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Mult Scler. 2018 Mar 1:1352458518763089. doi: 10.1177/1352458518763089. [Epub ahead of print]

Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials.

Author information

1
Department of Neurology, Klinikum rechts der Isar, Technische Universität München, München, Germany/German Competence Network Multiple Sclerosis (KKNMS), München, Germany.
2
German Competence Network Multiple Sclerosis (KKNMS), München, Germany/Max Planck Institute of Psychiatry, Munich, Germany/Munich Cluster for Systems Neurology (SyNergy), Munich, Germany/Department of Neurology, Klinikum rechts der Isar, Technische Universität München, München, Germany.
3
Bayer AG, Berlin, Germany.
4
German Competence Network Multiple Sclerosis (KKNMS), München, Germany/Max Planck Institute of Psychiatry, Munich, Germany/Neurological Clinic, Medical Park Bad Camberg, Bad Camberg, Germany.
5
Bayer AG, Berlin, Germany/Department of Neurology, University Hospital of Bonn, Bonn, Germany.
6
Department of Neurology, Surgery Brain Research Institutes, University of Chicago, Chicago, IL, USA.
7
Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Milan, Italy.
8
Rutgers, The State University of New Jersey, Newark, NJ, USA.
9
Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.
10
Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
11
Piedmont Healthcare, Mooresville, NC, USA.
12
University Hospital Basel, Basel, Switzerland.
13
Radiology and Nuclear Medicine, VU University Medical Centre Amsterdam, The Netherlands/UCL Institutes of Neurology and Healthcare Engineering, London, UK.
14
University of Rennes, Rennes, France.
15
University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, ON, Canada.
16
Department of Clinical Neuroimmunology, Hospital Vall d'Hebron, Barcelona, Spain.
17
German Competence Network Multiple Sclerosis (KKNMS), München, Germany/Max Planck Institute of Psychiatry, Munich, Germany/Munich Cluster for Systems Neurology (SyNergy), Munich, Germany/Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
18
Department of Neurology, Klinikum rechts der Isar, Technische Universität München, München, Germany/German Competence Network Multiple Sclerosis (KKNMS), München, Germany/Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

Abstract

BACKGROUND:

Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β.

OBJECTIVE:

To validate the proposed genetic markers and to identify new markers.

METHODS:

Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon® Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron®/BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants.

RESULTS:

We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10-4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10-3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10-15).

CONCLUSION:

The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies.

KEYWORDS:

HLA-DRB1; Multiple sclerosis; anti-drug antibodies; genetic variation; genome-wide association study; interferon beta

PMID:
29521573
DOI:
10.1177/1352458518763089

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