Thousands of genetic variants have been identified that contribute to the development of complex diseases, but determining how to fully elucidate their biological consequences for translation into clinical benefit is challenging. Conflicting evidence regarding the functional impact of genetic variants in the tyrosine kinase 2 (TYK2) gene, which is differentially associated with common autoimmune diseases, currently obscures the potential of TYK2 as a therapeutic target. We aimed to resolve this conflict by performing genetic meta-analysis across disorders, subsequent molecular, cellular, in vivo and structural functional follow-up and epidemiological studies. Our data revealed a protective homozygous effect that defined a signaling optimum between autoimmunity and immunodeficiency and identified TYK2 as a potential drug target for multiple autoimmune disorders.
Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS)1, it has been difficult to demonstrate which variants are causal and what role they play in disease. Moreover, the modest contribution these variants make to disease risk has raised questions regarding their medical relevance2. We have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes TNF receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS)3,4, but not with other autoimmune conditions such as rheumatoid arthritis (RA)5, psoriasis6 and Crohn’s disease7. By analyzing MS GWAS3,4 data in conjunction with the 1000 Genomes Project data8 we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF blocking drugs can promote onset or exacerbation of MS9-11, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.