title: Influence of the HLA-DRB1 genotype on antibody development to interferon beta in multiple sclerosis.
abstract: OBJECTIVE
  To determine relevant HLA-DRB1 alleles associated with the susceptibility of anti-interferon beta antibody development in a large patient cohort.
  
  
  METHODS
  In a case-control study, HLA-DRB1 genotyping was performed in a discovery cohort (n = 268) and a validation cohort (n = 825).
  
  
  METHODS
  Patients were recruited in Germany by primary care physicians and neurologists and were mainly of Northern European heritage.
  
  
  METHODS
  All patients had a diagnosis of multiple sclerosis and were receiving long-term interferon beta therapy.
  
  
  METHODS
  The antibody status to interferon beta was determined in all patients by capture enzyme-linked immunosorbent assay and in vivo myxovirus protein A assay and correlated with the HLA-DRB1 genotype.
  
  
  RESULTS
  In the discovery and validation cohorts, HLA-DRB1*04:01, *04:08, *16:01 were identified as genetic markers that are associated with an increased risk of anti-interferon beta antibody development (P < .05). In addition, alleles with a protective potential were identified, including HLA-DRB1*03:01, *04:04, *11:04. However, after correction for multiple testing, protective alleles did not reach statistical significance.
  
  
  CONCLUSIONS
  The HLA alleles identified in this study seem to be the major genetic determinant of antibody development, allowing the prediction of the individual risk of patients before initiation of therapy.
authors.affiliation: Department of Neurology, Technische Universität München, Munich, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Buck
authors.forename: Sabine
authors.initials: S
authors.lastname: Cepok
authors.forename: Steve
authors.initials: S
authors.lastname: Hoffmann
authors.forename: Verena
authors.initials: V
authors.lastname: Grummel
authors.forename: Angela
authors.initials: A
authors.lastname: Jochim
authors.forename: Achim
authors.initials: A
authors.lastname: Berthele
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.forename: Ralf
authors.initials: R
authors.lastname: Wassmuth
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001323:Autoantibodies / Q000096:biosynthesis*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D016899:Interferon-beta / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; C553505:HLA-DRB1*04:01 antigen; D016899:Interferon-beta