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Polymorphisms in the ALOX12 gene and osteoporosis

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Abstract

Summary

ALOX12 produces ligands for PPARγ thereby turning mesenchymal stem cells into adipocytes instead of osteoblasts. We investigated the effect of polymorphisms in the ALOX12 gene on BMD and fracture risk in two Danish cohorts and found four polymorphisms and a haplotype thereof to be associated with BMD and fracture risk.

Introduction

Stimulation of the PPARγ with ligands produced by the ALOX enzymes drives mesenchymal stem cells in an adipocyte direction at the expense of osteoblasts leading to decreased osteoblast number and BMD. Previously, polymorphisms in the ALOX12 gene have been associated with osteoporosis.

Methods

We examined the effect of ALOX12 polymorphisms on BMD and the risk of fractures in two Danish cohorts: AROS, a case–control population comprising 809 individuals and DOPS, a population comprising 1,716 perimenopausal women allocated to hormone therapy or not at baseline and followed for up to 10 years. On the basis of linkage disequilibrium (LD) between SNPs throughout the gene and previous genetic association studies we chose ten polymorphisms for investigation. Genotyping was carried out using the Sequenom MassARRAY genotyping system and TaqMan assays.

Results

In AROS, individuals heterozygous for the polymorphisms rs3840880, rs9897850, rs2292350 and rs1126667 had a 3.0–4.7% decreased lumbar spine BMD (p = 0.02–0.06) and an increased risk of vertebral fractures (p < 0.05) compared with individuals homozygous for either allele. In DOPS, none of the individual SNPs were associated with BMD or incident fractures. In both cohorts, the above-mentioned SNPs comprised an LD-block (pairwise D´ = 1.0, r 2 = 0.45–0.97). A haplotype comprising all the common alleles (frequency 9%) was associated with decreased bone loss at the hip (p < 0.05) and decreased incidence of osteoporotic fractures (p < 0.05) in DOPS and increased femoral neck BMD in AROS (p < 0.05).

Conclusion

Our study suggests that genetic variants in ALOX12 may influence BMD and fracture risk.

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Acknowledgements

This work was supported by a grant from The Villum Kann Rasmussen Foundation.

Conflicts of interest

None.

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Authors and Affiliations

  1. Department of Endocrinology and Internal Medicine, THG, Aarhus University Hospital, 8000, Aarhus C, Denmark

    T. Harsløf, L. B. Husted, M. Carstens, L. Stenkjær, L. Mosekilde, L. Rejnmark & B. L. Langdahl

  2. Department of Human Genetics, Aarhus University, Aarhus, Denmark

    M. Nyegaard & A. D. Børglum

  3. Department of Haematology, Aarhus University Hospital, Aalborg, Denmark

    M. Nyegaard

  4. Department of Endocrinology M, Odense University Hospital, 5000, Odense C, Denmark

    K. Brixen

  5. Department of Cardiology and Endocrinology, Hillerød Hospital, Hillerød, Denmark

    P. Eiken

  6. Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark

    J-E. B. Jensen

  7. Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark

    A. D. Børglum

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  1. T. Harsløf
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  2. L. B. Husted
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  12. B. L. Langdahl
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Correspondence to T. Harsløf.

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Harsløf, T., Husted, L.B., Nyegaard, M. et al. Polymorphisms in the ALOX12 gene and osteoporosis. Osteoporos Int 22, 2249–2259 (2011). https://doi.org/10.1007/s00198-010-1472-2

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  • DOI: https://doi.org/10.1007/s00198-010-1472-2

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