Large-scale association study between two coding LRP5 gene polymorphisms and bone phenotypes and fractures in men

Summary: Herein we investigated the association between polymorphisms in the LRP5 gene and bone phenotypes and fractures in three large male cohorts based on the rationale that mutations in LRP5 cause severe bone phenotypes. Results showed an association of the Val667Met SNP with spine BMD in 3,800 young and elderly men. Introduction: The low-density lipoprotein receptor-related protein 5 (LRP5)-Wnt signalling system is of importance for regulating osteoblastic activity, which became clear after findings that inactivating mutations in LRP5 cause osteoporosis. The overall aim of this study was to investigate the association between polymorphisms in the LRP5 gene and bone mineral density (BMD) in three large cohorts of young and elderly men. Methods: The cohorts used were MrOS Sweden (n=3014, aged 69-81 years) and MrOs Hong Kong (n=2000, aged >65 years) and the Swedish GOOD study (n=1068, aged 18-20 years). The polymorphisms Val667Met and Ala1330Val were genotyped using a TaqMan assay. Results: When combining the data from the Swedish cohorts in a meta-analysis (n=3,800), men carrying the 667Met-allele had 3% lower BMD at lumbar spine compared with non-carriers (p<0.05). The Val667Met SNP was not polymorphic in the Hong Kong population and thus were not included. There were no associations between the Ala1330Val SNP and bone phenotypes in the study populations. No associations between the LRP5 polymorphisms and self-reported fractures were seen in MrOs Sweden. Conclusions: Results from these three large cohorts indicate that the Val667Met polymorphism but not the Ala1330Val contributes to the observed variability in BMD in the Swedish populations.