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MDA5 variants trade antiviral activity for protection from autoimmune disease.

Chris Wallace·Rahul Singh·Yorgo Modis
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Abstract

Loss-of-function variants in MDA5, a key sensor of double-stranded RNA from viruses and retroelements, have been associated with protection from type 1 diabetes (T1D) in genome-wide association studies (GWAS). MDA5 loss-of-function variants have also been reported to increase the risk of inflammatory bowel disease (IBD). Whether these associations are linked or extend to other diseases remains unclear. Here, fine-mapping analysis of four large GWAS datasets shows that T1D-protective loss-of-function MDA5 variants also protect against psoriasis and hypothyroidism, while increasing the risk of IBD. The degree of autoimmune protection and IBD risk were linearly proportional. The magnitudes of the odds ratios for autoimmune protection and IBD risk were larger for rare MDA5 variants than for common variants, which were differentially expressed in different geographic populations. Our analysis suggests MDA5 genetic variants offer a direct fitness trade-off between viral clearance and autoimmune tissue damage.

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Interferon-Induced Helicase, IFIH1HumansGenome-Wide Association StudyAutoimmune DiseasesPolymorphism, Single NucleotideDiabetes Mellitus, Type 1Genetic Predisposition to DiseaseInflammatory Bowel DiseasesPsoriasisAutoimmune diseaseFitness trade-offGenome-wide association studies (GWAS)Human genetic variantsInflammatory bowel disease (IBD)Type 1 diabetes (T1D)Journal ArticleResearch Support, Non-U.S. Gov't

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Chris Wallace, Rahul Singh, Yorgo Modis. 2025-06-02. MDA5 variants trade antiviral activity for protection from autoimmune disease.. https://doi.org/10.1186/s12920-025-02171-y

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Interferon-Induced Helicase, IFIH1↗