Karolinska Institutet, Stockholm, Sweden.
Harvard University, Boston, Massachusetts.
Arthritis Rheumatol. 2021 Feb;73(2):203-211. doi: 10.1002/art.41517. Epub 2020 Dec 29.
To investigate the association between obesity-related traits and risk of rheumatoid arthritis (RA).
We conducted genetic correlation analysis and a 2-sample Mendelian randomization (MR) study, using genome-wide genetic data based on >850,000 individuals of European ancestry. Summary statistics were collected from the largest genome-wide association study conducted to date for body mass index (BMI; n = 806,810), waist-to-hip ratio (WHR; n = 697,734), WHR adjusted for BMI (WHRadjBMI; n = 694,649), and RA (n = 14,361, n = 43,923). We conducted cross-trait linkage disequilibrium score regression and ρ-HESS analyses to quantify genetic correlation between pairs of traits (causal overlap). For each obesity-related exposure, we utilized independent, genome-wide significant single-nucleotide polymorphisms (P < 5 × 10 ) as instruments to perform MR analysis (causal relationship). We interrogated the causal relationship both in the general population and in a sex-specific manner and calculated odds ratios (ORs) and 95% confidence intervals (95% CIs). Sensitivity analyses were performed to validate MR model assumptions.
Despite a negligible overall genetic correlation between the 3 obesity-related traits and RA, we found significant local genetic correlations at several regions on chromosome 6 (positions 28-29M, 30-35M, and 50-52M), highlighting a shared genetic basis. We further observed an increased risk of RA per SD increment (4.8 kg/m ) in genetically predicted BMI (OR 1.22 [95% CI 1.09-1.37]). The effect was consistent across sensitivity analyses and comparable between sexes (OR 1.22 [95% CI 1.04-1.44] in male subjects and 1.19 [95% CI 1.04-1.36] in female subjects). However, we did not find evidence supporting a causal role of either WHR (OR 0.98 [95% CI 0.84-1.14]) or WHRadjBMI (OR 0.90 [95% CI 0.79-1.04]) in RA.
Genetically predicted BMI significantly increases RA risk. Future studies are needed to understand the biologic mechanisms underlying this link.
探讨肥胖相关特征与类风湿关节炎（RA）风险之间的关联。
我们进行了遗传相关分析和两样本 Mendelian 随机化（MR）研究，使用了基于 >850,000 名欧洲血统个体的全基因组遗传数据。基于迄今为止最大的体重指数（BMI；n=806,810）、腰围-臀围比（WHR；n=697,734）、BMI 调整后的 WHR（WHRadjBMI；n=694,649）和 RA（n=14,361，n=43,923）的全基因组关联研究，收集了汇总统计数据。我们进行了跨特征连锁不平衡得分回归和 ρ-HESS 分析，以量化两对特征之间的遗传相关性（因果重叠）。对于每种肥胖相关的暴露，我们利用独立的、全基因组显著的单核苷酸多态性（P<5×10 ）作为工具进行 MR 分析（因果关系）。我们在一般人群和性别特异性的基础上探讨了因果关系，并计算了比值比（OR）和 95%置信区间（95%CI）。进行了敏感性分析以验证 MR 模型假设。
尽管 3 种肥胖相关特征与 RA 之间存在微不足道的总体遗传相关性，但我们在 6 号染色体上的几个区域（28-29M、30-35M 和 50-52M）发现了显著的局部遗传相关性，突出了共同的遗传基础。我们进一步观察到，遗传预测 BMI 每增加 1 SD（4.8kg/m ），RA 的风险增加（OR 1.22[95%CI 1.09-1.37]）。该效应在敏感性分析中一致，且在性别间相当（男性受试者中 OR 1.22[95%CI 1.04-1.44]，女性受试者中 OR 1.19[95%CI 1.04-1.36]）。然而，我们没有发现支持 WHR（OR 0.98[95%CI 0.84-1.14]）或 WHRadjBMI（OR 0.90[95%CI 0.79-1.04]）在 RA 中具有因果作用的证据。
遗传预测 BMI 显著增加了 RA 的风险。需要进一步的研究来了解这种关联的生物学机制。
