title: Single-nucleotide polymorphisms in HLA- and non-HLA genes associated with the development of antibodies to interferon-β therapy in multiple sclerosis patients.
abstract: Interferons-β (IFN-β) are the most widely used immunomodulatory drugs for treatment of multiple sclerosis (MS). The development of neutralizing antibodies (NABs) against IFN-β is one of the main reasons for treatment failure. While formulation of the drug has a proven impact on the development of NABs, the genetic predisposition to develop antibodies is poorly understood. We performed genome-wide single-nucleotide polymorphism (SNP) genotyping in 362 MS patients of whom 178 had developed and 184 had not developed antibodies on IFN-β therapy. Four candidate SNPs were validated in an independent cohort of 350 antibody-positive and 468 antibody-negative MS patients. One SNP within the human leucocyte antigen (HLA) region (rs9272105, P-value: 3.56 × 10⁻¹⁰) and one SNP in an intergenic region on chromosome 8q24.3 (rs4961252, P-value: 2.92 × 10⁻⁸ showed a genome-wide significant association with the anti-IFN-β antibody titers. We found no interaction between the genome-wide significant SNPs (rs9272105 and rs4961252) in our study and the previously described HLA-DR*0401 or *0408 alleles, indicating an additive effect of SNPs and HLA alleles. Testing for these SNPs and the HLA-DR*0401 or *0408 alleles allows to identify patients at risk to develop antibodies to IFN-β and may provide helpful information for individual treatment decisions.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Weber
authors.forename: S
authors.initials: S
authors.lastname: Cepok
authors.forename: C
authors.initials: C
authors.lastname: Wolf
authors.forename: A
authors.initials: A
authors.lastname: Berthele
authors.forename: M
authors.initials: M
authors.lastname: Uhr
authors.forename: Th
authors.initials: T
authors.lastname: Bettecken
authors.forename: D
authors.initials: D
authors.lastname: Buck
authors.forename: H P
authors.initials: HP
authors.lastname: Hartung
authors.forename: F
authors.initials: F
authors.lastname: Holsboer
authors.forename: B
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: B
authors.initials: B
authors.lastname: Hemmer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000097:blood*; D016022:Case-Control Studies; D002898:Chromosomes, Human, Pair 8; D021901:DNA, Intergenic; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D005858:Germany; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology / Q000627:therapeutic use*; D016899:Interferon-beta / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D021901:DNA, Intergenic; D006680:HLA Antigens; D007155:Immunologic Factors; D016899:Interferon-beta