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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 haplotyp...

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Autores principales: Mack, Steven J., Udell, Julia, Cohen, Franziska, Osoegawa, Kazutoyo, Hawbecker, Sharon K., Noonan, David A., Ladner, Martha B., Goodridge, Damian, Trachtenberg, Elizabeth A., Oksenberg, Jorge R., Erlich, Henry A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035897/
https://www.ncbi.nlm.nih.gov/pubmed/29307888
http://dx.doi.org/10.1038/s41435-017-0006-8
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author Mack, Steven J.
Udell, Julia
Cohen, Franziska
Osoegawa, Kazutoyo
Hawbecker, Sharon K.
Noonan, David A.
Ladner, Martha B.
Goodridge, Damian
Trachtenberg, Elizabeth A.
Oksenberg, Jorge R.
Erlich, Henry A.
author_facet Mack, Steven J.
Udell, Julia
Cohen, Franziska
Osoegawa, Kazutoyo
Hawbecker, Sharon K.
Noonan, David A.
Ladner, Martha B.
Goodridge, Damian
Trachtenberg, Elizabeth A.
Oksenberg, Jorge R.
Erlich, Henry A.
author_sort Mack, Steven J.
collection PubMed
description 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.
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spelling pubmed-60358972019-04-18 High Resolution HLA Analysis Reveals Independent Class I Haplotypes and Amino-Acid Motifs Protective for Multiple Sclerosis Mack, Steven J. Udell, Julia Cohen, Franziska Osoegawa, Kazutoyo Hawbecker, Sharon K. Noonan, David A. Ladner, Martha B. Goodridge, Damian Trachtenberg, Elizabeth A. Oksenberg, Jorge R. Erlich, Henry A. Genes Immun Article 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. 2018-01-08 2019-04 /pmc/articles/PMC6035897/ /pubmed/29307888 http://dx.doi.org/10.1038/s41435-017-0006-8 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Mack, Steven J.
Udell, Julia
Cohen, Franziska
Osoegawa, Kazutoyo
Hawbecker, Sharon K.
Noonan, David A.
Ladner, Martha B.
Goodridge, Damian
Trachtenberg, Elizabeth A.
Oksenberg, Jorge R.
Erlich, Henry A.
High Resolution HLA Analysis Reveals Independent Class I Haplotypes and Amino-Acid Motifs Protective for Multiple Sclerosis
title High Resolution HLA Analysis Reveals Independent Class I Haplotypes and Amino-Acid Motifs Protective for Multiple Sclerosis
title_full High Resolution HLA Analysis Reveals Independent Class I Haplotypes and Amino-Acid Motifs Protective for Multiple Sclerosis
title_fullStr High Resolution HLA Analysis Reveals Independent Class I Haplotypes and Amino-Acid Motifs Protective for Multiple Sclerosis
title_full_unstemmed High Resolution HLA Analysis Reveals Independent Class I Haplotypes and Amino-Acid Motifs Protective for Multiple Sclerosis
title_short High Resolution HLA Analysis Reveals Independent Class I Haplotypes and Amino-Acid Motifs Protective for Multiple Sclerosis
title_sort high resolution hla analysis reveals independent class i haplotypes and amino-acid motifs protective for multiple sclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035897/
https://www.ncbi.nlm.nih.gov/pubmed/29307888
http://dx.doi.org/10.1038/s41435-017-0006-8
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