A genome-wide association study identifies a novel susceptibility locus for the immunogenicity of polyethylene glycol

• Published in: Nature communications Vol. 8; no. 1; pp. 522 - 7
• Main Authors: Chang, Chia-Jung, Chen, Chien-Hsiun, Chen, Bing-Mae, Su, Yu-Cheng, Chen, Ying-Ting, Hershfield, Michael S., Lee, Ming-Ta Michael, Cheng, Tian-Lu, Chen, Yuan-Tsong, Roffler, Steve R., Wu, Jer-Yuarn
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.09.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/205/2138; 631/250/248; Adult; Aged; Aged, 80 and over; Antibodies; Asian Continental Ancestry Group - genetics; Bioavailability; China; Cohort Studies; Conjugation; Drug Hypersensitivity - etiology; Drug Hypersensitivity - genetics; Drug Hypersensitivity - immunology; Female; Genetic markers; Genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Heavy chains; Humanities and Social Sciences; Humans; Immunogenicity; Immunoglobulin G; Immunoglobulin G - immunology; Immunoglobulin M; Immunoglobulin M - immunology; Male; Middle Aged; multidisciplinary; Polyethylene glycol; Polyethylene Glycols - adverse effects; Polyethylenes; Polymorphism, Single Nucleotide; Science; Science (multidisciplinary); Susceptibility; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00622-4

Conjugation of polyethylene glycol (PEG) to therapeutic molecules can improve bioavailability and therapeutic efficacy. However, some healthy individuals have pre-existing anti-PEG antibodies and certain patients develop anti-PEG antibody during treatment with PEGylated medicines, suggesting that genetics might play a role in PEG immunogenicity. Here we perform genome-wide association studies for anti-PEG IgM and IgG responses in Han Chinese with 177 and 140 individuals, defined as positive for anti-PEG IgM and IgG responses, respectively, and with 492 subjects without either anti-PEG IgM or IgG as controls. We validate the association results in the replication cohort, consisting of 211 and 192 subjects with anti-PEG IgM and anti-PEG IgG, respectively, and 596 controls. We identify the immunoglobulin heavy chain ( IGH ) locus to be associated with anti-PEG IgM response at genome-wide significance ( P  = 2.23 × 10 −22 ). Our findings may provide novel genetic markers for predicting the immunogenicity of PEG and efficacy of PEGylated therapeutics. Some individuals develop antibodies against the polyethylene glycol that is commonly used in therapeutic preparations. Here the authors conduct a GWAS in Han Chinese and find the IGH locus is associated with anti-PEG IgM.