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A genetic risk score (GRS) was developed for predicting fracture risk based on lifetime prevalence of femoral fractures in 924 consecutive autopsies of Japanese males. A total of 922 non-synonymous single nucleotide polymorphisms (SNPs) located in 62 osteoporosis susceptibility genes were genotyped and evaluated for their association with the prevalence of femoral fracture in autopsy cases. GRS values were calculated as the sum of risk allele counts (unweighted GRS) or the sum of weighted scores estimated from logistic regression coefficients (weighted GRS). Five SNPs (α-ʟ-iduronidase rs3755955, C7orf58 rs190543052, homeobox C4 rs75256744, G patch domain-containing gene 1 rs2287679, and Werner syndrome rs2230009) showed a significant association (P < 0.05) with the prevalence of femoral fracture in 924 male subjects. Both the unweighted and weighted GRS adequately predicted fracture prevalence; 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. Multiple logistic regression analysis revealed that the odds ratio (OR) 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 a score <3 (n = 797). Likewise, the OR for a weighted GRS of 6-15 (n = 135) was 7.73 (95 % CI 3.89-15.36, P < 0.001) relative to scores of 0-5 (n = 786). The GRS based on risk allele profiles of the five SNPs could help identify at-risk individuals and enable implementation of preventive measures for femoral fracture. [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]

Estrogens are thought to play an important role in bone metabolism through estrogen receptors (ER). Dinucleotide (cytosine-adenine, CA) repeat polymorphism in the human ER-β gene ( ESR2) has been reported to be associated with bone mineral density. We aimed to further elucidate the importance of this polymorphism in the pathogenesis of osteoporosis by examining its association with the incidence of femoral fracture. Deoxyribonucleic acids extracted from the renal cortex of 1489 consecutive Japanese autopsies (799 male, mean age 79 years, 690 female, mean age 82 years) with complete clinical/pathological data were enrolled in the study. ESR2 CA repeat polymorphism was determined by polymerase chain reaction using fluorescein-labeled primers. The presence or absence of femoral fracture during each subject's lifetime was determined by thorough examination of the clinical record. Incidence of femoral fracture in subjects bearing at least one allele of 20 CA repeats (4/132, 3.0 %) was significantly lower than in those without this allele (127/1357, 9.4 %, P = 0.0098). After adjustments for age and sex, logistic regression analysis revealed that having no allele of 20 CA repeats was an independent risk factor of femoral fracture [adjusted odds ratio (OR) 3.875, 95 % confidence interval (CI) 1.392-10.788, P = 0.0095], which was emphasized among women (adjusted OR 6.360, 95 % CI 1.520-26.618, P = 0.0133). Japanese subjects, especially women, bearing at least one allele of 20 CA repeats in the ESR2 may have a lower risk of femoral fracture than those without it, suggesting this polymorphism plays a role in bone metabolism. [ABSTRACT FROM AUTHOR]