AB0004 THE ASSOCIATION OF THE RARE RS35667974 IFIH1 GENE POLYMORPHISM WITH SIX AUTOIMMUNE DISEASES: STRUCTURAL BIOLOGICAL INSIGHTS

Background: Genome wide association studies (GWAS) have successfully identified novel autoimmune disease-associated loci, with many of them shared by multiple disease-associated pathways but much of the genetics and pathophysiological mechanisms remain still obscure. Considering that most of the potential causal variants are still unknown, many studies showed that the missense variant rs35667974 at interferon induced with helicase C domain 1 (IFIH1) gene is protective for type 1 diabetes (T1D), psoriasis (PS) and psoriatic arthritis (PsA), while it was found to be also associated with ankylosing spondylitis (AS), Crohn’s disease (CD) and ulcerative colitis (UC). IFIH1 gene encodes a cytoplasmic RNA helicase that recognizes viral RNA and is involved in innate immunity through recognition of viral RNA [1]. Objectives: To investigate the role of the rare rs35667974 variant of IFIH1 gene, which resides in exon 14 and changes a conserved isoleucine at position #923 to valine in T1D, PS, PsA, AS, CD and UC [2-4] as well as the mechanism that may affect the function in the protein structure. Methods: Evolutionary analysis revealed heavily conserved sequence elements among species, indicating structural/functional importance of the mutation at position #923. In silico mutagenesis and three-dimensional (3D) homology modeling was used to localize the polymorphism under study on the IFIH1 protein. The mutant was constructed using molecular modeling with the program Maestro (Schrodinger, LLC) [5]. Molecular mechanics/dynamics studies were applied to validate structural/functional changes caused by the Ile923V substitution. All figures depicting 3D models were generated using the PyMOL molecular-graphics system V.2.2 [6]. Results: Evolutionary and structural analysis revealed that the position of residue Ile923 is located on a protein loop (921-927) directly interacting with mRNA both to the phosphoribose chain and the base pairs. Mutation of Ile to Val at position #923 will directly affect the said interaction with mRNA [7] (Figure 1). Moreover, it has been reported that pre-mRNA or mRNA levels did not correlate with Ile923Val, suggesting that, Ile923Val did not alter the expression of IFIH1 in a major way [7]. Conclusion: This study represents a comprehensive evaluation of the role of the shared rs35667974 variant of autoimmune locus IFIH1, reported to lead to a loss of function phenotype and, as a consequence, reduced levels of IFIH1 protein and activity that protect against autoimmunity. Structural analysis of rare shared genetic susceptibility or protection loci may provide insight to our understanding of the pathophysiology of autoimmune diseases and the research findings may affect the better management of the diseases under study. References: [1]Nejentsev S et al. (2009). Science 324:387–389. [2]Smyth DJ et al. (2006). Nat Genet. 38: 617–619. [3]Li Y et al. (2010). J Invest Dermatol 130:2768–2772. [4]Ellinghaus D et al. (2016). Nat Genet 48:510–518. [5]Schrodinger Release 2017-1: Maestro, Schrodinger, LLC, New York, NY, 2017. [6]Schrodinger LLC: The PyMOL Molecular Graphics System 2016 version 2.2. [7]Wu B et al. (2013). Cell 152:276-289[8] Downes K et al. (2010). PLoS One 5:e12646. Disclosure of Interests: None declared