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？=？3.37–04) 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