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Replication study of three functional polymorphisms associated with bone mineral density in a cohort of Spanish women

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Abstract

Gene candidate and genome-wide association studies have revealed tens of loci of susceptibility for osteoporosis. Some limitations such as sample size, use of confounding variables, and control for multiple testing and for population stratification, however, represent common problems in these studies that make replication in independent cohorts desirable and even necessary. The main objective of the present study is to replicate previous data on three functional polymorphisms in a cohort of Spanish women. To that end, we performed an association study of three functional polymorphisms previously associated with bone phenotypes in the LRP5, TNFRSF11B, and FGFBP1 genes with low bone mineral density (BMD) in a cohort of 721 Spanish women, most of them postmenopausal. We detected a strong significant association, even when correcting for multiple comparisons, for polymorphism rs312009 in the LRP5 gene with low BMD at the lumbar-spine site. These were women with the CC genotype, which showed the worst bone parameters. Moreover, these women had a higher risk of osteoporosis (adjusted odds ratio 2.82, P = 0.001) than women with the TT/TC genotype. This association seems to be caused because the rs312009 single nucleotide polymorphism (SNP) is located at a binding site for the transcription factor RUNX2 at the 5′ region of the LRP5 gene, and the T allele seems to be a better transcriber than the C allele. Regarding the other two SNPs, only the rs4876869 SNP in the TNFRSF11B gene showed a suggestive trend for both skeletal sites. These results underscore the significance of the LRP5 gene in bone metabolism and emphasize the significance of the replication of previous results in independent cohorts.

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Acknowledgments

The authors are indebted to Mrs N. Capafons, an undergraduate biology student, and to Mrs R. Aliaga for their excellent technical assistance. This work was supported by Grants PI09/0184 and PI12/02582 from the Fondo de Investigación Sanitaria (FIS, Madrid, Spain). Layla Panach is a predoctoral fellow from the Ministerio de Educación, Cultura y Deporte (Programa de Formación del Profesorado Universitario).

Conflict of interest

All authors have no conflicts of interest.

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Authors and Affiliations

  1. Research Foundation, Institute of Health Research INCLIVA, Valencia, Spain

    Layla Panach & Miguel Ángel García-Pérez

  2. Orthopedic Surgery and Traumatology, Clinic Hospital, Institute of Health Research INCLIVA, Valencia, Spain

    Damián Mifsut

  3. Department of Functional Biology and Physical Anthropology, University of Valencia, Valencia, Spain

    Juan J. Tarín

  4. Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain

    Antonio Cano

  5. Department of Genetics, University of Valencia, C/Dr. Moliner 50, 46100, Burjassot, Valencia, Spain

    Miguel Ángel García-Pérez

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  1. Layla Panach
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  2. Damián Mifsut
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  3. Juan J. Tarín
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  4. Antonio Cano
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  5. Miguel Ángel García-Pérez
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Correspondence to Miguel Ángel García-Pérez.

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Panach, L., Mifsut, D., Tarín, J.J. et al. Replication study of three functional polymorphisms associated with bone mineral density in a cohort of Spanish women. J Bone Miner Metab 32, 691–698 (2014). https://doi.org/10.1007/s00774-013-0539-5

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  • DOI: https://doi.org/10.1007/s00774-013-0539-5

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