Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta: a GWAS
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RESEARCH ARTICLE
Open Access
Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta: a GWAS Till F. M. Andlauer1,2*, Jenny Link3, Dorothea Martin1, Malin Ryner3, Christina Hermanrud3, Verena Grummel1, Michael Auer4, Harald Hegen4, Lilian Aly1,5, Christiane Gasperi1, Benjamin Knier1,5, Bertram Müller-Myhsok2,6,7, Poul Erik Hyldgaard Jensen8, Finn Sellebjerg8, Ingrid Kockum3, Tomas Olsson3, Marc Pallardy9, Sebastian Spindeldreher10,11, Florian Deisenhammer4, Anna Fogdell-Hahn3, Bernhard Hemmer1,7* and on behalf of the ABIRISK consortium
Abstract Background: Upon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon β (IFNβ) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon β preparations. Methods: We analyzed a large sample of 2757 genotyped and imputed patients from two cohorts (Sweden and Germany), split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis. Results: Binding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFNβ-1a s.c.- (odds ratio (OR) = 3.55 (95% confidence interval = 2.81–4.48), p = 2.1 × 10−26) and rs28366299 in IFNβ-1b s.c.-treated patients (OR = 3.56 (2.69– 4.72), p = 6.6 × 10−19). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFNβ-1a s.c. (OR = 2.88 (2.29–3.61), p = 7.4 × 10−20) while DR3-DQ2 was protective (OR = 0.37 (0.27–0.52), p = 3.7 × 10−09). The haplotype DR4-DQ3 was the major risk haplotype for IFNβ-1b s.c. (OR = 7.35 (4.33–12.47), p = 1.5 × 10−13). These haplotypes exhibit large population-specific frequency differences. The best prediction models were achieved for ADA in IFNβ-1a s.c.-treated patients. Here, the prediction in the Swedish cohort showed AUC = 0.91 (0.85–0.95), sensitivity = 0.78, and specificity = 0.90; patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR = 73.9 (11.8–463.6, p = 4.4 × 10−6) of developing nADA. In the German cohort, the AUC of the same model was 0.83 (0.71–0.92), sensitivity = 0.80, specificity = 0.76, with an OR = 13.8 (3.0–63.3, p = 7.5 × 10−4). (Continued on next page)
* Correspondence: [email protected]; [email protected] 1 Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str 22, 81675 Munich, Germany Full list
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