Functional significance of the rare rs35667974 IFIH1 gene polymorphism, associated with multiple autoimmune diseases, using a structural biological approach

Abstract

Autoimmune diseases, which affect approximately 5% of human population, are a range of diseases in which the immune response to self-antigens results in damage or dysfunction of tissues. Recent 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). Recently, this variant was found to be also associated with ankylosing spondylitis (AS), Crohn’s disease (CD) and ulcerative colitis (UC). The IFIH1 gene encodes a cytoplasmic RNA helicase otherwise known as melanoma differentiation-associated 5 (MDA5) that recognizes viral RNA and is involved in innate immunity through recognition of viral RNA. In the present study we sought to investigate the association of the rare rs35667974 variant of IFIH1 gene, which resides in exon 14 and changes a conserved isoleucine at position #923 to valine, in the development of various autoimmune diseases and give a reason for the selectivity affecting different autoimmune diseases. Evolutionary studies and three-dimensional (3 D) homology modelling were employed on the MDA5 protein product, through its association with dsRNA, recognition factor controlling cytokine and chemokine signalling, to investigate the protective role of the MDA5 variant for certain autoimmune diseases.

Keywords:

• Autoimmune diseases
• gene polymorphism
• three-dimensional structure
• interferon induced with helicase C domain 1 (IFIH1)
• MDA5

Authors’ contributions

MIZ, ACA, GNG and EEE substantially contributed to the conception and design of the work, including acquisition, analysis and interpretation of data. MIZ, ACA, GNG and EEE contributed towards drafting the work and revising it critically for important intellectual content and approved the version to be published. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors have read and approved the final manuscript. GNG and EEE confirm the authenticity of all the raw data used.

Availability of data and materials

The data that support the findings of this study are available from the authors upon reasonable request. EEE and ACA confirm the origin of all data selected from public databases.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

Funding was received by “INSPIRED-The National Research Infrastructures on Integrated Structural Biology, Drug Screening Efforts and Drug Target Functional Characterization” (grant no. 5002550) and “OPENSCREENGR An Open-Access Research Infrastructure of Chemical Biology and Target-Based Screening Technologies for Human and Animal Health, Agriculture and the Environment” (grant no. 5002691) projects, which are implemented under the Action “Reinforcement of the Research and Innovation Infrastructure”, funded by the Operational Program “Competitiveness, Entrepreneurship and Innovation” (National Strategic Reference Framework (NSRF); grant no. 2014-2020) and co-financed by Greece and the European Union (European Regional Development Fund).