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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 Japanese autopsy cases carried out at Tokyo Metropolitan Geriatric Hospital 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 C4, 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. [ABSTRACT FROM AUTHOR]

Werner syndrome is a rare autosomal recessive disorder caused by mutations in the human WRN gene and characterized by the early onset of normal aging symptoms. Given that patients with this disease exhibit osteoporosis, the present study aimed to determine whether the WRN gene contributes to the etiology of osteoporosis. A genetic association study of eight non-synonymous polymorphisms in the WRN gene and the incidence of femoral fracture was undertaken in 1,632 consecutive Japanese autopsies in which 140 patients had experienced the fracture during their lifetime. The results were validated in 251 unrelated postmenopausal Japanese women with osteoporosis and 269 non-institutionalized, community-dwelling Japanese adults. A statistically significant association was observed between rs2230009 (c.340G > A)--which results in a Val to Ile substitution--and fracture risk; the incidence of femoral fracture increased dose-dependently with the number of A alleles (p = 0.0120). Femoral neck bone and whole bone densities were lower among postmenopausal women with osteoporosis and community-dwelling adults, respectively, if they were of the AG instead of the GG genotype. The results suggest that Japanese subjects bearing at least one A allele of rs2230009 of the WRN gene are at a significantly higher risk of femoral fracture, possibly due to decreased bone density. [ABSTRACT FROM AUTHOR]

We previously reported 2 osteoporosis-susceptibility genes-formiminotransferase N-terminal sub-domain containing gene (FONG) and thrombospondin, type 1, domain-containing 7A (THSD7A)-in which we identified two common single-nucleotide polymorphisms, rs7605378 (FONG) and rs12673692 (THSD7A). The former was associated with a predisposition to osteoporosis and the latter with bone mineral density. To further elucidate the importance of these polymorphisms in the pathogenesis of osteoporosis, we examined their association with the incidence of vertebral fracture. DNA extracted from the renal cortex of 2427 consecutive Japanese autopsies (1331 men, mean age: 79 years; 1096 women, mean age: 82 years) were examined in this study. The presence or absence of vertebral fracture during each subject's lifetime was determined by a thorough examination of the clinical records, as well as autopsy reports. After adjustments for sex and age at autopsy, logistic regression analysis revealed that homozygotes for the risk alleles of rs7605378 (A-allele) or rs12673629 (A-allele) possess an increased risk of vertebral fracture. The subjects simultaneously homozygous for both the risk alleles of rs7605378 (AA genotype) and rs12673629 (AA genotype) showed significantly higher risk of vertebral fracture (odds ratio 2.401, 95% confidence interval 1.305-4.416, P=0.0048) than those who had at least one non-risk allele of either rs7605378 (AC/CC genotypes) or rs12673629 (AG/GG genotypes). The results suggest that Japanese subjects homozygous for the risk alleles of rs7605378 and rs12673629 have a higher risk of vertebral fracture. [ABSTRACT FROM AUTHOR]

Aim: Sarcopenia is the significant degenerative loss of skeletal muscle mass and strength associated with aging, and it is one of the components of frailty. We previously reported an association between the 29C>T polymorphism in the transforming growth factor-β1 gene (rs1800470) and the prevalence of vertebral fractures in subjects with postmenopausal osteoporosis. The association was not attributable to bone mineral density, which suggests that polymorphism influences some aspects of bone quality that affects strength and/or frailty rather than bone strength itself. Thus, we examined the relationship between genetic polymorphism and lean body mass in a Japanese population. Methods: A total of 479 adults comprising 143 men and 336 women, age 23 to 85 years, participated in the present study. Fat-free mass was measured by dual energy X-ray absorptiometry, and the relative skeletal muscle index was calculated as the ratio of appendicular (sum of arms and legs) fat-free mass to the square of height. Results: Total, leg, and appendicular fat-free mass as well as the relative skeletal muscle index were significantly lower in male subjects with CT/TT genotypes compared to those with CC genotype. Female subjects did not show any genotype-dependent differences when analyzed as a group, but when those without menstruation (postmenopausal women) were analyzed, arm fat-free mass was significantly lower in the CT/TT genotypes than in the CC genotype. Conclusions: T allele of the 29C>T polymorphism in the transforming growth factor-β1 gene might be a risk factor of sarcopenia in a Japanese population. Geriatr Gerontol Int 2012; 12: 292-297. [ABSTRACT FROM AUTHOR]