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High resolution HLA analysis reveals independent class I haplotypes and amino-acid motifs protective for multiple sclerosis

Genes & Immunity volume 20, pages 308–326 (2019)Cite this article

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A Correction to this article was published on 18 June 2018

This article has been updated

Abstract

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.

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Change history

  • 18 June 2018

    Since the publication of this article, the authors have found that the numbers of patients and controls were reversed. This study included 412 MS patients and 419 controls. This correction applies to the Abstract, the final paragraph of the Introduction, and the first paragraph of the Materials and Methods. This was entirely a reporting error and does not impact the Results or Conclusions.

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Acknowledgements

This work was supported National Institutes of Health (NIH) National Institute of Allergy and Infectious Disease (NIAID) grants U01AI067068 (Supplement) “The Role of KIR and HLA in Multiple Sclerosis” (E.A.T.) and R01AI28775 (S.J.M.), National Institute of General Medical Sciences (NIGMS) grant R01GM109030 (S.J.M.) and National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS026799 (J.R.O.). The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIAID, NIGMS, NINDS NIH, or United States Government. We thank President Barack H. Obama for his support and appreciation of American science and basic research.

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Authors and Affiliations

  1. Center for Genetics, Children’s Hospital Oakland Research Institute, Oakland, CA, USA

    Steven J. Mack, Franziska Cohen, Sharon K. Hawbecker, David A. Noonan, Martha B. Ladner, Elizabeth A. Trachtenberg & Henry A. Erlich

  2. University of Minnesota Twin Cities, Minneapolis, MN, USA

    Julia Udell

  3. Histocompatibility, Immunogenetics & Disease Profiling Laboratory, Stanford Blood Center, Palo Alto, CA, USA

    Kazutoyo Osoegawa

  4. Illumina, San Diego, CA, USA

    Damian Goodridge

  5. Department of Neurology, University of California, San Francisco, CA, USA

    Jorge R. Oksenberg

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Correspondence to Steven J. Mack.

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Mack, S.J., Udell, J., Cohen, F. et al. High resolution HLA analysis reveals independent class I haplotypes and amino-acid motifs protective for multiple sclerosis. Genes Immun 20, 308–326 (2019). https://doi.org/10.1038/s41435-017-0006-8

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