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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.

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]