title: 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.
abstract: 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 <or=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.
authors.affiliation: Division of Bone Diseases, University Hospital of Geneva, Geneva 1211, Switzerland. serge.ferrari@medecine.unige.ch
authors.forename: Serge L
authors.initials: SL
authors.lastname: Ferrari
authors.forename: Samuel
authors.initials: S
authors.lastname: Deutsch
authors.forename: Urmila
authors.initials: U
authors.lastname: Choudhury
authors.forename: Thierry
authors.initials: T
authors.lastname: Chevalley
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Bonjour
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Rene
authors.initials: R
authors.lastname: Rizzoli
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000166:cytology*; D002648:Child; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D011973:Receptors, LDL