A Frequent Regulatory Variant of the Estrogen-Related Receptor α Gene Associated With BMD in French-Canadian Premenopausal Women

Authors

  • Nathalie Laflamme PhD,

    Corresponding author
    1. Institut National de Santé Publique du Quebec, Ste-Foy, Quebec, Canada
    2. Centre de Recherche de l'Hôpital St-Francois d'Assise du Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec, Canada
    3. Department of Medical Biology, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
    • Institut National de Santé Publique du Quebec 945, Rue Wolfe, Sainte-Foy, Quebec G1V 5B3, Canada
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  • Sylvie Giroux,

    1. Centre de Recherche de l'Hôpital St-Francois d'Assise du Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec, Canada
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  • J Concepción Loredo-Osti,

    1. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
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  • Latifa Elfassihi,

    1. Centre de Recherche de l'Hôpital St-Francois d'Assise du Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec, Canada
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  • Sylvie Dodin,

    1. Centre de Recherche de l'Hôpital St-Francois d'Assise du Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec, Canada
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  • Claudine Blanchet,

    1. Centre de Recherche de l'Hôpital St-Francois d'Assise du Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec, Canada
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  • Kenneth Morgan,

    1. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    2. Department of Medicine, McGill University and Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
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  • Vincent Giguère,

    1. Molecular Oncology Group, Department of Medicine, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
    2. Department of Biochemistry, McGill University, Montreal, Quebec, Canada
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  • François Rousseau

    1. Centre de Recherche de l'Hôpital St-Francois d'Assise du Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec, Canada
    2. Department of Medical Biology, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
    3. Centre for the Development, Evaluation and Rational Implementation of New Diagnostic Tools in Medicine (CEDERINDT)/Consortium Interdisciplinaire d'Evaluation des Technologies Diagnostiques du Quebec (CETDEQ), Quebec City, Quebec, Canada
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  • The authors have no conflict of interest.

Abstract

Genes are important BMD determinants. We studied the association of an ESRRA gene functional variant with BMD in 1335 premenopausal women. The ESRRA genotype was an independent predictor of L2-L4 BMD, with an effect similar to smoking and equivalent to a 10-kg difference in weight.

Introduction: Several genetic polymorphisms have been associated with osteoporosis or osteoporosis fractures, but no functional effect has been shown for most of these gene variants. Because functional studies have implicated estrogen-related receptor α (ESRRA) in bone metabolism, we evaluated whether a recently described regulatory variant of the ESRRA gene is associated with lumbar and hip BMD as measured by DXA and with heel bone parameters as measured by quantitative ultrasound (QUS).

Materials and Methods: Heel bone parameters were measured by right calcaneal QUS in 1335 healthy French-Canadian premenopausal women, and one-half of these women also had their BMD evaluated at two sites: femoral neck and lumbar spine (L2-L4) by DXA. All bone measures were tested separately for association with the ESRRA genotype by analysis of covariance. The significance of the ESRRA contribution to the model was also assessed by two different permutation tests.

Results: A statistically significant association between ESRRA genotype and lumbar spine BMD was observed: women carrying the long ESRRA genotype had a 3.9% (0.045 g/cm2) higher lumbar spine BMD than those carrying the short ESRRA genotype (p = 0.004), independently of other risk factors measured. This effect of ESRRA genotype is similar to the effect of smoking and equivalent to a 10-kg difference in weight. This association was confirmed by permutation tests (p = 0.004). The same trend was observed for femoral neck BMD (2.6%, p = 0.07). However, no association was observed between ESRRA and QUS heel bone measures.

Conclusion: These results support the genetic influence of this ESRRA regulatory variant on BMD.

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