Abstract
Introduction: Many observational studies have identified aortic aneurysm (AA) as a cardiovascular complication of immune-mediated inflammatory diseases (IMIDs). However, due to the effects of various confounders, it is still uncertainty whether this association holds or whether reverse causality is involved. Here we conducted a two-sample bidirectional MR study to infer the causal relationships between the two diseases.
Method: We obtained genetic association datasets from public GWAS databases in populations of European ancestry. Abiding by the assumptions of Mendelian randomization (MR), we selected valid instrumental variables from genetic variants. Different statistic methods were performed for MR analysis and sensitivity analysis, and the inverse variance weighted (IVW) method was regarded as the most efficient estimate of the causal effect in this study.
Results: The IVW method found evidence that genetically predicted AA had a causal effect on rheumatoid arthritis (RA) (OR = 1.06, 95%CI = 1.01-1.12, p = 0.029), but not of RA or other IMIDs on AA. Besides, no evidence showed that AA may increase the risk of inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE) and psoriasis (PSO). The sensitivity analysis confirmed the absence of heterogeneity or horizontal pleiotropy effect.
Conclusion: In summary, our study discovered that genetically predicted AA may increase the risk of RA, while no evidence was found that patients with RA had an increased risk of AA. Furthermore, we confirmed no evidence of association between IBD, CD, UC, SLE, PSO and AA. This is in accordance with other reports that demonstrated the human leukocyte antigen molecule in inflammatory aortic aneurysm was a genetic risk loci. Our study provides directions for future research on genetic susceptibility to inflammatory aortic aneurysm.
Keywords: aortic aneurysm, immune-mediated inflammatory diseases, Mendelian randomization, inflammatory aortic aneurysm, rheumatoid arthritis.
Introduction
Aortic aneurysm (AA) is a chronic condition of the aorta characterized by localized distension or weakening of its wall, which may lead to rupture and severe internal bleeding resulting in shock(1). With an incidence rate of approximately 3 per 100,000 individuals worldwide(2), AA ranks second only to atherosclerosis in prevalence and represents the most common disease affecting the aorta(3). AA is considered to be a chronic degenerative disease caused by local damage to the aortic wall, mainly related to chronic inflammatory infiltration(4). Ruptured aortic aneurysms can result in immediate fatality. For patients with apparent symptoms or large diameter aortic aneurysms, open surgery or endovascular repair remains the sole treatment option(4, 5).
Immune-mediated inflammatory diseases (IMIDs) are a collection of chronic inflammatory disorders that involve multiple systems and organs, characterized by common mechanisms of inflammation and immune dysregulation(6). IMIDs comprise a spectrum of disorders, and the presence of multiple systemic symptoms impose a significant burden on healthcare resources(7). Individuals with immune-mediated inflammatory diseases (IMIDs) are at a significantly increased risk of cardiovascular complications, due to both the disease itself and certain corticosteroid medications used in its treatment(8, 9). Of note, atherosclerosis(10) and large vessel vasculitis(11), which are prone to the development of dilated aortic aneurysms, are considered to be immune system-mediated processes. This suggests a potential common genetic etiology or pathogenesis between AA and IMIDs. Although observational studies(12-20) have linked IMIDs with cardiovascular disease (CVD), it is still unclear whether patients with AA are at increased risk of IMIDs. Reverse causation may also account for the association, whereby AA increases the risk of IMIDs rather than vice versa(21). Confounding factors can easily distort the interpretation from observational studies, leading to a fallacious inference of causality. Meanwhile, despite being the standard epidemiological design for establishing causal relationships, randomized controlled trials (RCTs) have some limitations. These include the significant investment of time, manpower and financial resources required to conduct them, as well as strict inclusion and exclusion criteria that can limit the representativeness and external validity of research findings. Therefore, more robust methods are required to assess causality using available data.
Mendelian randomization (MR) experiments use variants of genetic loci as instrumental variables (IVs) to investigate the association between exposure and health outcomes. Unlike conventional RCTs and observational studies, MR studies are not suffered to confounders. In MR, genetic variants serve as IVs for exposures to help the identification potential causal effect with disease-related outcomes(22, 23). Generally, the IVs must fulfill these three assumptions: (1) the IVs are strongly associated with the exposure; (2) the IVs are independent of other factors that may affect the inference of causal relationship; and (3) the IVs do not affect the outcome except with its potential effect on the exposure(24). Besides, germ-line genotypes are established during conception and precede the observed variables in temporal sequence, thus avoiding issues of reverse causality(25). Here, we obtained public datasets from various genome-wide association studies (GWASs) of IMIDs (including IBD, CD, UC, RA, SLE, and PSO) and AA in populations of European ancestry and performed a two-sample bidirectional MR study to infer the magnitude and direction of causal associations between the two diseases.
Methods