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A Digenic Combination of Polymorphisms Within ESR1 and ESR2 Genes Are Associated With Age at Menarche in the Spanish Population

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Abstract

In the present study, the authors look at an association of genetic variants within estrogen synthesis and signaling pathways and age at menarche (AAM) in Spanish women. They analyzed 9 polymorphisms in 6 different genes in 714 well-characterized postmenopausal women from Spain. They performed a quantitative trait locus study of these markers individually or in digenic combinations in relation to AAM. None of the studied markers, with the exception of the follicle-stimulating hormone receptor (P = .013), were significantly associated with AAM in the Spanish population, and no marker demonstrated an association of statistical significance after multiple testing corrections (P > .0055). In contrast, linear regression analysis suggests epistatic interactions including ESR1 and ESR2 loci in relation to AAM in the series (P = .003). The results suggest that epistatic interactions of ESR1 and ESR2 alleles could be associated with advancing AAM among Spanish women.

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References

  1. Massart F., Parrino R., Seppia P., Federico G., Saggese G. How do environmental estrogen disruptors induce precocious puberty? Minerva Pediatr. 2006;58:247–254.

    CAS  PubMed  Google Scholar 

  2. Foster CM, Ross JL, Shawker T., et al. Absence of pubertal gonadotropin secretion in girls with McCune-Albright syndrome. J Clin Endocrinol Metab. 1984;58:1161–1165.

    Article  CAS  Google Scholar 

  3. Onland-Moret NC, Peeters PH, van Gils CH, et al. Age at menarche in relation to adult height: the EPIC study. Am J Epidemiol. 2005;162:623–632

    Article  CAS  Google Scholar 

  4. Long JR, Xu H., Zhao LJ, et al. The oestrogen receptor alpha gene is linked and/or associated with age of menarche in different ethnic groups. J Med Genet. 2005;42:796–800.

    Article  CAS  Google Scholar 

  5. Stavrou I., Zois C., Chatzikyriakidou A., Georgiou I., Tsatsoulis A. Combined estrogen receptor alpha and estrogen receptor beta genotypes influence the age of menarche. Hum Reprod. 2006;21: 554–557.

    Article  CAS  Google Scholar 

  6. Kitagawa I., Kitagawa Y., Kawase Y., Nagaya T., Tokudome S. Advanced onset of menarche and higher bone mineral density depending on vitamin D receptor gene polymorphism. Eur J Endocrinol. 1998;139:522–527.

    Article  CAS  Google Scholar 

  7. Gorai I., Tanaka K., Inada M., et al. Estrogen-metabolizing gene polymorphisms, but not estrogen receptor-alpha gene polymorphisms, are associated with the onset of menarche in healthy postmenopausal Japanese women. J Clin Endocrinol Metab. 2003;88:799–803.

    Article  CAS  Google Scholar 

  8. Xita N., Tsatsoulis A., Stavrou I., Georgiou I. Association of SHBG gene polymorphism with menarche. Mol Hum Reprod. 2005;11:459–462.

    Article  CAS  Google Scholar 

  9. Deighton CM, Sykes H., Walker DJ Rheumatoid arthritis, HLA identity, and age at menarche. Ann Rheum Dis. 1993;52:322–326.

    Article  CAS  Google Scholar 

  10. Zhao J., Xiong DH, Guo Y., Yang TL, Recker RR, Deng HW Polymorphism in the insulin-like growth factor 1 gene is associated with age at menarche in Caucasian females. Hum Reprod. 2007;22:1789–1794.

    Article  CAS  Google Scholar 

  11. Guo Y., Xiong DH, Yang TL, Guo YF, Recker RR, Deng HW Polymorphisms of estrogen-biosynthesis genes CYP 17 and CYP19 may influence age at menarche: a genetic association study in Caucasian females. Hum Mol Genet. 2006;15:2401–2408.

    Article  CAS  Google Scholar 

  12. Guo Y., Shen H., Xiao P., et al. Genomewide linkage scan for quantitative trait loci underlying variation in age at menarche. J Clin Endocrinol Metab. 2006;91:1009–1014.

    Article  CAS  Google Scholar 

  13. De Castro F., Moron FJ, Montoro L., et al. Human controlled ovarian hyperstimulation outcome is a polygenic trait. Pharmacogenetics. 2006;14:285–293.

    Article  Google Scholar 

  14. De Castro F., Moron FJ, Montoro L., Galan JJ, Real LM, Ruiz A. Re: polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst. 2005;97: 152–153.

    Article  Google Scholar 

  15. Galan JJ, Buch B., Cruz N., et al. Multilocus analyses of estrogen-related genes reveal involvement of the ESR1 gene in male infertility and the polygenic nature of the pathology. Fertil Steril. 2005;84:910–918.

    Article  CAS  Google Scholar 

  16. Moron FJ, Mendoza N., Vazquez F., et al. Multilocus analysis of estrogen-related genes in Spanish postmenopausal women suggests an interactive role of ESR1, ESR2 and NRIP1 genes in the pathogenesis of osteoporosis. Bone. 2006;39:213–221.

    Article  CAS  Google Scholar 

  17. Otsuka F., Yamamoto S., Erickson GF, Shimasaki S. Bone morphogenetic protein-15 inhibits follicle-stimulating hormone (FSH) action by suppressing FSH receptor expression. J Biol Chem. 2001;276:11387–11392.

    Article  CAS  Google Scholar 

  18. Moron FJ, Galan JJ, Ruiz A. Controlled ovarian hyperstimulation pharmacogenetics: a simplified model to genetically dissect estrogen-related diseases. Pharmacogenomics. 2007;8:775–785.

    Article  CAS  Google Scholar 

  19. Moron FJ, de Castro F., Royo JL et al. Bone morphogenetic protein 15 (BMP15) alleles predict over-response to recombinant follicle stimulation hormone and iatrogenic ovarian hyperstimulation syndrome (OHSS). Pharmacogenet Genomics. 2006;16:485–495.

    Article  CAS  Google Scholar 

  20. Weel AE, Uitterlinden AG, Westendorp IC, et al. Estrogen receptor polymorphism predicts the onset of natural and surgical menopause. J Clin Endocrinol Metab. 1999;84:3146–3150.

    CAS  PubMed  Google Scholar 

  21. Boot AM, van der Sluis IM, de Muinck Keizer-Schrama SM, et al. Estrogen receptor alpha gene polymorphisms and bone mineral density in healthy children and young adults. Calcif Tissue Int. 2004;74:495–500.

    Article  CAS  Google Scholar 

  22. Dunning AM, Dowsett M., Healey CS, et al. Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst. 2004;96:936–945.

    Article  CAS  Google Scholar 

  23. Hoh J., Ott J. Mathematical multi-locus approaches to localizing complex human trait genes. Nat Rev Genet. 2003;4:701–709.

    Article  CAS  Google Scholar 

  24. Marchini J., Donnelly P., Cardon LR Genome-wide strategies for detecting multiple loci that influence complex diseases. Nat Genet. 2005;37:413–417.

    Article  CAS  Google Scholar 

  25. Cowley SM, Hoare S., Mosselman S., Parker MG Estrogen receptors alpha and beta form heterodimers on DNA. J Biol Chem. 1997;272:19858–19862.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Servicio de Ginecología y Obstetricia, Hospital Universitario Virgen de las Nieves, Granada, Spain

    Nicolás Mendoza MD, PhD

  2. Departamento de Genómica Estructural, Neocodex, Avda, Charles Darwin n °6, Acc. A. Parque Tecnológico Isla de la Cartuja, 41092, Sevilla, Spain

    Francisco Jesús Morón MS, Mari C. Rivero, Luis M. Real PhD, Antonio González-Pérez MS & Agustín Ruiz MD, PhD

  3. Servicio de Ginecología y Obstetricia, Hospital San Juan de Alicante, Alicante, Spain

    Francisco Quereda MD, PhD

  4. Clínica de Ginecología, CEOGA, Lugo, Spain

    Francisco Vázquez MD, PhD

  5. Clínica Sanatorio Bilbaíno, Servicio de Ginecología, Bilbao, Spain

    Txantón Martínez-Astorquiza MD, PhD

  6. Clínica Diatros, Gavá, Barcelona, Spain

    Rafael Sánchez-Borrego MD, PhD

Authors
  1. Nicolás Mendoza MD, PhD
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  2. Francisco Jesús Morón MS
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  3. Francisco Quereda MD, PhD
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  4. Francisco Vázquez MD, PhD
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  5. Mari C. Rivero
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  6. Txantón Martínez-Astorquiza MD, PhD
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  7. Luis M. Real PhD
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  8. Rafael Sánchez-Borrego MD, PhD
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  9. Antonio González-Pérez MS
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  10. Agustín Ruiz MD, PhD
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Corresponding author

Correspondence to Agustín Ruiz MD, PhD.

Additional information

We are deeply grateful to the postmenopausal women for having participated in this study. We are very grateful to Ana Salinas and Eva Molero for their collaboration during this work. Neocodex (a biomedical and genomics research company and the principal responsible for this research) has been partially funded by the Ministerio de Educación y Ciencia of Spain (PTQ2003-0546, PTQ2004-3-0718) and the European Commission (Gendisrupt project QLK4-CT-2002-02403).

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Mendoza, N., Morón, F.J., Quereda, F. et al. A Digenic Combination of Polymorphisms Within ESR1 and ESR2 Genes Are Associated With Age at Menarche in the Spanish Population. Reprod. Sci. 15, 305–311 (2008). https://doi.org/10.1177/1933719107314064

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  • DOI: https://doi.org/10.1177/1933719107314064

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