%0 Journal Article
%T High resolution HLA analysis reveals independent class I haplotypes and amino-acid motifs protective for multiple sclerosis
%J -
%D 2018
%R https://doi.org/10.1038/s41435-017-0006-8
%X 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)ˋ=ˋ3.98; 95% confidence interval (CI)ˋ=ˋ3每5.31; p-value (p) =ˋ2.22Eˋ16), as was DRB1*03:01~DQB1*02:01 (ORˋ=ˋ1.63; CIˋ=ˋ1.19每2.24; pˋ=ˋ1.41Eˋ03). Hardy每Weinberg (HW) analysis in MS patients revealed a significant DRB1*03:01~DQB1*02:01 homozyote excess (15 observed; 8.6 expected; pˋ=ˋ0.016). The OR for this genotype (5.27; CIˋ=ˋ1.47每28.52; pˋ=ˋ0.0036) suggests a recessive MS risk model. Controls displayed no HW deviations. The C*03:04~B*40:01 haplotype (ORˋ=ˋ0.27; CIˋ=ˋ0.14每0.51; pˋ=ˋ6.76Eˋ06) was highly protective for MS, especially in haplotypes with A*02:01 (ORˋ=ˋ0.15; CIˋ=ˋ0.04每0.45; pˋ=ˋ6.51Eˋ05). By itself, A*02:01 is moderately protective, (ORˋ=ˋ0.69; CIˋ=ˋ0.54每0.87; pˋ=ˋ1.46Eˋ03), and haplotypes of A*02:01 with the HLA-B Thr80 Bw4 variant (Bw4T) more so (ORˋ=ˋ0.53; CIˋ=ˋ0.35每0.78; pˋ=ˋ7.55Eˋ04). Protective associations with the Bw4 KIR ligand resulted from linkage disequilibrium (LD) with DRB1*15:01, but the Bw4T variant was protective (ORˋ=ˋ0.64; CIˋ=ˋ0.49每0.82; pˋ=ˋ3.37每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
%U https://www.nature.com/articles/s41435-017-0006-8