Abstract
(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 (ESR1), which is widely studied to explore the gender difference in knee OA. Several polymorphisms in ESR1 [PvuII (rs2234693) and BtgI (rs2228480)] were confirmed as the risk factors of OA. However, the evidence of the last widely investigated polymorphism, ESR1 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 ESR1 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 ESR1 XbaI and knee OA [OR: 0.78 (95% CI: 0.59–1.04)] with a high heterogeneity (I2: 78%). The result of Caucasians also concluded the null association [OR: 1.05 (95% CI: 0.56–1.95), I2: 87%]. (5) Conclusions: The association between ESR1 XbaI and knee OA was not similar with other polymorphisms in ESR1, which is not a causal relationship. This study integrated all current evidence to elaborate this conclusion for suggesting no necessity of future studies.
Highlights
Knee osteoarthritis (OA) is a leading cause of disability in most developed countries [1,2,3,4]
trial sequential analysis (TSA) result show that the current cumulative samples were sufficient to reach a decisive conclusion and our case–control sample provided the critical information in Asians
To the best of our knowledge, this study is the first meta-analysis to explore the correlation between estrogen receptor 1 (ESR1) Xbal and knee OA using TSA
Summary
Knee osteoarthritis (OA) is a leading cause of disability in most developed countries [1,2,3,4]. Genetic factors play a key role in knee OA pathogenesis. Previous research suggested that OA is primarily influenced by genetic risk factors due to common population polymorphisms in multiple genes [7,8,9]. Women are more likely than men to show a deactivation or alteration of miRNAs that are important for estrogen signaling and collagen production [13]. The estrogen receptor α (ERα) is a nuclear receptor that is activated by the sex hormone estrogen. ERα is encoded by the gene estrogen receptor 1 (ESR1) which is widely studied to explore the gender difference in knee OA. ESR1 is a ligand-activated transcription factor composed of several domains important for hormone binding [14]. The polymorphisms of ESR1 have frequently been investigated for describing the genetic effect in OA
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