Genetic Variation in Candidate Osteoporosis Genes, Bone Mineral Density, and Fracture Risk: The Study of Osteoporotic Fractures

Abstract

Candidate osteoporosis gene variants were examined for associations with fracture risk and bone mineral density (BMD). A total of 9704 white women were recruited at four U.S. clinical centers and enrolled into the Study of Osteoporotic Fractures, a longitudinal cohort study. Genotyping of 31 polymorphisms from 18 candidate osteoporosis genes was performed in 6752 women. Incident radiographic fractures were identified at the third and eighth examinations compared with the baseline examination. BMD was measured at the total hip by dual-energy X-ray absorptiometry. Analyses were adjusted for age, clinic site, and self-reported ethnicity. During a mean follow-up of 14.5 years, a total of 849 hip, 658 vertebral, and 2496 nonhip/nonvertebral fractures occurred in 6752 women. Women carrying the ALOX15_G48924T T/T genotype had a higher rate of hip fracture (hazard ratio [HR] = 1.33;95% confidence interval [95% CI] = 1.00-1.77) compared with the G/G genotype. Compared with those carrying the PRL_T228C T/T genotype, women with either the C/ C (HR = 0.80; 95% CI = 0.67-0.95) or C/T (HR = 0.81; 95% CI = 0.68-0.97) genotype had a lower rate of nonvertebral/nonhip fractures. Women carrying theBMP2_A125611G G/G genotype had a higher rate of vertebral fracture (odds ratio [OR] = 1.51; 95% CI = 1.03-2.23) compared with the A/ Correspondence to: Gregory J. Tranah. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptA genotype. Women with the ESR1_C1335G G/G genotype had a higher rate of vertebral fracture (OR = 1.64; 95% CI = 1.07-2.50) compared with the C/C genotype. Compared with those with the MMP2_C595T C/C genotype, women with the C/T (OR = 0.79; 95% CI = 0.65-0.96) or T/T (OR = 0.44; 95% CI = 0.27-0.72) genotype had a lower rate of vertebral fracture. In conclusion, polymorphisms in several candidate genes were associated with hip, vertebral, and nonhip/ nonvertebral fractures but not with total hip BMD in this large population based cohort study. KeywordsGenetics; Polymorphism; Osteoporosis; BMD; FractureOsteoporosis is a disorder characterized by low bone mass and increased risk of fracture. Many factors influence the risk of osteoporosis, including diet, physical activity, medication use, coexisting diseases, and a family history of the disorder. Research into the genetic basis of osteoporosis has been motivated by evidence that bone traits tend to be highly heritable. Whereas genetic factors explain 50% to 80% [1-4] of the biological variation in bone density and other bone phenotypes, these factors are not sufficient to explain fracture risk [5]. Deng et al. [5] report that the genetic correlation between bone density and fracture is not significant and that most genes found to be relevant to bone density may not be important for hip fracture.Osteoporosis, like other genetically complex diseases, is the product of multiple genetic and environmental factors, and their interactions [6,7]. To date, several approaches have been attempted to identify osteoporosis-related genes...

Susceptibility genes for osteoporotic fracture in postmenopausal chinese women

“…(38) The GG genotype of the C1335G polymorphism in ESR1 conferred a high risk of vertebral fracture compared with the CC genotype (OR, 1.64; 95% CI, 1.07-2.50). (47) In this study, the AA genotype of rs9397448 and the CC genotype of rs2234693 were significantly associated with osteoporotic hip fracture, whereas the TT genotype of rs1643821 was significantly associated with osteoporotic wrist fracture. Haplotype AC of rs9397448 and rs2234693 was a risk factor, whereas haplotype GT of rs9397448 and rs2234693 was a protective factor for all types of osteoporotic fracture, particularly vertebral fracture.…”

Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density

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“…Several recent studies (5)(6)(7)(8)(9)(10) have demonstrated the effectiveness of this strategy. To date, dozens of quantitative trait loci (QTLs) (regions of the genome harboring genetic variation influencing a quantitative trait) affecting BMD have been identified in the mouse (11), and recently the pace of identifying QTL genes has rapidly progressed.…”

Genetics of osteoporosis: accelerating pace in gene identification and validation

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