High resolution HLA analysis reveals independent class I haplotypes and amino-acid motifs protective for multiple sclerosis.
Journal
Genes and immunity
ISSN: 1476-5470
Titre abrégé: Genes Immun
Pays: England
ID NLM: 100953417
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
18
04
2017
accepted:
11
08
2017
revised:
31
07
2017
pubmed:
9
1
2018
medline:
21
5
2019
entrez:
9
1
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 29307888
doi: 10.1038/s41435-017-0006-8
pii: 10.1038/s41435-017-0006-8
pmc: PMC6035897
mid: NIHMS899528
doi:
Substances chimiques
HLA-DQ beta-Chains
0
HLA-DQB1 antigen
0
HLA-DRB1 Chains
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
308-326Subventions
Organisme : NINDS NIH HHS
ID : R01 NS102153
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM109030
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI128775
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS026799
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI067068
Pays : United States
Commentaires et corrections
Type : ErratumIn
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