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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2018
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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. |
format | Online Article Text |
id | pubmed-6035897 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
record_format | MEDLINE/PubMed |
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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