Our aim was to investigate relative contributions of central and peripheral mechanisms to knee osteoarthritis (OA) diagnosis and their independent causal association with knee OA. We performed longitudinal analysis using data from UK-Biobank participants. Knee OA was defined using International Classification of Diseases manual 10 codes from participants' hospital records. Central mechanisms were proxied using multisite chronic pain (MCP) and peripheral mechanisms using body mass index (BMI). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated, and proportional risk contribution (PRC) was estimated from receiver-operator-characteristic (ROC) analysis. To estimate the causal effects, we performed 2-sample multivariable Mendelian Randomisation (MR) analysis. We selected genetic instruments from the largest Genome Wide Association Study of BMI (N = 806,834) and MCP (N = 387,649) and estimated the instruments genetic associations with knee OA in the largest available dataset (62,497 cases and 333,557 control subjects). The multivariable MR was performed using modified inverse-variance weighting methods. Of the 203,410 participants, 6% developed knee OA. Both MCP (OR 1.23, 95% CI; 1.21-1.24) and BMI (1.10, 95% CI; 1.10-1.11) were associated with knee OA diagnosis. The PRC was 6.9% (95% CI; 6.7%-7.1%) for MCP and 21.9% (95% CI; 21.4%-22.5%) for BMI; the combined PRC was 38.8% (95% CI; 37.9%-39.8%). Body mass index and MCP had independent causal effects on knee OA (OR 1.76 [95% CI, 1.64-1.88] and 1.83 [95% CI, 1.54-2.16] per unit change, respectively). In conclusion, peripheral risk factors (eg, BMI) contribute more to the development of knee OA than central risk factors (eg, MCP). Peripheral and central factors are independently causal on knee OA.

中文翻译：

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中枢和外周危险因素与膝骨关节炎的因果关系：使用英国生物银行数据进行的纵向和孟德尔随机研究。

我们的目的是调查中枢和外周机制对膝骨关节炎 (OA) 诊断的相对贡献及其与膝骨关节炎的独立因果关系。我们使用英国生物银行参与者的数据进行了纵向分析。膝关节 OA 的定义使用来自参与者医院记录的国际疾病分类手册 10 代码。使用多部位慢性疼痛（MCP）代表中枢机制，使用体重指数（BMI）代表外周机制。估计比值比 (OR) 和 95% 置信区间 (CI)，并根据接受者操作者特征 (ROC) 分析估计比例风险贡献 (PRC)。为了估计因果效应，我们进行了 2 样本多变量孟德尔随机化 (MR) 分析。我们从最大的 BMI (N = 806,834) 和 MCP (N = 387,6​​49) 全基因组关联研究中选择了遗传仪器，并在最大的可用数据集中（62,497 例病例和 333,557 名对照受试者）估计了仪器与膝关节 OA 的遗传关联。使用改进的逆方差加权方法进行多变量 MR。在 203,410 名参与者中，6% 患有膝骨关节炎。 MCP（OR 1.23，95% CI；1.21-1.24）和 BMI（1.10，95% CI；1.10-1.11）均与膝关节 OA 诊断相关。 MCP 的 PRC 为 6.9%（95% CI；6.7%-7.1%），BMI 为 21.9%（95% CI；21.4%-22.5%）；合并的 PRC 为 38.8%（95% CI；37.9%-39.8%）。体重指数和 MCP 对膝关节 OA 具有独立的因果影响（每单位变化 OR 分别为 1.76 [95% CI, 1.64-1.88] 和 1.83 [95% CI, 1.54-2.16]）。总之，外围危险因素（例如 BMI）比中心危险因素（例如 MCP）对膝关节 OA 的发生影响更大。周围因素和中枢因素对膝关节 OA 具有独立的因果关系。