High Resolution HLA Analysis Reveals Independent Class I Haplotypes and Amino-Acid Motifs Protective for Multiple Sclerosis

We investigated association between HLA class I and class II alleles and haplotypes, and KIR loci and their HLA class I ligands, with multiple sclerosis (MS) in 412 European-American MS patients and 419 ethnically-matched controls, using next generation sequencing. The DRB1*15:01~DQB1*06:02 haplotype was highly predisposing (odds ratio (OR) = 3.98; 95% confidence interval (CI) = 3−5.31; p-value (p) = 2.22E−16), as was DRB1*03:01~DQB1*02:01 (OR = 1.63; CI = 1.19–2.24; p = 1.41E−03). Hardy-Weinberg (HW) analysis in MS patients revealed a significant DRB1*03:01~DQB1*02:01 homozyote excess (15 observed, 8.6 expected; p = 0.016). The OR for this genotype (5.27; CI = 1.47–28.52; p = 0.0036) suggests a recessive MS risk model. Controls displayed no HW deviations. The C*03:04~B*40:01 haplotype (OR = 0.27; CI = 0.14–0.51; p = 6.76E−06) was highly protective for MS, especially in haplotypes with A*02:01 (OR = 0.15; CI = 0.04–0.45; p = 6.51E−05). By itself, A*02:01 is moderately protective, (OR = 0.69; CI = 0.54–0.87; p = 1.46E−03), and haplotypes of A*02:01 with the HLA-B Thr80 Bw4 variant (Bw4T) more so (OR = 0.53; CI = 0.35–0.78; p = 7.55E−04). Protective associations with the Bw4 KIR ligand resulted from linkage disequilibrium (LD) with DRB1*15:01, but the Bw4T variant was protective (OR = 0.64; CI = 0.49–0.82; p = 3.37E−04) independent of LD with DRB1*15:01. The Bw4I variant was not associated with MS. Overall, we find specific class I HLA polymorphisms to be protective for MS, independent of the strong predisposition conferred by DRB1*15:01.