Association between age-related cardiovascular disease and systemic lupus erythematosus: a Mendelian randomization analysis

Xiang, Liu1; Wang, Qingwen2; Zheng, Xuejia3; Chen, Ruiyuan4; Liu, Chengcheng5; Zhu, Feng3; Tao, Fulin6; Zhang, Junning7; He, Jingquan8,*; Dai, Yong3,6,*

1School of Computer Science and Engineering, Anhui University of Science & Technology, Huainan, Anhui Province, China

2Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, Guangdong Province, China

3The First Hospital, Anhui University of Science and Technology, Huainan, Anhui Province, China

4Taizhou University of Medicine, Taizhou, Zhejiang Province, China

5School of Mathematics and Big Data, Anhui University of Science & Technology, Huainan, Anhui Province, China

6School of Medicine, Anhui University of Science & Technology, Huainan, Anhui Province, China

7School of Public Health, Anhui University of Science & Technology, Huainan, Anhui Province, China

8Department of Radiotherapy, Shenzhen Traditional Chinese Medicine Hospital, The Forth Clinical Medical College, Guangzhou Traditional Chinese Medicine University, Shenzhen, Guangdong Province, China

*Correspondence to: Jingquan He, MD, astroh@163.com; Yong Dai, MD, daiyong22@aust.edu.cn.

Abstract

Current research has demonstrated that individuals with systemic lupus erythematosus face a markedly greater risk of cardiovascular disease. However, the exact mechanism linking specific types of heart disease to the incidence of systemic lupus erythematosus remains unclear, and the evidence is insufficient. This study explored and clarified the intrinsic connection between genetic factors of heart disease and susceptibility to systemic lupus erythematosus by investigating the potential causal link between the two. Utilizing aggregated genome-wide association study data, we applied a standardized quality control protocol to select single nucleotide polymorphisms as genetic instrumental variables. Five Mendelian randomization approaches were used to evaluate causal effects, including inverse variance weighting, Mendelian randomization-Egger method, weighting median method, simple mode method, and weighting mode method. Inverse variance weighting was used as the core analysis method, and Mendelian randomization-Egger was used to assess heterogeneity and perform multi-effect testing; Finally, the leave-one-out method was used for sensitivity analysis to ensure the robustness of the results. The Mendelian randomization analysis identified significant associations between valvular heart disease (odds ratio (OR) = 1.866, 95% confidence interval (CI): 1.230–2.830, P = 0.003), hypertensive heart disease (OR = 1.148, 95% CI: 1.041–1.264, P = 0.005), and endocarditis (OR = 1.141, 95% CI: 1.031–1.126, P = 0.011) with increased susceptibility to systemic lupus erythematosus. Additionally, five significant single nucleotide polymorphisms were shared between heart diseases and systemic lupus erythematosus. These findings suggest that patients with valvular heart disease, hypertensive heart disease, or endocarditis should undergo regular screening and risk assessment for systemic lupus erythematosus to facilitate early detection and intervention.

年龄相关心血管疾病与系统性红斑狼疮之间的关联：孟德尔随机化分析

摘要

现有研究表明，系统性红斑狼疮患者患心血管疾病的风险显著增高。然而，特定类型心脏疾病与系统性红斑狼疮发病率之间的确切机制尚不明确，且证据不足。此研究旨在通过探讨年龄相关心血管疾病与系统性红斑狼疮之间的潜在因果关系，揭示心脏疾病遗传因素与系统性红斑狼疮易感性之间的内在联系。利用汇总的全基因组关联研究数据，采用标准化质量控制协议筛选单核苷酸多态性作为遗传工具变量。通过5种孟德尔随机化（MR）方法评估因果效应，包括逆方差加权法、孟德尔随机化-Egger法、中位数加权法、简单模式法和模式加权法。逆方差加权法被用作核心分析方法，孟德尔随机化-Egger法用于评估异质性并进行多效应检验；最后，采用留一法进行敏感性分析以确保结果的稳健性。孟德尔随机化分析识别出瓣膜性心脏病（OR = 1.866，95% CI：1.230–2.830，P = 0.003）、高血压性心脏病（OR = 1.148，95% CI：1.041–1.264， P = 0.005）和心内膜炎（OR = 1.141，95% CI：1.031–1.126，P = 0.011）与系统性红斑狼疮的易感性增加之间存在显著关联。此外，心脏疾病与系统性红斑狼疮之间共享了五个显著的单核苷酸多态性。这些发现表明，患有瓣膜性心脏病、高血压性心脏病或心内膜炎的患者应定期进行系统性红斑狼疮的筛查和风险评估，以促进早期检测和干预。