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Genetic risk score predicts patients' susceptibility to osteoporosis-related bone fractures

Researchers created a genetic profile that could assist in determining individuals at risk for bone fractures associated with osteoporosis, according to study results published in the Journal of Bone Mineral Research.  

“We have known for many years that a number of genetic variants are linked to low bone density and to fracture — but until now, we have struggled to transform that knowledge into clinical benefit to patients,” Tuan Nguyen, PhD, professor, Garvan Institute of Medical Research and University of Technology, Sydney, said in a press release. “Our study shows, for the first time, that we can classify an individual's risk of breaking a bone much more reliably when we take genetic factors into account alongside clinical factors. This is a major step towards personalized medicine for osteoporosis.”

Nguyen and colleagues genotyped 62 bone mineral density (BMD)-associated single-nucleotide polymorphisms (SNPs) in 557 men and 902 women who previously participated in the Dubbo Osteoporosis Epidemiology Study. Researchers used X-ray to determine fragility fracture frequency and calculated femoral neck BMD using dual-energy X-ray absorptiometry. They calculated a weighted polygenic risk score (GRS) as a function of the number of risk alleles and their BMD-associated regression coefficients for each SNP. The relationship between GRS and fracture risk was assessed by the Cox's proportional hazards model.

According to researchers, patients with greater GRS had lower femoral neck BMD (P < .01), but the adaptation in GRS accounted for less than 2% of total variance in BMD. Each unit increase in GRS was associated with a hazard ratio of 1.2 (95% CI, 1.04-1.38) for fracture, and this connection was independent of age, prior fracture and fall. In a subset of 33 SNPs, the increase was also independent of femoral neck BMD. The distinct connection between GRS and fracture was only seen in vertebral and wrist fractures and the area under the receiver operating characteristic curve for the model with GRS and clinical risk factors was 0.71 (95% CI, 0.68-0.74). With GRS, the correct reclassification of fracture vs. non-fracture ranged from 12% for hip fracture to 23% for wrist fracture.

"Once we have validated our findings in other populations, we will be looking to develop a cost-effective gene profiling test that will be available for clinicians to use,” Nguyen said in the press release. “The test will determine a 'genetic risk score' on the basis of a blood sample, which contains ample DNA for profiling.”– by Janel Miller

Disclosure: Nguyen reports receiving honoraria for consulting and speaking in symposia sponsored by Merck Sharp & Dohme, Roche, Sanofi-Aventis, Novartis, and Bridge Healthcare Pty Ltd Vietnam, and receiving Sanofi-Aventis, BUPA and NHMRC project grant. Please see the study for all other authors’ financial disclosures.