A TA Repeat Polymorphism in the Estrogen Receptor Gene Is Associated with Osteoporotic Fractures but Polymorphisms in the First Exon and Intron Are Not

Estrogen and the estrogen receptor (ER) play a central role in bone metabolism as illustrated by the loss of bone mass after menopause and the osteopenia in individuals with defect aromatase or ER. We therefore wanted to investigate the effect of polymorphisms in the ER‐α gene on bone mass, bone turnover, and the prevalence of osteoporotic fractures in a study of 160 women and 30 men with vertebral fractures and 124 women and 64 men who are normal. Three previously described polymorphisms, G261‐C in exon 1 and T‐C and A‐G in intron 1, in the ER gene were determined by restriction fragment length polymorphism (RFLP) using BstUI, Pvu II, and Xba I after polymerase chain reaction (PCR). A TA repeat polymorphism in the promoter region was examined by PCR and electrophoresis. The distribution of BstUI, Pvu II, and Xba I RFLPs was similar in the osteoporotic patients and the normal controls. No significant differences could be shown in bone mass or bone turnover between the genotypes. The mean number of TA repeats was lower in patients with osteoporotic fractures, 17.3 ± 2.8 versus 18.6 ± 2.8 in the normal controls (p < 0.01). This also was reflected in a significantly increased odds ratio of osteoporotic fractures in individuals with 11–18 repeats of 2.64 (95% CIs, 1.61‐4.34). Furthermore, bone mineral density (BMD) of the lumbar spine was lower in individuals with low mean number of repeats than in individuals with high mean number of repeats (0.790 ± 0.184 g/cm2 vs. 0.843 ± 0.191 g/cm2; p < 0.05). This difference also was found in BMD of the total hip. Using multiple linear regression, mean number of TA repeats was a predictor of lumbar spine BMD (p < 0.05) and a BMD‐independent predictor of fractures (p < 0.05). Mean number of TA repeats was not associated with levels of biochemical markers of bone turnover. All four polymorphisms were in linkage disequilibrium. A TA repeat polymorphism in the ER gene is associated with increased risk of osteoporotic fractures and a modest reduction in bone mass. Polymorphisms in the first exon and first intron of the ER gene are not associated with osteoporotic fractures, bone mass, or bone turnover.

[1]  E. Simpson,et al.  Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. , 1995, The Journal of clinical endocrinology and metabolism.

[2]  P. Geusens,et al.  Lack of association between estrogen receptor genotypes and bone mineral density, fracture history, or muscle strength in elderly women. , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[3]  T. Kameda,et al.  Mammalian mature osteoclasts as estrogen target cells. , 1996, Biochemical and biophysical research communications.

[4]  L. del Senno,et al.  PvuII RFLP inside the human estrogen receptor gene. , 1987, Nucleic acids research.

[5]  J..  Estrogen Modulates the Recruitment of Myelopoietic Cell Progenitors in Rat Through a Stromal Cell-Independent Mechanism Involving Apoptosis , 2002 .

[6]  W D Dupont,et al.  Analysis of the PvuII restriction fragment-length polymorphism and exon structure of the estrogen receptor gene in breast cancer and peripheral blood. , 1992, Cancer research.

[7]  S. Lehrer,et al.  A variant estrogen receptor messenger ribonucleic acid is associated with reduced levels of estrogen binding in human mammary tumors. , 1988, Molecular endocrinology.

[8]  S. Lehrer,et al.  An estrogen receptor genetic polymorphism and the risk of primary and secondary recurrent spontaneous abortion. , 1994, American journal of obstetrics and gynecology.

[9]  P. Patsalis,et al.  Fragile X premutations and (TA)n estrogen receptor polymorphism in women with ovarian dysfunction. , 1999, American journal of medical genetics.

[10]  R. Renkawitz-Pohl,et al.  Intron and upstream sequences regulate expression of the Drosophila beta 3-tubulin gene in the visceral and somatic musculature, respectively. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Eva Enmark,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1997 by The Endocrine Society Human Estrogen Receptor �-Gene Structure, Chromosomal Localization, and Expression Pattern* , 2022 .

[12]  S. Thung,et al.  Oestrogen receptor B-region polymorphism and spontaneous abortion in women with breast cancer , 1990, The Lancet.

[13]  G. Aguiari,et al.  Dinucleotide repeat polymorphism in the human estrogen receptor (ESR) gene. , 1992, Human molecular genetics.

[14]  K. Mann,et al.  Evidence of estrogen receptors in normal human osteoblast-like cells. , 1988, Science.

[15]  S. Cummings,et al.  Associations between low levels of serum estradiol, bone density, and fractures among elderly women: the study of osteoporotic fractures. , 1998, The Journal of clinical endocrinology and metabolism.

[16]  B. Aronow,et al.  Evidence for a complex regulatory array in the first intron of the human adenosine deaminase gene. , 1989, Genes & development.

[17]  S. Chanprasertyothin,et al.  Serum oestradiol and oestrogen‐receptor gene polymorphism are associated with bone mineral density independently of serum testosterone in normal males , 1998, Clinical endocrinology.

[18]  C. Bunten,et al.  Bone Mineral Density and Its Change in White Women: Estrogen and Vitamin D Receptor Genotypes and Their Interaction , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[19]  K. Korach,et al.  Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. , 1994, The New England journal of medicine.

[20]  Klaus Engelke,et al.  Universal standardization for dual X‐ray absorptiometry: Patient and phantom cross‐calibration results , 1994, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[21]  M. Brandi,et al.  Vitamin D and estrogen receptor allelic variants in Italian postmenopausal women: evidence of multiple gene contribution to bone mineral density. , 1998, The Journal of clinical endocrinology and metabolism.

[22]  P. Chambon,et al.  Genomic organization of the human oestrogen receptor gene. , 1988, The EMBO journal.

[23]  A. Freemont,et al.  Demonstration of estrogen receptor mRNA in bone using in situ reverse-transcriptase polymerase chain reaction. , 1997, Bone.

[24]  J. Hopper,et al.  Genetic determinants of bone mass in adults. A twin study. , 1987, The Journal of clinical investigation.

[25]  A. Wilcox,et al.  Risk of miscarriage and a common variant of the estrogen receptor gene. , 1993, American journal of epidemiology.

[26]  I. Han,et al.  Nonassociation of estrogen receptor genotypes with bone mineral density and estrogen responsiveness to hormone replacement therapy in Korean postmenopausal women. , 1997, The Journal of clinical endocrinology and metabolism.

[27]  Mark L. Johnson,et al.  Change of bone mass in postmenopausal Caucasian women with and without hormone replacement therapy is associated with vitamin D receptor and estrogen receptor genotypes , 1998, Human Genetics.

[28]  P. Laurberg,et al.  Relations between diurnal variations in serum osteocalcin, cortisol, parathyroid hormone, and ionized calcium in normal individuals. , 1991, Acta endocrinologica.

[29]  J. Pike,et al.  Estrogen modulates the recruitment of myelopoietic cell progenitors in rat through a stromal cell-independent mechanism involving apoptosis. , 1996, Blood.

[30]  Y. Ouchi,et al.  Estrogen receptor gene polymorphism and bone mineral density at the lumbar spine of pre- and postmenopausal women. , 1997, Bone.

[31]  C C Laurie,et al.  The effect of an intronic polymorphism on alcohol dehydrogenase expression in Drosophila melanogaster. , 1994, Genetics.

[32]  T. Zama,et al.  Genotype distribution of estrogen receptor polymorphisms in men and postmenopausal women from healthy and coronary populations and its relation to serum lipid levels. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[33]  K. Heimdal,et al.  Association studies of estrogen receptor polymorphisms in a Norwegian testicular cancer population. , 1995, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[34]  S. Grant,et al.  Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I α 1 gene , 1996, Nature Genetics.

[35]  S. Chanprasertyothin,et al.  Estrogen receptor gene polymorphism is associated with bone mineral density in premenopausal women but not in postmenopausal women , 1998, Journal of endocrinological investigation.

[36]  M. Tomita,et al.  Association of vitamin D and estrogen receptor gene polymorphism with the effect of hormone replacement therapy on bone mineral density in Japanese women. , 1999, American journal of obstetrics and gynecology.

[37]  G G Klee,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1998 by The Endocrine Society Relationship of Serum Sex Steroid Levels and Bone Turnover Markers with Bone Mineral Density in Men and Women: A Key Role for Bioavailable Estroge , 2022 .

[38]  J. Eisman,et al.  Prediction of bone density from vitamin D receptor alleles , 1994, Nature.

[39]  Y. Ouchi,et al.  Association of estrogen receptor dinucleotide repeat polymorphism with osteoporosis. , 1995, Biochemical and biophysical research communications.

[40]  T. Spector,et al.  Allelic variation at the interleukin-1 receptor antagonist gene is associated with early postmenopausal bone loss at the spine. , 1998, Bone.

[41]  C. Mautalen,et al.  Influence of the menopausal age on the severity of osteoporosis in women with vertebral fractures. , 1994, Maturitas.

[42]  S. Cummings,et al.  Endogenous Hormones and the Risk of Hip and Vertebral Fractures Among Older Women , 1999 .

[43]  Y. Ouchi,et al.  Association of bone mineral density with polymorphism of the estrogen receptor gene , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[44]  E. Eriksen,et al.  Osteoporotic Fractures Are Associated with an 86‐Base Pair Repeat Polymorphism in the Interleukin‐1‐Receptor Antagonist Gene But Not with Polymorphisms in the Interleukin‐1β Gene , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[45]  YasuoIkeda,et al.  Genotype Distribution of Estrogen Receptor Polymorphisms in Men and Postmenopausal Women From Healthy and Coronary Populations and Its Relation to Serum Lipid Levels , 1997 .

[46]  F. McGuigan,et al.  Polymorphisms of the interleukin-6 gene are associated with bone mineral density. , 1997, Bone.

[47]  R. Piva,et al.  Analysis of a DNA Sequence Upstream of the Human Estrogen Receptor Gene a , 1993, Annals of the New York Academy of Sciences.

[48]  A. Wilcox,et al.  B region variant of the estrogen receptor gene. , 1992, Nucleic acids research.

[49]  S. Cummings,et al.  Hormonal Predictors of Bone Loss in Elderly Women: A Prospective Study , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.