Polymorphisms in the Low-Density Lipoprotein Receptor.Related Protein 5 (LRP5) Gene Are Associated with Variation in Vertebral Bone Mass, Vertebral Bone Size, and Stature in Whites
L. Ferrari, Serge et al., Polymorphisms in the Low-Density Lipoprotein Receptor.Related Protein 5 (LRP5) Gene Are Associated with Variation in Vertebral Bone Mass, Vertebral Bone Size, and Stature in Whites, American journal of human genetics , 74(5), 2004, pp. 866-875
Stature, bone size, and bone mass are interrelated traits with high heritability, but the major genes that govern these phenotypes remain unknown. Independent genomewide quantitative-trait locus studies have suggested a locus for bone-mineral density and stature at chromosome 11q12-13, a region harboring the low-density lipoprotein receptor.related protein 5 (LRP5) gene. Mutations in the LRP5 gene were recently implicated in osteoporosis-pseudoglioma and .high-bone-mass. syndromes. To test whether polymorphisms in the LRP5 gene contribute to bone-mass determination in the general population, we studied a cross-sectional cohort of 889 healthy whites of both sexes. Significant associations were found for a missense substitution in exon 9 (c.2047G.A) with lumbar spine (LS).bone-mineral content (BMC) (P=.0032), with bone area (P=.0014), and with stature (P=.0062). The associations were observed mainly in adult men, in whom LRP5 polymorphisms accounted for .15% of the traits. variances. Results of haplotype analysis of five single-nucleotide polymorphisms in the LRP5 region suggest that additional genetic variation within the locus might also contribute to bone-mass and size determination. To confirm our results, we investigated whether LRP5 haplotypes were associated with 1-year gain in vertebral bone mass and size in 386 prepubertal children. Significant associations were observed for changes in BMC (P=.0348) and bone area (P=.0286) in males but not females, independently supporting our observations of a mostly male-specific effect, as seen in the adults. Together, these results suggest that LRP5 variants significantly contribute to LS.bone-mass and size determination in men by influencing vertebral bone growth during childhood.