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