A genome-wide screen for variants influencing certolizumab pegol response in a moderate to severe rheumatoid arthritis population

• Published in: PloS one 2022-04, Vol.17 (4), p.e0261165-e0261165
• Main Authors: White, Ian R, Kleinstein, Sarah E, Praet, Christophe, Chamberlain, Chris, McHale, Duncan, Maia, Jessica M, Xie, Pingxing, Goldstein, David B, Urban, Thomas J, Shea, Patrick R
• Format: Article
• Language: English
• Subjects: Antibodies; Antirheumatic Agents - therapeutic use; Arthritis; Arthritis, Rheumatoid - chemically induced; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - genetics; Autoimmune diseases; Biology and Life Sciences; Biomarkers; Certolizumab Pegol - therapeutic use; Crohn's disease; Drug therapy; Genetic aspects; Genetic diversity; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Health risks; Health services; Humans; Inflammatory diseases; Machine learning; Medical research; Medicine; Medicine and Health Sciences; Monoclonal antibodies; Nucleotides; Patient outcomes; Patients; Population control; Potassium channels; Psoriasis; Psoriatic arthritis; Rheumatic diseases; Rheumatoid arthritis; Signs and symptoms; Single-nucleotide polymorphism; Skin diseases; TNF inhibitors; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Tumor necrosis factor-α
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0261165

Certolizumab pegol (CZP) is a PEGylated Fc-free tumor necrosis factor (TNF) inhibitor antibody approved for use in the treatment of rheumatoid arthritis (RA), Crohn's disease, psoriatic arthritis, axial spondyloarthritis and psoriasis. In a clinical trial of patients with severe RA, CZP improved disease symptoms in approximately half of patients. However, variability in CZP efficacy remains a problem for clinicians, thus, the aim of this study was to identify genetic variants predictive of CZP response. We performed a genome-wide association study (GWAS) of 302 RA patients treated with CZP in the REALISTIC trial to identify common single nucleotide polymorphisms (SNPs) associated with treatment response. Whole-exome sequencing was also performed for 74 CZP extreme responders and non-responders within the same population, as well as 1546 population controls. No common SNPs or rare functional variants were significantly associated with CZP response, though a non-significant enrichment in the RA-implicated KCNK5 gene was observed. Two SNPs near spondin-1 and semaphorin-4G approached genome-wide significance. The results of the current study did not provide an unambiguous predictor of CZP response.