Bone fractures and bone mineral density linked to gene variants

Bone fractures and bone mineral density linked to gene variants

According to a study published in the Journal of the American Medical Association, variants of the gene LRP5 are significantly associated with an increase in the risk of fractures (up to 20%). Researcher Joyce B. J. van Meurs, Ph.D. (Erasmus MC, Rotterdam, the Netherlands) and colleagues also find an association between the gene variants and lower levels of bone mineral density in the spine and hip.

Osteoporosis is a disease that deteriorates bones and increases the risk of fracture. It is characterized by low bone mineral density (BMD) and alterations in the amount and variety of proteins in bone. Previous research has found that up to 80% of the variance in BMD (a major predictor of osteoporotic fractures) is due to genetic factors. Though we do not know exactly which genes cause someone to be at a greater or lower risk for osteoporosis and osteoporotic fractures, it is believed that several common gene variants are responsible for determining this risk. Inconclusive studies with small sample sizes have suggested that some gene variants contribute to change in BMD in the general population. Others claim that variations of the gene LRP5 have been linked to bone mass accrual and susceptibility to osteoporosis.

Dr. van Meurs and colleagues improved previous studies by using individual-level data from the full Genetic Markers for Osteoporosis (GENOMOS) consortium - data from 37,534 individuals from 18 teams in Europe and North America. The researchers used the large data set to examine the association between variants to the genes LRP5 and LRP6 to bone mineral density and risk of fracture. An imaging technique called dual-energy x-ray absorptiometry was used to measure bone mineral density, and data on fractures came from questionnaires, medical records, or radiographic documentation. For some groups, new fracture data were available that came from routine surveillance methods like radiographic examination.

The researchers found that genetic variation of the LRP5 gene is linked to both BMD and risk of fracture. Members of this large-scale, multi-collaborative study found effect sizes that were modest in magnitude, but consistent across studies. "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," write the authors.

Van Meurs and colleagues add: "Our findings demonstrate that the modest effects of common genetic variations in complex diseases can be effectively addressed through large consortia and coordinated, standardized analysis. Such effects might be missed by smaller and potentially underpowered individual studies. This prospective collaborative study with individual level-data of 37,534 participants shows an effect of LRP5 genetic variation on both BMD and risk of fracture. While some other common variants have been associated previously with osteoporosis phenotypes [physical manifestations] with large-scale evidence, this may be the first time that an association in this field crosses the threshold of genome-wide statistical significance."

"Although the magnitude of the effect was modest, the effect was very consistent in different populations and independent of sex or age. This suggests a role for LRP5 in determining BMD and fracture risk throughout life in the general population. 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," conclude the authors

Joyce B. J. van Meurs, et al.

JAMA. 299[11]:1277-1290.

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