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

Chia Jung Chang; Chien Hsiun Chen; Bing Mae Chen; Yu-Cheng Su; Ying Ting Chen; Michael S. Hershfield; Ming Ta Michael Lee; Tian Lu Cheng; Yuan Tsong Chen; Steve R. Roffler; Jer Yuarn Wu

doi:10.1038/s41467-017-00622-4

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

Chia Jung Chang, Chien Hsiun Chen, Bing Mae Chen, Yu-Cheng Su, Ying Ting Chen, Michael S. Hershfield, Ming Ta Michael Lee, Tian Lu Cheng, Yuan Tsong Chen^*, Steve R. Roffler, Jer Yuarn Wu

^*Corresponding author for this work

Department of Biological Science and Technology

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

Abstract

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.

Original language	English
Article number	522
Pages (from-to)	1-7
Number of pages	7
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00622-4
State	Published - 12 Sep 2017

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

abstract = "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.",

author = "Chang, {Chia Jung} and Chen, {Chien Hsiun} and Chen, {Bing Mae} and Yu-Cheng Su and Chen, {Ying Ting} and Hershfield, {Michael S.} and Lee, {Ming Ta Michael} and Cheng, {Tian Lu} and Chen, {Yuan Tsong} and Roffler, {Steve R.} and Wu, {Jer Yuarn}",

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AU - Chen, Chien Hsiun

AU - Chen, Bing Mae

AU - Su, Yu-Cheng

AU - Chen, Ying Ting

AU - Hershfield, Michael S.

AU - Lee, Ming Ta Michael

AU - Cheng, Tian Lu

AU - Chen, Yuan Tsong

AU - Roffler, Steve R.

AU - Wu, Jer Yuarn

PY - 2017/9/12

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N2 - 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.

AB - 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.

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

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