St John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.
Department of Medical and Molecular Genetics, School of Basic & Medical Biosciences, King's College London, London, United Kingdom.
JAMA Cardiol. 2024 Nov 1;9(11):1009-1017. doi: 10.1001/jamacardio.2024.2859.
The epidemiological link between immune-mediated diseases (IMIDs) and cardiovascular disease has often been attributed to systemic inflammation. However, the direction of causality and the biological mechanisms linking cardiovascular disease with IMIDs are incompletely understood. Given the robust epidemiological association and the growing body of supportive mechanistic evidence, psoriasis is an exemplary IMID model for exploring this relationship.
To assess the bidirectional relationships between genetic predictors of psoriasis and the 2 major forms of cardiovascular disease, coronary artery disease (CAD) and stroke, and to evaluate the association between genetic predictors of cardiovascular disease with 9 other IMIDs.
DESIGN, SETTING, AND PARTICIPANTS: This was a genetic association study using mendelian randomization (MR), a powerful genetic tool to help distinguish causation from associations observed in epidemiological studies, to provide supportive evidence for causality between traits. The study conducted 2-sample MR analyses using summary-level data from large-scale genome-wide association meta-analysis studies (GWAS) for each trait. The analysis focused on individuals of European descent from GWAS meta-analyses, involving CAD, stroke, psoriasis, and 9 other IMIDs. Data were analyzed from January 2023 to May 2024.
Genetic predictors of CAD, stroke, psoriasis, and 9 other IMIDs.
The primary outcomes were the associations of genetic predictors of CAD and stroke with the risk of psoriasis and 9 other IMIDs, determined using inverse-variance weighted (IVW) MR estimates.
This study included 181 249 cases and 1 165 690 controls with CAD, 110 182 cases and 1 503 898 controls with stroke, 36 466 cases and 458 078 controls with psoriasis, for a total of approximately 3 400 000 individuals, and 9 other IMIDs. In contrast to previous assumptions, genetic predictors of psoriasis were found to have no association with CAD or stroke. In the reverse direction, genetic predictors of both CAD (MR estimate IVW odds ratio [OR], 1.07; 95% CI, 1.04-1.10; P = .003) and stroke (IVW OR, 1.22; 95% CI, 1.05-1.41; P = .01) were found to have risk-increasing associations with psoriasis. Adjusting for stroke rendered the associations of genetically predicted CAD with psoriasis risk nonsignificant (and vice versa), suggesting that a shared effect underlying genetic risk for CAD and stroke associates with increased psoriasis risk. No risk-increasing associations were observed for genetic predictors of cardiovascular disease with other common IMIDs, including rheumatoid arthritis and inflammatory bowel disease.
Findings of this mendelian randomization study indicate that genetic predictors of cardiovascular disease were associated with increased psoriasis risk with no reciprocal effect or association with other IMIDs. Elucidating mechanisms underpinning this association could lead to novel therapeutic approaches in both diseases.
免疫介导性疾病（IMIDs）和心血管疾病之间的流行病学联系通常归因于全身炎症。然而，心血管疾病与 IMIDs 之间的因果关系方向和生物学机制仍不完全清楚。鉴于其强大的流行病学关联和越来越多的支持性机制证据，银屑病是探索这种关系的理想 IMID 模型。
评估银屑病的遗传预测因子与 2 种主要形式的心血管疾病（冠心病 [CAD] 和中风）之间的双向关系，并评估心血管疾病的遗传预测因子与其他 9 种 IMIDs 之间的关联。
设计、设置和参与者：这是一项使用孟德尔随机化（MR）的遗传关联研究，MR 是一种强大的遗传工具，可帮助区分流行病学研究中观察到的因果关系和关联，为性状之间的因果关系提供支持证据。该研究使用大型全基因组关联荟萃分析研究（GWAS）的汇总水平数据，针对每种性状进行了 2 样本 MR 分析。该分析重点关注欧洲血统的个体，涉及 CAD、中风、银屑病和其他 9 种 IMIDs。数据于 2023 年 1 月至 2024 年 5 月进行分析。
CAD、中风、银屑病和其他 9 种 IMIDs 的遗传预测因子。
主要结局是 CAD 和中风的遗传预测因子与银屑病和其他 9 种 IMIDs 风险之间的关联，使用逆方差加权（IVW）MR 估计值确定。
本研究共纳入 181249 例 CAD 病例和 1165690 例对照、110182 例中风病例和 1503898 例对照、36466 例银屑病病例和 458078 例对照，总计约 340 万人，以及其他 9 种 IMIDs。与之前的假设相反，银屑病的遗传预测因子与 CAD 或中风没有关联。在相反的方向上，CAD（MR 估计 IVW 比值比 [OR]，1.07；95%CI，1.04-1.10；P = .003）和中风（IVW OR，1.22；95%CI，1.05-1.41；P = .01）的遗传预测因子都与银屑病风险呈正相关。调整中风后，CAD 的遗传预测因子与银屑病风险的关联不再显著（反之亦然），表明 CAD 和中风的遗传风险的共同影响与银屑病风险的增加有关。心血管疾病的遗传预测因子与其他常见的 IMIDs（包括类风湿关节炎和炎症性肠病）没有发现风险增加的关联。
这项孟德尔随机化研究的结果表明，心血管疾病的遗传预测因子与银屑病风险增加有关，而没有相互作用或与其他 IMIDs 有关。阐明这种关联的潜在机制可能会为这两种疾病带来新的治疗方法。
