092403
HY Chen WC Chen HD Tsai CD Hsu FJ Tsai et al. (2001) ArticleTitleRelation of the estrogen receptor alpha gene microsatellite polymorphism to bone mineral density and the susceptibility to osteoporosis in postmenopausal Chinese women in Taiwan Maturitas 40 143–150 Occurrence Handle10.1016/S0378-5122(01)00233-X Occurrence Handle11716992
AM Albagha FE McGuigan DM Reid SH Ralston (2001) ArticleTitleEstrogen receptor alpha gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom J Bone Miner Res 16 128–134 Occurrence Handle11149476
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Yim, C., Choi, J., Choi, H. et al. Association of estrogen receptor α gene microsatellite polymorphism with annual changes in bone mineral density in Korean women with hormone replacement therapy. J Bone Miner Metab 23, 395–400 (2005). https://doi.org/10.1007/s00774-005-0619-2
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DOI: https://doi.org/10.1007/s00774-005-0619-2