MDA5 variants trade antiviral activity for protection from autoimmune disease

• Published in: BMC medical genomics Vol. 18; no. 1; pp. 101 - 8
• Main Authors: Wallace, Chris, Singh, Rahul, Modis, Yorgo
• Format: Journal Article
• Language: English
• Published: London BioMed Central 02.06.2025; BioMed Central Ltd; BMC
• Subjects: Analysis; Antiviral activity; Antiviral agents; Autoimmune disease; Autoimmune diseases; Autoimmune Diseases - genetics; Biomedical and Life Sciences; Biomedicine; Crohn's disease; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Double-stranded RNA; Fitness trade-off; Gastrointestinal diseases; Gene Expression; Genes; Genetic analysis; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic research; Genome-wide association studies; Genome-wide association studies (GWAS); Genome-Wide Association Study; Genomics; Health aspects; Human genetic variants; Human Genetics; Humans; Hypothyroidism; Infections; Inflammation; Inflammatory bowel disease; Inflammatory bowel disease (IBD); Inflammatory bowel diseases; Inflammatory Bowel Diseases - genetics; Interferon-Induced Helicase, IFIH1 - genetics; Microarrays; Physiological aspects; Polymorphism, Single Nucleotide; Psoriasis; Psoriasis - genetics; Risk factors; RNA; RNA viruses; Thyroid hormones; Type 1 diabetes; Type 1 diabetes (T1D); Viral infections; White people; United Kingdom; Fitness trade-off; Autoimmune disease; Genome-wide association studies (GWAS); Inflammatory bowel disease (IBD); Human genetic variants; Type 1 diabetes (T1D)
• ISSN: 1755-8794; 1755-8794
• DOI: 10.1186/s12920-025-02171-y

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.