Background: Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory disease that affects the central nervous system. Although the true etiology of MS remains unknown, recent research suggests that it arises from a combination of genetic vulnerability and environmental factors. The human leukocyte antigen (HLA) region is a highly polymorphic locus on chromosome 6 encoding antigen-presenting molecules central to adaptive immunity. MS exhibits significant genetic and geographic heterogeneity, reflecting complex interactions between HLA polymorphisms and environmental influences. Risk and protective alleles differ across populations, reinforcing the importance of studying such variations to better understand the disease’s pathogenesis and guide therapeutic strategies. Methods: This systematic review followed the “Preferred Reporting Items for Systematic reviews and Meta-Analyses” (PRISMA) guidelines, and a bibliographic search was conducted in the Medline (PubMed) and Web of Science databases using the keywords “Multiple Sclerosis”, “Genetic Polymorphisms”, “SNPs”, and “Human Leukocyte Antigen”. Results: Twenty-one studies were included, comprising a total of over 50,000 participants across diverse populations. The reviewed studies demonstrate that the alleles DRB1*15:01, DQB1*06:02, DRB1*03:01, DRB1*04:01, DRB1*15:03, DPB1*03:01, as well as the haplotypes DRB1*15:01~DQB1*06:02 and DRB1*15:01~DQA1*01:02~DQB1*06:02, show high expression and are strongly associated with MS susceptibility. In contrast, the alleles A*02:01 and DRB1*01:01 have shown a protective role. Discussion: The evidence confirms a central role of HLA class II alleles and conserved extended haplotypes, particularly DRB1*15:01-containing haplotypes, in MS susceptibility, while highlighting protective alleles and marked variability across ancestral backgrounds. These findings underscore the importance of high-resolution HLA typing, standardized haplotype definitions and inclusion of diverse populations to refine MS risk estimates.
Pinheiro et al. (2026) studied this question.