rs3135388

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.

Functional analysis of 284 MS-associated genetic variants using integrative approaches including GRAIL analysis, eQTL analysis, and differential gene expression. Identified 45 SNPs acting as cis-regulators on 19 MS-associated genes, with 6 key SNPs (rs3095329, rs9469220, rs2647046, rs11154801, rs1062158, rs7194) showing strong functional evidence via transcription factor binding sites or microRNA targets and differential expression in immune cells.

This study examined whether genetic variants that predict higher 25-hydroxyvitamin D (25(OH)D) levels are associated with reduced multiple sclerosis (MS) risk in 1,655 MS cases and 6,349 controls. SNPs in GC (rs2282679) were significant predictors of 25(OH)D levels but showed no association with MS risk. The CYP2R1 rs10741657 'A' allele was associated with increased 25(OH)D and reduced MS risk among HLA-DR15 negative individuals (OR=0.89, 95% CI: 0.79-1.01) but not HLA-DR15 positive individuals. CYP27B1 rs703842 'C' allele was inversely associated with MS risk, with stronger effects in HLA-DR15 negative (OR=0.79, 95% CI: 0.69-0.90) versus positive individuals (OR=0.91, 95% CI: 0.80-1.04), suggesting vitamin D's protective effect on MS may be attenuated by the HLA-DR15 risk allele.

This pathway-based association study identified genetic variations in the IL7RA/IL7 signaling pathway that increase multiple sclerosis susceptibility. Two novel genes replicated in an independent dataset: IL7 (rs2587156, p=8.29×10−6, OR=1.35) and SOCS1 (rs441349, p=3.48×10−7, OR=1.25). Additional candidate genes with suggestive evidence include PRKCE (p=3.47×10−4), BCL2 (p=4.32×10−4), and TYK2. The study analyzed 2,961 MS cases and controls in discovery, with 4,831 samples in replication, examining 7,865 SNPs across 73 genes in this biologically-relevant immune pathway.