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The Effect of LRP5 Polymorphisms on Bone Mineral Density Is Apparent in Childhood

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Abstract

Bone mass acquired during childhood is the primary determinant of adult bone mineral density (BMD) and osteoporosis risk. Bone accrual is subject to genetic influences. Activating and inactivating LRP5 gene mutations elicit extreme bone phenotypes, while more common LRP5 polymorphisms are associated with normal variation of BMD. Our aim was to test the hypothesis that LRP5 gene polymorphisms influence bone mass acquisition during childhood. The association between LRP5 gene polymorphisms and bone size and mineralization was examined in 819 unrelated British Caucasian children (n = 429 boys) aged 9 years. Height, weight, pubertal status (where available), total-body and spinal bone area, bone mineral content (BMC), BMD, and area-adjusted BMC (aBMC) were assessed. Dual-energy X-ray absorptiometry (DXA)-gene associations were assessed by linear regression, with adjustment for age, gender, pubertal status, and body size parameters. There were 140, 79, 12, and 2 girls who achieved Tanner stages I-IV, respectively, and 179 and 32 boys who achieved Tanner stages I and II, respectively. The rs2306862 (N740N) coding polymorphism in exon 10 of the LRP5 gene was associated with spinal BMD and aBMC (each P = 0.01) and total-body BMD and aBMC (P = 0.04 and 0.03, respectively). Adjusting for pubertal stage strengthened associations between this polymorphism and spinal BMD and aBMC (P = 0.01 and 0.002, respectively). Individuals homozygous for the T allele had greater spinal BMD and aBMC scores than those homozygous for the C allele. A dose effect was apparent as the mean spinal BMD and aBMC of heterozygous TC individuals were intermediate between those of their TT and CC counterparts. The N740N polymorphism in exon 10 of LRP5 was associated with spinal BMD and aBMC in pre- and early pubertal children. These results indicate that LRP5 influences volumetric bone density in childhood, possibly through effects on trabecular bone formation.

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Acknowledgements

We are extremely grateful to all the mothers and children who took part and to the midwives for their cooperation and help in recruitment. The whole ALSPAC Study Team comprises interviewers, computer technicians, laboratory technicians, clerical workers, research scientists, volunteers, and managers who continue to make the study possible. The ALSPAC study could not have been undertaken without the financial support of the Medical Research Council, the Wellcome Trust, UK government departments, medical charities, and others. The ALSPAC study is part of the World Health Organization-initiated European Longitudinal Study of Pregnancy and Childhood. This work was also funded by the Arthritis Research Campaign (UK).

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Authors and Affiliations

  1. Institute of Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford, OX3 7LD, UK

    M. Audrey Koay, Carles Vilariño-Güell & Matthew A. Brown

  2. Clinical Sciences at South Bristol, University of Bristol, Bristol, UK

    Jonathan H. Tobias

  3. Community Based Medicine, University of Bristol, Bristol, UK

    Sam D. Leary & Colin D. Steer

  4. Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, 4102, Australia

    Matthew A. Brown

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  1. M. Audrey Koay
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Correspondence to Matthew A. Brown.

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Koay, M.A., Tobias, J.H., Leary, S.D. et al. The Effect of LRP5 Polymorphisms on Bone Mineral Density Is Apparent in Childhood. Calcif Tissue Int 81, 1–9 (2007). https://doi.org/10.1007/s00223-007-9024-2

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