DataSheet1_Causal associations between CD40/CD40L and aortic diseases: A mendelian randomization study.PDF

Background: CD40 and CD40L have been reported as associated with aortic dissection (AD) and aortic aneurysm (AA), but the causality of the associations has not been established yet.Methods: We conducted a two-sample Mendelian randomization (MR) study to assess the causal inference between CD40/CD40L and aortic diseases including AD and AA. The instrumental variables (IVs) for CD40 and CD40L were selected from a high-quality protein quantitative trait loci dataset released by a genomic study involving 30,931 individuals of European ancestry. The genome-wide association studies summary statistics for AD and AA were from the FinnGen Release 7, with 288638 controls for all outcomes of interests, 680 cases for AD and 6,092 cases for AA, also from European ancestry. For AA subtypes, there were 5,881 cases of thoracic AA (TAA) and 2,434 cases of abdominal AA (AAA) respectively. Inverse-variance weighted and Wald ratio were applied for calculating causal estimates. Horizontal pleiotropy and heterogeneity were assessed using MR-Egger regression analysis and Cochran Q test, respectively. Leave-one-out analyses were further performed.Results: Three single-nucleotide polymorphisms (SNPs) for CD40 and one SNP for CD40L were selected as IVs. We found genetic proxied CD40 levels inversely associated with the risk of AD (odds ratio [OR]: 0.777, 95% confidence interval [CI]: 0.618–0.978, p = 0.031) and AA (OR: 0.905, 95% CI: 0.837–0.978, p = 0.012), consistent across TAA (both p < 0.050). There were trends of increased risks of AD and AA in the presence of CD40L while not reaching statistical significance. No significant horizontal pleiotropy or heterogeneity was observed.Conclusion: Our MR study provides evidence supporting the causal association between CD40 and the reduced risks of both AD and AA.

背景：CD40与CD40L已被报道与主动脉夹层（AD）和主动脉瘤（AA）相关联，但尚未确立其因果关系的确定性。方法：本研究采用双样本孟德尔随机化（MR）研究，以评估CD40/CD40L与主动脉疾病（包括AD和AA）之间的因果推断。CD40和CD40L的 instrumental variables（IVs）来自一项涉及30,931名欧洲血统个体的高质量蛋白质数量性状位点（QTL）数据集。AD和AA的全基因组关联研究（GWAS）汇总统计数据来源于FinnGen Release 7，其中包含288,638名对照者，针对所有感兴趣的结果，以及680名AD病例和6,092名AA病例，均来自欧洲血统。在AA亚型中，分别有5,881例胸主动脉瘤（TAA）和2,434例腹主动脉瘤（AAA）。采用逆方差加权法和Wald比率计算因果估计值。通过MR-Egger回归分析和Cochran Q检验分别评估水平多效性和异质性。进一步进行了留一法分析。结果：选出了CD40的三个单核苷酸多态性（SNPs）和CD40L的一个SNPs作为IVs。我们发现遗传中介的CD40水平与AD（优势比[OR]：0.777，95%置信区间[CI]：0.618–0.978，p = 0.031）和AA（OR：0.905，95% CI：0.837–0.978，p = 0.012）的风险呈负相关，这一结果在TAA中均一致（p < 0.050）。在存在CD40L的情况下，AD和AA的风险趋势增加，但未达到统计学意义。未观察到显著的水平多效性或异质性。结论：我们的MR研究提供了证据，支持CD40与AD和AA降低风险之间的因果关联。