Implementation of personalized medicine for fracture risk assessment in osteoporosis

The present review summarizes our efforts to identify genetic polymorphisms associated with osteoporotic fractures and to establish a genetic risk score ( GRS ) to predict fracture risk in consecutive J apanese autopsy cases carried out at T okyo M etropolitan G eriatric H ospital between 1995 and 2011. Three single nucleotide polymorphisms in transforming growth factor β‐1, rs1800470; thrombospondin, type 1, domain‐containing 7A, rs12673692; and formiminotransferase N ‐terminal subdomain‐containing gene, rs7605378, showed a significant association with vertebral fracture prevalence, whereas five (α‐ l ‐iduronidase, rs3755955; C7orf58 , rs190543052; homeobox C 4, rs75256744; G  patch domain‐containing gene 1, rs2287679; and Werner syndrome, rs2230009) were significantly associated with femoral fracture. GRS values were calculated as the sum of risk allele counts (unweighted GRS ) or of weighted scores estimated from logistic regression coefficients (weighted GRS ). Both GRS values using the five single nucleotide polymorphisms adequately predicted femoral fracture prevalence for 924 male subjects; the areas under receiver‐operating characteristic curves were 0.750 (95% confidence interval [ CI ] 0.660–0.840) and 0.770 (95% CI 0.681–0.859), respectively. Logistic regression analysis showed that the odds ratio for the association between fracture prevalence and unweighted GRS ≥3 ( n  = 124) was 8.39 (95% CI 4.22–16.69, P  < 0.001) relative to GRS  < 3 ( n  = 797). Likewise, the odds ratio for a weighted GRS of 6–15 ( n  = 135) was 7.73 (95% CI 3.89–15.36, P  < 0.001) relative to GRS 0–5 ( n  = 786). Therefore, the GRS based on the risk allele profiles of these five single nucleotide polymorphisms could help identify at‐risk individuals and enable implementation of preventive measures for femoral fracture. G eriatr G erontol I nt 2016; 16 (Suppl. 1): 57–65.