rs201278923

This post-mortem autopsy study of 228 MS brain donors identified four distinct neuropathology-based subgroups using clustering analysis on white matter lesion patterns and microglial characteristics. Genetic validation using 288 MS-associated SNPs found that rs3135388A (HLA-DRB1*15:01 tagging SNP) was significantly associated with two subgroups (p < 0.001), and polygenic risk scores correlated with neuropathological dimensions, suggesting genetic architecture partially underlies MS pathological heterogeneity.

This case-control study examined SNP rs3129934, a tag for the HLA-DR2 haplotype (HLA-DRB1*15:01/HLA-DQB1*06:02) that confers risk for multiple sclerosis. All 73 Wixárika (Huichol) indigenous subjects from Mexico were homozygous CC (absence of risk T allele), compared to 25.8% T allele frequency in 60 Mestizo MS patients and 12.7% in 71 healthy Mestizo controls (p<0.0001). The complete absence of the MS risk allele in this unmixed Amerindian population is consistent with the absence of reported MS cases in the Wixárika ethnic group.

This review examines the relationship between host genetic factors and the microbiome in rheumatoid arthritis (RA). The authors synthesize evidence that 349 SNPs identified through GWAS meta-analyses of >100,000 participants contribute to RA susceptibility, with 100 SNPs replicated. Key genetic loci include HLA-DRB1 (shared epitope), PTPN22, PADI4, STAT4, TNFAIP3, and CARD9. The review discusses how RA-associated genetic variants may influence disease pathogenesis through altered microbiome composition and immune responses to commensal taxa, particularly Prevotella copri and Porphyromonas gingivalis in the gut and oral microbiota.

Nested case-control study within the Nurses' Health Study cohorts (192 RA cases, 567 controls) found anti-citrullinated peptide autoantibodies (ACPAs) strongly associated with rheumatoid arthritis risk (RR 4.9), with strongest association within 5 years of onset (RR 17.6). HLA-DRB1 shared epitope alleles and ACPA positivity together conferred 10-fold increased risk overall and 33-fold within 5 years. HLA-SE-positive cases showed reactivity to more ACPA peptide types.

MedlinePlus Genetics educational summary describing the HLA-DQB1 gene function and its associations with multiple autoimmune diseases including celiac disease (DQ2/DQ8 haplotypes), narcolepsy (HLA-DQB1*06:02), type 1 diabetes (DR3/DR4 haplotypes), and multiple sclerosis. The DQ2 and DQ8 haplotypes are present in 30% of the general population but only 3% with these variants develop celiac disease, indicating additional genetic and environmental factors required for disease manifestation.