Exploring the role of genetic variants in susceptibility to autoimmune Diseases: A molecular genetics approach.

PMID 41237580 | DOI 10.1016/j.humimm.2025.111614 · Human immunology · 2025 · View on PubMed ↗

Autoimmune diseases occur when the immune system mistakenly attacks healthy tissues, leading to chronic inflammation and progressive organ damage. These conditions affect millions worldwide and often result in long-term disability. The underlying reasons for increased vulnerability remain uncertain, particularly regarding the combined influence of genetic variations and lifestyle factors on disease risk. The purpose of this study is to identify key genetic variants associated with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes, and to investigate how these variants interact with environmental exposures to influence risk and age of onset. Publicly available genetic and molecular data were analyzed, including genome-wide association studies (NHGRI-EBI GWAS Catalog, ImmunoBase, and dbGaP), DNA sequencing datasets (1000 Genomes Project, Genomic Data Commons, and SRA), gene expression profiles (GEO and ArrayExpress), and epigenetic marks (ENCODE and RegulomeDB). This study identifies several significant genetic variants associated with autoimmune diseases, including PTPN22, HLA-DRB1, HLA-DQA1, IRF5, IL10, and other immune-regulatory genes. Notably, the PTPN22 rs2476601 variant increased the risk by approximately 1.8 times, while the HLA-DRB1 rs3135388 variant increased the risk by around 2.1 times. Additional variants, such as HLA-DQ, IRF, and IL10, also play significant roles in immune dysregulation and susceptibility to autoimmune diseases, with specific allele associations yet to be fully explored. Pathway analysis revealed that these genes are primarily involved in antigen presentation, cytokine signaling, and T-cell activation-key processes underlying the pathogenesis of autoimmune diseases. Smoking and vitamin D deficiency further elevated risk in genetically susceptible individuals and were linked with earlier disease onset. The findings highlight genetic markers such as IL2RA and TIM-3 as potential tools for early screening and therapeutic targeting. Integrating genetic testing with lifestyle assessment can support personalized prevention, guide drug development, and improve clinical practice. Validation in diverse populations and long-term studies is recommended to confirm clinical usefulness.