Background: The RANKL/RANK/OPG signaling pathway plays a critical role in osteoclastogenesis and bone remodeling. The associations between sequence variants of the osteoprotegerin (OPG) gene and osteoporosis risk have been widely investigated but remain inconclusive. Objective: We performed a meta-analysis to evaluate the associations between OPG gene variants and osteoporosis risk. Methods: We searched electronic databases and included studies meeting inclusion criteria. The genetic associations of four common OPG variants, A163G, T245G, T950C, and G1181C, with osteoporosis risk were explored. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for multiple genetic models. Subgroup analyses including ethnicity, gender, menopausal status, sample size, and control source were also performed. Results: Twenty-six studies comprising 4879 osteoporosis cases and 5708 controls were included. The A163G variant was found to be significantly associated with an increased risk of osteoporosis under both the allelic (G vs. A: OR = 1.45, 95% CI 1.29-1.64, p < 0.001) and dominant models (GG+GA vs. AA: OR = 1.48, 95% CI 1.29-1.70, p < 0.001). Significant associations were also found between the T245G variant and osteoporosis risk. In addition, we observed a reduced risk of osteoporosis in women with the CC genotype at T950C (OR = 0.76, 95% CI 0.64-0.89, p = 0.001) and among Caucasians with the GG or CG genotypes at the G1181C locus (OR = 0.78, 95% CI 0.64-0.94, p = 0.010). In postmenopausal women, only the GG/GA genotypes at the A163G variant were more predisposed to osteoporosis (OR = 1.31, 95% CI 1.00-1.71), whereas CC/CG carriers of G1181C locus may have reduced risk (OR = 0.83, 95% CI 0.66-1.03). Conclusions: Common variants of the OPG gene are associated with osteoporosis risk, especially in the Caucasian population and in the female subgroup. These genetic markers could potentially be used as predictive markers for osteoporosis.
Keywords: meta-analysis; osteoporosis; osteoprotegerin; sequence variant.