Single-nucleotide polymorphisms in HLA- and non-HLA genes associated with the development of antibodies to interferon-β therapy in multiple sclerosis patients

Interferons-beta (IFN-beta) are the most widely used immunomodulatory drugs for treatment of multiple sclerosis (MS). The development of neutralizing antibodies (NABs) against IFN-beta 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-beta 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 x 10(-10)) and one SNP in an intergenic region on chromosome 8q24.3 (rs4961252, P-value: 2.92 x 10(-8)) showed a genome-wide significant association with the anti-IFN-beta 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-b and may provide helpful information for individual treatment decisions. The Pharmacogenomics Journal (2012) 12, 238-245; doi: 10.1038/tpj.2011.14; published online 19 April 2011