Evaluation of Association between Estrogen receptor α Polymorphisms and Osteoporotic Fracture Risk: an updated meta-analysis

Abstract Background Many studies have investigated the association between the Estrogen receptor α (ESR1) polymorphisms and the osteoporotic fracture risk. However, several studies have reported conflicting results. Since 1999, researchers have published five meta-analyses exploring the association of ESR1 PvuII (rs2234693: T/C) and ESR1 XbaI (rs9340799: G/A) polymorphisms with osteoporotic fracture risk. However, several complications emerged in their meta-analysis, starting with mistakes during the inclusion process. Moreover, the reliability of the statistically significant associations was not tested. Several novel studies have been published on the subject from 2015 onwards; hence, we designed an updated meta-analysis to explore the associations between ESR1 PvuII and ESR1 XbaI polymorphisms and osteoporotic fracture risk and to study potential meta-analysis complications. Methods Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled to evaluate the association between ESR1 PvuII and ESR1 XbaI polymorphisms and osteoporotic fracture risk. To evaluate the credibility of the statistically significant associations, we applied the false-positive report probability (FPRP) test, the Bayesian False Discovery Probability (BFDP) and Venice criteria in previous meta-analysis and the current study. Results The current meta-analysis had a larger sample size than the previous ones: 29 studies with 3,193 cases and 18,048 controls for ESR1 PvuII polymorphism, 12 studies with 1,155 cases and 3,191 controls for ESR1 XbaI polymorphism. Five gene models were used to explore the association between the two polymorphisms and osteoporotic fracture risk and partial positive results were similar to published meta-analyses results. For the overall analysis, we observed an increased risk of fracture with the ESR1 PvuII T allele (C vs T: OR = 0.85, 95%CI:0.78–0.92; CC vs TT: OR = 0.74, 95%CI:0.63–0.87; TC + CC vs TT: OR = 0.81, 95%CI:0.72–0.92; CC vs TT + TC: OR = 0.81, 95%CI:0.72–0.92) and some subgroups, such as Caucasians, source of control from Population-based, Female, Vertebra, Hip, and Postmenopausal. A significantly increased osteoporotic fracture risk also was found in the ESR1 XbaI polymorphism (GG vs AA: OR = 0.66, 95%CI:0.48–0.89; GG vs AA + AG: OR = 0.69, 95%CI:0.54–0.89) and several subgroups, such as Caucasians, Male, Female, and vertebra. However, when we assessed the credibility of the results, we suspected that the presented positive results were false-positive results in our study. Conclusions The positive results should be carefully interpreted, to avoid lowering their credibility. We suggest that significant associations between ESR1 PvuII and ESR1 XbaI polymorphisms and osteoporotic fracture risk might be because of inadequate positive results’ interpretation and hence, do not represent a link between genes and osteoporotic fracture risk.