Gene Variants Associated with Risk of Bone Fractures

Joyce B. J. van Meurs, Ph.D., of Erasmus MC, Rotterdam, the Netherlands and colleagues examined the association between variants to the genes LRP5 and LRP6 to bone mineral density (BMD) and risk of fracture using large-scale evidence, with the combined analysis of individual-level data of the full Genetic Markers for Osteoporosis (GENOMOS) consortium, including data from 37,534 individuals from 18 participating teams in Europe and North America.

BMD was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; new fracture data were available for some groups, determined via routine surveillance methods, including radiographic examination for vertebral fractures.

“In this large-scale multicenter collaborative study, we obtained evidence that genetic variation of the LRP5 gene is associated with both BMD and fracture risk. The magnitude of the effects was modest but very consistent across studies,” the authors write. “Based on the general acceptance that a 1-standard deviation reduction in bone mass doubles the fracture rate, an increase of fracture risk of about 15 percent to 20 percent is expected.

This is similar to the observed effects on fracture, although adjustment for BMD only partly reduced the increase in fracture risk. This could raise the possibility of effects on bone quality, bone dimension, or other nonskeletal determinants of fracture, but also could be due to error in measurement of BMD. Further work will be required to address this point.”

“Although any single marker explains only a small portion of the phenotype risk, identification of several such osteoporosis risk variants may eventually help in improving clinical prediction. Single genetic risk variants such as LRP5 may also offer useful insights about mechanisms and pathways that may be useful in drug development,” the researchers conclude.; Source: Wiley-Blackwell