Inuit HLA variation and neuroimmune disease

Abstract

Worldwide risk of autoimmune diseases, particularly multiple sclerosis (MS), varies between populations. One key factor is immune variation attributed to genetic variation. The human leukocyte antigen (HLA) system plays a central role in antigen presentation, immune regulation, and host-pathogen interactions. Variation across HLA genes has substantial clinical implications, influencing risk for autoimmune and neurodegenerative diseases. For instance, HLA-DRB1*15:01 remains the strongest and most consistently replicated genetic risk factor for MS, with similar HLA-associated patterns observed in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Since HLA loci evolve under strong selective pressures, population-level HLA diversity reflects distinct histories of pathogen exposure, geography, climate, diet, and demographic isolation. Indigenous groups such as the First Nations, Métis, and Inuit therefore exhibit unique HLA distributions shaped by their ancestral environments. The variation in HLA genes as well as environmental factors have shaped the difference in MS prevalence and severity in these Indigenous populations compared to non-Indigenous groups.