Genetically Predicted Association of 91 Circulating Inflammatory Proteins with Multiple Sclerosis: A Mendelian
Xin'ai Li1, Zhiguo Ding1,2,3, Shuo Qi1,2,3
1Department of Thyropathy, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100013, 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.
Insights
This Mendelian randomization study investigated inflammatory proteins and multiple sclerosis (MS). While CCL25 and CXCL10 showed potential links to increased MS risk, and NRTN to decreased risk, these associations require further validation in larger studies.
Area of Science:
- Immunology
- Genetics
- Neuroscience
Background:
- Multiple sclerosis (MS) is linked to inflammation, but causal relationships between specific circulating inflammatory proteins and MS risk remain unclear.
- Understanding these links is crucial for identifying potential therapeutic targets and biomarkers for MS.
Purpose of the Study:
- To investigate the causal effect of 91 circulating inflammatory proteins on the risk of developing multiple sclerosis (MS) using Mendelian randomization (MR).
- To explore potential novel biomarkers and therapeutic targets for MS based on inflammatory protein associations.
Main Methods:
- A two-sample Mendelian randomization (MR) approach was utilized, analyzing data from a large-scale genome-wide association study (GWAS).
- Inverse-variance-weighted (IVW) analysis was the primary method, fortified by MR Egger, weighted median, simple mode, and weighted mode.
- Sensitivity analyses, including Bonferroni and false discovery rate (FDR) corrections, were performed to ensure robustness and exclude heterogeneity and pleiotropy.
Main Results:
- Forward MR analysis suggested that higher levels of CCL25 and CXCL10 may be associated with an increased risk of MS.
- Conversely, elevated levels of neurturin (NRTN) were associated with a decreased risk of MS.
- Reverse MR analysis did not reveal a causal relationship between MS and the studied inflammatory cytokines, and initial findings did not survive stringent statistical corrections.
Conclusions:
- While certain inflammatory proteins like CCL25, CXCL10, and NRTN show potential associations with MS risk, these links are weak and require further investigation.
- The study highlights the need for larger sample sizes to confirm these findings and their clinical relevance.
- Despite limitations, the research offers insights into the complex interplay between inflammation and MS, suggesting avenues for future biomarker and therapeutic target discovery.
