OBJECTIVES: 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 of observational studies.

METHODS: Medline, Embase, Epistemonikos, and Cochrane Database of Systematic Reviews were searched for meta-analyses up to July 2021. Published meta-analyses of observational studies describing the association between non-HLA genes and the risk of MS in affected patients, as defined by established diagnostic criteria (example, McDonald) compared to healthy controls were included in this study. 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. The associations were the rs987107 polymorphisms of IL7RA, the rs2104286 and rs12722489 polymorphisms of IL2RA, and the T244 polymorphism of IL7R.

CONCLUSIONS: 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.