Response to anti-IL17 therapy in inflammatory disease is not strongly impacted by genetic background

Cong Zhang; Konstantin Shestopaloff; Benjamin Hollis; Chun Hei Kwok; Claudia Hon; Nicole Hartmann; Chengeng Tian; Magdalena Wozniak; Luis Santos; Dominique West; Stephen Gardiner; Ann-Marie Mallon; Aimee Readie; Ruvie Martin; Thomas Nichols; Michael T Beste; Jonas Zierer; Enrico Ferrero; Marc Vandemeulebroecke; Luke Jostins-Dean

doi:10.1016/j.ajhg.2023.08.010

Response to anti-IL17 therapy in inflammatory disease is not strongly impacted by genetic background

Am J Hum Genet. 2023 Oct 5;110(10):1817-1824. doi: 10.1016/j.ajhg.2023.08.010. Epub 2023 Sep 1.

Authors

Cong Zhang¹, Konstantin Shestopaloff², Benjamin Hollis³, Chun Hei Kwok⁴, Claudia Hon⁵, Nicole Hartmann⁶, Chengeng Tian¹, Magdalena Wozniak⁷, Luis Santos⁸, Dominique West⁹, Stephen Gardiner¹⁰, Ann-Marie Mallon⁸, Aimee Readie¹¹, Ruvie Martin¹¹, Thomas Nichols¹⁰, Michael T Beste⁵, Jonas Zierer¹², Enrico Ferrero¹², Marc Vandemeulebroecke¹³, Luke Jostins-Dean¹⁴

Affiliations

¹ China Novartis Institutes for Bio-medical Research CO., Shanghai, China.
² Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Statistics, University of Oxford, Oxford, UK.
³ Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
⁴ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁵ Novartis Institutes for BioMedical Research, 220 Massachusetts Avenue, Cambridge, MA 02139, USA.
⁶ Novartis Pharma AG, Lichtstrasse 35, Basel, CH, Switzerland.
⁷ Novartis Ireland Limited, Dublin, Ireland.
⁸ The Alan Turing Institute, London, UK.
⁹ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹⁰ Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹¹ Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
¹² Novartis Institutes for BioMedical Research, Basel, CH, Switzerland.
¹³ Novartis Pharma AG, Global Drug Development, Basel, CH, Switzerland. Electronic address: marc.vandemeulebroecke@novartis.com.
¹⁴ Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. Electronic address: luke.jostins@kennedy.ox.ac.uk.

Abstract

Response to the anti-IL17 monoclonal antibody secukinumab is heterogeneous, and not all participants respond to treatment. Understanding whether this heterogeneity is driven by genetic variation is a key aim of pharmacogenetics and could influence precision medicine approaches in inflammatory diseases. Using changes in disease activity scores across 5,218 genotyped individuals from 19 clinical trials across four indications (psoriatic arthritis, psoriasis, ankylosing spondylitis, and rheumatoid arthritis), we tested whether genetics predicted response to secukinumab. We did not find any evidence of association between treatment response and common variants, imputed HLA alleles, polygenic risk scores of disease susceptibility, or cross-disease components of shared genetic risk. This suggests that anti-IL17 therapy is equally effective regardless of an individual's genetic background, a finding that has important implications for future genetic studies of biological therapy response in inflammatory diseases.

Keywords: biological therapy; clinical trials; genome-wide association studies; inflammatory diseases; rheumatic diseases.

MeSH terms

Arthritis, Psoriatic* / drug therapy
Arthritis, Psoriatic* / genetics
Arthritis, Rheumatoid* / drug therapy
Arthritis, Rheumatoid* / genetics
Genotype
Humans
Psoriasis* / drug therapy
Psoriasis* / genetics

Grants and funding

WT_/Wellcome Trust/United Kingdom