Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men

Douglas P. Kiel, Serge L. Ferrari, L. Adrienne Cupples, David Karasik, Danielle Manen, Alma Imamovic, Alan G. Herbert, Josée Dupuis

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Polymorphisms in the LRP5 gene have been associated with bone mineral density (BMD) in men and/or women. However, the functional basis for this association remains obscure. We hypothesized that LRP5 alleles could modulate Wnt signaling and the relationship between physical activity and BMD. This genetic association study was performed in the population-based Framingham Study Offspring Cohort, and included a subset of 1797 unrelated individuals who provided blood samples for DNA and who had BMD measurements of the hip and spine. Ten single-nucleotide polymorphisms (SNPs) spanning the LRP5 gene were genotyped and used for association and interaction analyses with BMD by regression methods. LRP5 haplotypes were transiently co-expressed with Wnt3a, MesD and Dkk1 in HEK293 cells and their activity evaluated by the TCF-Lef reporter assay. Six out of ten SNPs in LRP5 were associated with one or more of the femur or spine BMDs in men or women after adjustment for covariates, and these associations differed between genders. In men ≤ age 60 years, 3 SNPs were significantly associated with BMD: rs2306862 on Exon 10 with femoral neck BMD (p = 0.01) and Ward's BMD (p = 0.01); rs4988321/p. V667M with Ward's BMD (p = 0.02); and intronic rs901825 with trochanter BMD (p = 0.03). In women, 3 SNPs in intron 2 were significantly associated with BMD: rs4988330 for trochanter (p = 0.01) and spine BMD (p = 0.003); rs312778 with femoral neck BMD (p = 0.05); and rs4988331 with spine BMD (p = 0.04). For each additional rare allele, BMD changed by 3-5% in males and 2-4% in females. Moreover, there was a significant interaction between physical activity and rs2306862 in exon 10 (p for interaction = 0.02) and rs3736228/p. A1330V in exon 18 (p for interaction = 0.05) on spine BMD in men. In both cases, the TT genotype was associated with lower BMD in men with higher physical activity scores, conversely with higher BMD in men with lower physical activity scores. In vitro, TCF-Lef activity in presence of Wnt3a was significantly reduced in cells expressing LRP5 haplotypes carrying the T allele of exon 10 and 18 compared to the wild-type allele, whereas co-expression of Dkk1 completely inhibited Wnt3a response through all LRP5 haplotypes. In summary, genetic variation in exons 10 and 18 of the LRP5 gene modulates Wnt signaling and the relationship between physical activity and BMD in men. These observations suggest that Wnt-LRP5 may play a role in the adaptation of bone to mechanical load in humans, and may explain some gender-related differences in bone mass.

Original languageEnglish
Pages (from-to)587-596
Number of pages10
JournalBone
Volume40
Issue number3
DOIs
StatePublished - Mar 2007
Externally publishedYes

Bibliographical note

Funding Information:
Supported by a grant from the National Institutes of Health (R01 AR/AG 41398). From the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195).

Keywords

  • Association study
  • BMD
  • Gene environment interaction
  • In vitro Wnt signaling
  • LRP5
  • Physical activity

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