Genetically Predicted Association of 91 Circulating Inflammatory Proteins with Multiple Sclerosis: A Mendelian Randomization Study

Author:

Li Xin’ai1ORCID,Ding Zhiguo123,Qi Shuo123,Wang Peng4,Wang Junhui5ORCID,Zhou Jingwei6

Affiliation:

1. Department of Thyropathy, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100013, China

2. Sun Simiao Institute, Beijing University of Chinese Medicine, Tongchuan 727000, China

3. Thyropathy Hospital, Sun Simiao Hospital, Beijing University of Chinese Medicine, Tongchuan 727000, China

4. The Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China

5. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada

6. The 1st Ward, Department of Nephrology and Endocrinology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100010, China

Abstract

Previous studies have validated a close association between inflammatory factors and multiple sclerosis (MS), but their causal relationship is not fully profiled yet. This study used Mendelian randomization (MR) to investigate the causal effect of circulating inflammatory proteins on MS. Data from a large-scale genome-wide association study (GWAS) were analyzed using a two-sample MR method to explore the relationship between 91 circulating inflammatory proteins and MS. The inverse-variance-weighted (IVW) analysis was employed as the main method for evaluating exposures and outcomes. Furthermore, series of the methods of MR Egger, weighted median, simple mode, and weighted mode were used to fortify the final results. The results of the IVW method were corrected with Bonferroni (bon) and false discovery rate (fdr) for validating the robustness of results and ensuring the absence of heterogeneity and horizontal pleiotropy. The sensitivity analysis was also performed. The results of the forward MR analysis showed that higher levels of CCL25 were found to be associated with an increased risk of MS according to IVW results, OR: 1.085, 95% CI (1.011, 1.165), p = 2.42 × 10−2, adjusted p_adj_bon = 1, p_adj_fdr = 0.307. Similarly, higher levels of CXCL10 were found to be associated with an increased risk of MS, OR: 1.231, 95% CI (1.057, 1.433), p = 7.49 × 10−3, adjusted p_adj_bon = 0.682, p_adj_fdr = 0.227. In contrast, elevated levels of neurturin (NRTN) were associated with a decreased risk of MS, OR: 0.815, 95% CI (0.689, 0.964), p = 1.68 × 10−2, adjusted p_adj_bon = 1, p_adj_fdr = 0.307. Reverse MR analysis showed no causal relationship between MS and the identified circulating inflammatory cytokines. The effects of heterogeneity and level pleiotropy were further excluded by sensitivity analysis. This study provides new insights into the relationship between circulating inflammatory proteins and MS and brings up a new possibility of using these cytokines as potential biomarkers and therapeutic targets. The data in this study show that there are only weak associations between inflammatory molecules and MS risk, which did not survive bon and fdr correction, and the obtained p-values are quite low. Therefore, further studies on larger samples are needed.

Funder

Science and Technology Department of Shanxi Province

Shanxi Central Administration Bureau

Publisher

MDPI AG

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