Author:
Wu Jialing,Zhang Xi,Wu Dongze,Jin Ou,Gu Jieruo
Abstract
Abstract
Background
Altered interleukin (IL)-18 levels are associated with immune-mediated inflammatory diseases (IMIDs), but no studies have investigated their causal relationship. This study aimed to examine the causal associations between IL-18 and IMIDs.
Methods
We performed a two-sample Mendelian randomization (MR) analysis. Genetic variants were selected from genome-wide association study datasets following stringent assessments. We then used these variants as instrumental variables to estimate the causal effects of IL-18 levels on the risk of developing five common IMIDs: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ankylosing spondylitis (AS), and psoriasis. We used the inverse variance-weighted (IVW) method as the primary analysis, with sensitivity analyses performed to avoid potential bias. Reverse-direction MR analyses were performed to rule out the possibility of reverse associations.
Results
We found that genetically determined higher circulating IL-18 levels were causally associated with a higher risk for SLE (PIVW = 0.009; OR, 1.214; 95% CI, 1.049 − 1.404) and IBD (PIVW < 0.001; OR, 1.142; 95% CI, 1.062 − 1.228), but found no significant associations of IL-18 with RA (PIVW = 0.496; OR, 1.044; 95% CI, 0.923 − 1.180), AS (PIVW = 0.021; OR, 1.181; 95% CI, 1.025 − 1.361), or psoriasis (PIVW = 0.232; OR, 1.198; 95% CI, 0.891 − 1.611). In the reverse direction, no causal relationship existed between SLE or IBD and IL-18 levels. Globally, sensitivity studies using alternative MR methods supported the results that were robust and reliable. The Cochran’s Q test, MR-Egger intercept, and MR-Pleiotropy RESidual Sum and Outlier excluded the influence of heterogeneity, horizontal pleiotropy, and outliers.
Conclusions
We have demonstrated that elevated IL-18 levels increase the risk of SLE and IBD but not RA, AS, or psoriasis. The results enhanced our understanding of IL-18 in the pathology of IMIDs.
Funder
the Scientific research project of Guangdong Provincial Bureau of Traditional Chinese Medicine
the National Natural Science Foundation of China
the Guangdong Clinical Research Center of Immune Disease
the Science and Technology Planning Project of Guangdong Province, China
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics