Influence of the HLA-DRB1 Genotype on Antibody Development to Interferon Beta in Multiple Sclerosis

Objective: To determine relevant HLA-DRB1 alleles associated with the susceptibility of anti-interferon beta antibody development in a large patient cohort. Design: In a case-control study, HLA-DRB1 genotyping was performed in a discovery cohort (n = 268) and a validation cohort (n = 825). Setting: Patients were recruited in Germany by primary care physicians and neurologists and were mainly of Northern European heritage. Patients: All patients had a diagnosis of multiple sclerosis and were receiving long-term interferon beta therapy. Main Outcome Measures: 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. Conclusion: 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.