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

Ferrari, Serge Livio; Deutsch, Samuel; Choudhury, Urmila; Chevalley, Thierry; Bonjour, Jean-Philippe; Dermitzakis, Emmanouil; Rizzoli, René; Antonarakis, Stylianos

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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
Authors		Ferrari, Serge Livio Deutsch, Samuel Choudhury, Urmila Chevalley, Thierry Bonjour, Jean-Philippe Dermitzakis, Emmanouil Rizzoli, René Antonarakis, Stylianos
Published in		American Journal of Human Genetics. 2004, vol. 74, no. 5, p. 866-875
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.
Keywords		Adolescent — Adult — Amino Acid Substitution — Bone Density/ genetics — Bone and Bones/ cytology — Child — Chromosomes, Human, Pair 11/genetics — Cohort Studies — Cross-Sectional Studies — European Continental Ancestry Group/ genetics — Female — Gene Frequency — Genetic Variation — Humans — LDL-Receptor Related Proteins — Male — Middle Aged — Mutation, Missense/ genetics — Polymorphism, Single Nucleotide/ genetics — Receptors, LDL/ genetics
Identifiers		DOI: 10.1086/420771 PMID: 15077203
Full text		Article - Limited access to UNIGE Other version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1181981/pdf/AJHGv74p866.pdf
Structures		Faculté de médecine / Section de médecine clinique / Département de médecine interne des spécialités
Citation (ISO format)		FERRARI, Serge Livio 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. In: American Journal of Human Genetics, 2004, vol. 74, n° 5, p. 866-875. https://archive-ouverte.unige.ch/unige:8744