ABSTRACT
BACKGROUND: Multiple sclerosis (MS) is multifactorial in nature, with both genetic and environmental factors contributing to disease risk. In this umbrella review, we aimed to summarize various non-HLA genes that have been investigated for their association with MS risk in meta-analyses (MAs) of observational studies. METHODS: Medline, Embase, Epistemonikos, and Cochrane Database of Systematic Reviews were searched for MAs up to July 2021. Evidence of association was ranked according to established criteria as follows: convincing, highly suggestive, suggestive, weak, or not significant. RESULTS: From 1,533 publications, 85 full-text articles were evaluated for eligibility, and 15 articles were selected that described 114 genetic associations. No associations were supported by convincing evidence. One association between the rs2104286 (A vs G contrast) polymorphism of the interleukin 2RA (IL2RA) gene and increased MS susceptibility was initially supported by highly suggestive evidence (OR 1.17; 95% CI 1.10-1.25) but it was downgraded to suggestive in the sensitivity and subgroup analyses. We also found six associations supported by suggestive evidence in the main analysis. CONCLUSION: The findings of this study imply that the cytokines genes interleukin IL2RA and IL7R may play a role in the development of MS. Data from more and better-designed studies are needed to establish robust evidence.
