3.2 The causal effect of AA on IMIDs
The initial screening identified 138 potentially independent SNPs that
meet the inclusion criteria. Genetic variables associated with
depression, anxiety, smoking, glucocorticoids and non-steroidal
anti-inflammatory drugs use, obesity or malnutrition(12, 40, 41), as
known to have causal associations with IMIDs, were removed. After
harmonizing the exposure and outcome
datasets, a total of 112 SNPs were obtained with most F-statistics
greater than 10 (21 SNPs for AA on IBD, 21 SNPs for AA on CD, 21 SNPs
for AA on UC, 15 SNPs for AA on RA, 13 SNPs for AA on SLE, 21 SNPs for
AA on PSO, Supplementary Table S2). 112 independent SNPs associated with
AA were selected as IVs to explore the effect of AA on IMIDs. As shown
in Figure 2 and the scatter plot (Supplementary Figure S3), the IVW
method indicated that patients with
AA had a 6% increased risk of RA (OR = 1.06, 95%CI = 1.01-1.12,p = 0.029). MR-PRESSO method also presented unanimous evidence of
causality between AA and RA (OR = 1.06, 95% CI = 1.01-1.11, p =
0.019). Cochran’s Q test showed there was no heterogeneity in IVs
related to RA (Q = 11.82, p = 0.621). Moreover, both results of
MR-PRESSO (no outlier was found, Table 1) and MR-Egger regression
(intercept = -0.01, p = 0.570, Figure 2) provided no evidence of
horizontal pleiotropy. However, the effect of genetically predicted AA
on IBD, CD, UC, SLE, PSO did not reach statistical significance in
either IVW or MR-PRESSO method (Figure 2 and Table 1). Sensitivity
analysis of the above MR results suggested that there was no underlying
heterogeneity and horizontal pleiotropy (all p value of Cochran’s
Q and Egger-intercept > 0.05, Table 2).
Discussion
We conducted a two-sample bidirectional MR study to investigate the
causal relationship between IMIDs (mainly including IBD, CD, UC, RA,
SLE, and PSO) and AA. We found evidence of a causal effect of AA on RA,
but not of RA or other IMIDs on AA. Although evidence from previous
observational studies supported a causal relationship between some
certain types of IMIDs and AA(12-20), causal inference cannot be made
with great certainty in these studies for the possibility of residual
confounding factors and various bias.
A retrospective case-control study
with age- and gender-matched cohort from Israel, which adjust for
different factors including socioeconomic and smoking, found that AA is
more prevalent in patients with RA compared with controls (OR: 1.406,
95%CI: 1.094-1.789, p = 0.006). It is worth mentioning that the
information regarding the treatment of RA patients and assessment of RA
severity had not been formally investigated, as well as congenital
diseases predisposing for AA(12). Contrary to above findings, a cohort
study in England showed no evidence of a link between RA and AA, even
after adjusting for age, gender, cardiovascular disease risk factors or
anti-inflammatory drugs(13).
Nonetheless, these studies lacked detailed information on daily tobacco
use and alcohol consumption, family history of AA, as well as the
imaging data, which all could bias causal inference towards a positive
or negative direction. In addition, selection bias is also a problem
that cannot be ignored. The same problems existed in studies of the
association between SLE and AA(14, 15). People with SLE may experience a
variety of symptoms and receive examination more frequently than people
without SLE, therefore, they are more likely to be diagnosed with AA.
Similarly, the two cohort studies on psoriasis failed to account for
confounders such as body weight, smoking status, detail imaging
findings, and assessment of psoriasis severity(16, 17). Moreover, the
estimates from these observational studies are subject to substantial
uncertainty with a wide confidence interval, indicating causal effects
and their magnitude should be viewed with caution. Several isolated case
reports have claimed that CD and UC were frequently observed
comorbidities in AA patients(18-20),
thus, we also conducted an
investigation to explore the causal association of these diseases in AA
individuals. However, either by forward or backward analysis, we did not
fnd causal association between IBD, CD, UC and AA.
Genetic predisposition to AA is present from birth, therefore the MR
results of our study would not be affected by the acquired drug
treatment or other known or unknown exposure factors of AA patients.
However, the exact mechanism by which genetically predisposed AA
increases the risk of RA is still not completely understood. A study
investigated the incidence of autoimmune diseases in patients with
inflammatory aortic aneurysm (IAA). The serologic tests and biopsy
findings were analyzed for the presence of autoimmune diseases before
surgery in all cases. Autoimmune diseases were shown to be statistically
significant in the inflammatory aortic group compared with the
non-inflammatory aortic aneurysm group(21). Previous studies have
provided evidence that a genetic predisposition to IAA exists and
suggested that it may be related to human leukocyte antigen (HLA)
molecule in IAA. HLA molecules play a critical role in the immune
recognition process of specific antigen-presenting cells, which can be
expressed by macrophages and dendritic cells.
Amino acid polymorphism of HLA-DR
molecule mediates immune responses to different antigens in different
individuals and have also been found to be associated with the
development of many diseases. A study investigating the genetic risk
associated with HLA-DR gene polymorphism in patients with IAA revealed
that HLA-DR B1*15 and HLA-DR B1*0404 allele were significantly enriched
in these patients compared to control subjects(42). Moreover,
observation with B-cell-enriched lymphoid follicles and CD3-positive T
cells from the aneurysm wall of IAA patient suggested that a potential
shared pathogenesis with IgG4-related diseases(43). The etiology of RA
remains elusive, and several studies have consistently demonstrated its
association with genetic factors. As early as 1976,
Stastny(44) reported a correlation
between RA and the HLA-DR4 allele of
the human leukocyte antigen class II. Many studies have confirmed the
association between RA and HLA-DR4 in a various of different ethnic
groups, but the subtypes of HLA-DR4 and other types of HLA-DR vary
widely among ethnic groups
(45-48).
Given the limited sample size and racial difference in previous studies,
more large-scale research should focus on investigating the genetic
contribution of HLA risk loci in IAA
patients worldwide. Furthermore, the investigation of the genetic
determinants and their role in the pathogenesis of RA necessitates
further explore. Hopefully, the efficacy of autoantigen immunoregulation
in treating RA has been demonstrated in animal studies. Clinical trials
of autologous modified dendritic cells exposed to citrulline peptide by
percutaneous injection are currently underway (49).
Unlike previous observational studies examining the association between
IMIDs and AA, we used MR method to deal with known and unknown
confounding factors such as smoking, alcohol or fallacies caused by
reverse causation. Thus, our results overcome the limitations of
observational studies to reflect causal associations and effects of
IMIDs and AA. Our work also had some limitations. While we concluded
that exposure to genetically predisposed AA increased the lifetime risk
of RA, this does not mean that this conclusion can be used directly to
infer the possible impact of interventions targeting genetically
predisposed AA patients on RA risk. Besides, owing to constraints within
the GWAS database, we did not distinguish the anatomic site of the
aortic aneurysm. Although the thoracic aorta and the abdominal aorta
share certain anatomical features, these two disease subtypes exhibit
marked differences with respect to their pathophysiological mechanisms.
Finally, our study was dependent on
data from European population, which limits generalizability to other
racial populations.
Conclusion
In summary, our study has showed genetically predicted AA may increase
the risk of RA, while there was no evidence that RA had an increased
risk of AA. Furthermore, we found no evidence of association between
IBD, CD, UC, SLE, PSO and AA. This finding is in line with other
research that demonstrated the genetic risk determinants are linked to
HLA molecules in IAA patients. IAA may be a separate entity with similar
pathogenesis with IgG4-related disease. Our study provides directions
for future research on genetic susceptibility to IAA. The antigen
binding role of IAA risk genes in the disease origin of RA needs
additional investigation.