Background and objectives: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, leading to demyelination of neurons and potentially debilitating physical and mental symptoms. The disease is more prevalent in women than in men. The major histocompatibility complex (MHC) region has been identified as a major genetic determinant for autoimmune diseases, and its role in some neurological disorders including MS was evaluated. An intergenic single-nucleotide polymorphism (SNP), rs9275596, located between the HLA-DQB1 and HLA-DQA2 genes, is in significant association with various autoimmune diseases according to genome-wide association studies (GWASs). A cumulative effect of this SNP with other polymorphisms from this region was revealed. The aim of the study was to verify the data on rs9275596 association in multiple sclerosis in a case/control study of the Latvian population and to evaluate eventual functional significance of allele substitutions. Materials and Methods: rs9275596 (chr6:32713854; GRCh38.p12) was genotyped in 273 MS patients and 208 controls on main and sex-specific associations. Eventual functional significance of allele substitutions was evaluated in silico using publicly available tools. Results: The rs9275596 rare alleles were identified as a disease susceptibility factor in association with the MS main group and in affected females (p < 0.001 and p < 0.01, respectively). Risk factor genotypes with rare alleles included were associated with the MS common cohort (p < 0.002) and female cohort (odds ratio, OR = 2.24) and were identified as disease susceptible in males (OR = 2.41). It was shown that structural changes of rs9275596 affect the secondary structure of DNA. Functional significance of allele substitutions was evaluated on the eventual sequence affinity to transcription factors (TFs) and splicing signals similarity. A possible impact of the particular polymorphisms on the transcription and splicing efficiency is discussed. Conclusions: Our results suggest susceptibility of rs9275596 to multiple sclerosis in Latvians.
Keywords: Human leukocyte antigen (HLA); autoimmune diseases; multiple sclerosis; rs9275596; the major histocompatibility complex (MHC).