| Summary: | (1) Background: The prevalence of knee osteoarthritis (OA) in women is significantly higher than in men. The estrogen receptor α (ERα) has been considered to play a key role due to a large gender difference in its expression. ERα is encoded by the gene estrogen receptor 1 (<i>ESR1</i>), which is widely studied to explore the gender difference in knee OA. Several polymorphisms in <i>ESR1</i> [PvuII (rs2234693) and BtgI (rs2228480)] were confirmed as the risk factors of OA. However, the evidence of the last widely investigated polymorphism, <i>ESR1</i> Xbal (rs9340799), is still insufficient for concluding its effect on knee OA. (2) Objective: This study proposed a case–control study to investigate the association between <i>ESR1</i> Xbal and knee OA. Moreover, a meta-analysis and trial sequential analysis (TSA) were conducted to enlarge the sample size for obtaining a conclusive evidence. (3) Methods: In total, 497 knee OA cases and 473 healthy controls were recruited between March 2015 and July 2018. The Kellgren–Lawrence grading system was used to identify the knee OA cases. To improve the evidence level of our study, we conducted a meta-analysis including the related studies published up until December 2018 from PubMed, Embase, and previous meta-analysis. The results are expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CI) for evaluating the effect of this polymorphism on knee OA risk. TSA was used to estimate the sample sizes required in this issue. (4) Results: We found non-significant association between the G allele and knee OA [Crude-OR: 0.97 (95% CI: 0.78–1.20) and adjusted-OR: 0.90 (95% CI: 0.71–1.15) in allele model] in the present case–control study, and the analysis of other genetic models showed a similar trend. After including six published studies and our case–control studies, the current evidence with 3174 Asians showed the conclusively null association between <i>ESR1</i> XbaI and knee OA [OR: 0.78 (95% CI: 0.59–1.04)] with a high heterogeneity (<i>I<sup>2</sup></i>: 78%). The result of Caucasians also concluded the null association [OR: 1.05 (95% CI: 0.56–1.95), <i>I<sup>2</sup></i>: 87%]. (5) Conclusions: The association between <i>ESR1</i> XbaI and knee OA was not similar with other polymorphisms in <i>ESR1</i>, which is not a causal relationship. This study integrated all current evidence to elaborate this conclusion for suggesting no necessity of future studies.
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