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PTHR1 Polymorphisms Influence BMD Variation through Effects on the Growing Skeleton

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Abstract

We investigated whether polymorphisms in PTHR1 are associated with bone mineral density (BMD), to determine whether the association of this gene with BMD was due to effects on attainment of peak bone mass or effects on subsequent bone loss. The PTHR1 gene, including its 14 exons, their exon-intron boundaries, and 1,500 bp of its promoter region, was screened for polymorphisms by denaturing high-performance liquid chromatography (dHPLC) and sequencing in 36 osteoporotic cases. Eleven single-nucleotide polymorphisms (SNPs), one tetranucleotide repeat, and one tetranucleotide deletion were identified. A cohort of 634 families, including 1,236 men (39%) and 1,926 women (61%) ascertained with probands with low BMD (Z< −2.0) and the Children in Focus subset of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (785 unrelated individuals, mean age 118 months), were genotyped for the five most informative SNPs (minor allele frequency >5%) and the tetranucleotide repeat. In our osteoporosis families, association was noted between lumbar spine BMD and alleles of a known functional tetranucleotide repeat (U4) in the PTHR1 promoter region (P = 0.042) and between two and three marker haplotypes of PTHR1 polymorphisms with lumbar spine, femoral neck, and total hip BMD (P = 0.021–0.047). This association was restricted to the youngest tertile of the population (age 16–39 years, P = 0.013–0.048). A similar association was found for the ALSPAC cohort: two marker haplotypes of SNPs A48609T and C52813T were associated with height (P = 0.006) and total body less head BMD (P = 0.02), corrected for age and gender, confirming the family findings. These findings suggest a role for PTHR1 variation in determining peak BMD.

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Acknowledgements

We are extremely grateful to all the families from the ALSPAC and FAMOS cohorts who took part in this study. With respect to the ALSPAC participants, we thank the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council, the Wellcome Trust, and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, and MAB and CV will serve as guarantors for the contents. This research was specifically funded by the Arthritis Research Campaign (UK) and the National Health and Medical Research Council (Australia); E. L. D. was funded by Action Research (UK).

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Authors and Affiliations

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

    Carles Vilariño-Güell, Lisa J. Miles, Emma L. Duncan, John A. Wass & Matthew A. Brown

  2. Bone Research Group, Institute of Medical Sciences, University of Aberdeen Medical School, Aberdeen, AB25 2ZD, UK

    Stuart H. Ralston & David M. Reid

  3. Molecular Medicine Group, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK

    Stuart H. Ralston

  4. School of Clinical Medicines, University of Cambridge, Cambridge, CB2 2SP, UK

    Juliet E. Compston

  5. MRC Environmental Epidemiology Unit, Southampton General Hospital, Southampton, SO16 6YD, UK

    Cyrus Cooper

  6. Department of Endocrinology, Århus Amtssygehus, Århus, DK-8000, Denmark

    Bente L. Langdahl

  7. Department of Medicine and Therapeutics, Western Infirmary, Glasgow, G11 6NT, UK

    Alasdair MacLelland

  8. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, 3015 CE, The Netherlands

    Huibert A. Pols & Andre G. Uitterlinden

  9. Unit of Paediatric and Perinatal Epidemiology, Division of Community-Based Medicine, University of Bristol, Bristol, BS8 1AU, UK

    Colin D. Steer

  10. Clinical Sciences at South Bristol, University of Bristol, Bristol, BS2 8AE, UK

    Jon H. Tobias

  11. Diamantina Institute of Cancer, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, 4102, Australia

    Matthew A. Brown

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  1. Carles Vilariño-Güell
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  2. Lisa J. Miles
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  3. Emma L. Duncan
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  8. Alasdair MacLelland
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  9. Huibert A. Pols
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  11. Andre G. Uitterlinden
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  12. Colin D. Steer
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  14. John A. Wass
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  15. Matthew A. Brown
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Correspondence to Matthew A. Brown.

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Vilariño-Güell, C., Miles, L.J., Duncan, E.L. et al. PTHR1 Polymorphisms Influence BMD Variation through Effects on the Growing Skeleton. Calcif Tissue Int 81, 270–278 (2007). https://doi.org/10.1007/s00223-007-9072-7

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  • DOI: https://doi.org/10.1007/s00223-007-9072-7

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