Genetic Association Reveals Protection against Recurrence of <italic toggle="yes">Clostridium difficile</italic> Infection with Bezlotoxumab Treatment

ABSTRACT Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B, indicated to prevent recurrence of C. difficile infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic...

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Autores principales:	Judong Shen, Devan V. Mehrotra, Mary Beth Dorr, Zhen Zeng, Junhua Li, Xun Xu, David Nickle, Emily R. Holzinger, Aparna Chhibber, Mark H. Wilcox, Rebecca L. Blanchard, Peter M. Shaw
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Clostridium difficile antibacterials bezlotoxumab genomics Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/adb561e16b8649aeaf98ce58ff6ef478
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spelling	oai:doaj.org-article:adb561e16b8649aeaf98ce58ff6ef4782021-11-15T15:30:15ZGenetic Association Reveals Protection against Recurrence of <italic toggle="yes">Clostridium difficile</italic> Infection with Bezlotoxumab Treatment10.1128/mSphere.00232-202379-5042https://doaj.org/article/adb561e16b8649aeaf98ce58ff6ef4782020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00232-20https://doaj.org/toc/2379-5042ABSTRACT Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B, indicated to prevent recurrence of C. difficile infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic variation influences bezlotoxumab response. DNA from 704 participants who achieved initial clinical cure in the phase 3 MODIFY I/II trials was genotyped. Single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) imputation were performed using IMPUTE2 and HIBAG, respectively. A joint test of genotype and genotype-by-treatment interaction in a logistic regression model was used to screen genetic variants associated with response to bezlotoxumab. The SNP rs2516513 and the HLA alleles HLA-DRB107:01 and HLA-DQA102:01, located in the extended major histocompatibility complex on chromosome 6, were associated with the reduction of rCDI in bezlotoxumab-treated participants. Carriage of a minor allele (homozygous or heterozygous) at any of the identified loci was related to a larger difference in the proportion of participants experiencing rCDI versus placebo; the effect was most prominent in the subgroup at high baseline risk for rCDI. Genotypes associated with an improved bezlotoxumab response showed no association with rCDI in the placebo cohort. These data suggest that a host-driven, immunological mechanism may impact bezlotoxumab response. Trial registration numbers are as follows: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II). IMPORTANCE Clostridium difficile infection is associated with significant clinical morbidity and mortality; antibacterial treatments are effective, but recurrence of C. difficile infection is common. In this genome-wide association study, we explored whether host genetic variability affected treatment responses to bezlotoxumab, a human monoclonal antibody that binds C. difficile toxin B and is indicated for the prevention of recurrent C. difficile infection. Using data from the MODIFY I/II phase 3 clinical trials, we identified three genetic variants associated with reduced rates of C. difficile infection recurrence in bezlotoxumab-treated participants. The effects were most pronounced in participants at high risk of C. difficile infection recurrence. All three variants are located in the extended major histocompatibility complex on chromosome 6, suggesting the involvement of a host-driven immunological mechanism in the prevention of C. difficile infection recurrence.Judong ShenDevan V. MehrotraMary Beth DorrZhen ZengJunhua LiXun XuDavid NickleEmily R. HolzingerAparna ChhibberMark H. WilcoxRebecca L. BlanchardPeter M. ShawAmerican Society for MicrobiologyarticleClostridium difficileantibacterialsbezlotoxumabgenomicsMicrobiologyQR1-502ENmSphere, Vol 5, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Clostridium difficile antibacterials bezlotoxumab genomics Microbiology QR1-502
spellingShingle	Clostridium difficile antibacterials bezlotoxumab genomics Microbiology QR1-502 Judong Shen Devan V. Mehrotra Mary Beth Dorr Zhen Zeng Junhua Li Xun Xu David Nickle Emily R. Holzinger Aparna Chhibber Mark H. Wilcox Rebecca L. Blanchard Peter M. Shaw Genetic Association Reveals Protection against Recurrence of <italic toggle="yes">Clostridium difficile</italic> Infection with Bezlotoxumab Treatment
description	ABSTRACT Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B, indicated to prevent recurrence of C. difficile infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic variation influences bezlotoxumab response. DNA from 704 participants who achieved initial clinical cure in the phase 3 MODIFY I/II trials was genotyped. Single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) imputation were performed using IMPUTE2 and HIBAG, respectively. A joint test of genotype and genotype-by-treatment interaction in a logistic regression model was used to screen genetic variants associated with response to bezlotoxumab. The SNP rs2516513 and the HLA alleles HLA-DRB107:01 and HLA-DQA102:01, located in the extended major histocompatibility complex on chromosome 6, were associated with the reduction of rCDI in bezlotoxumab-treated participants. Carriage of a minor allele (homozygous or heterozygous) at any of the identified loci was related to a larger difference in the proportion of participants experiencing rCDI versus placebo; the effect was most prominent in the subgroup at high baseline risk for rCDI. Genotypes associated with an improved bezlotoxumab response showed no association with rCDI in the placebo cohort. These data suggest that a host-driven, immunological mechanism may impact bezlotoxumab response. Trial registration numbers are as follows: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II). IMPORTANCE Clostridium difficile infection is associated with significant clinical morbidity and mortality; antibacterial treatments are effective, but recurrence of C. difficile infection is common. In this genome-wide association study, we explored whether host genetic variability affected treatment responses to bezlotoxumab, a human monoclonal antibody that binds C. difficile toxin B and is indicated for the prevention of recurrent C. difficile infection. Using data from the MODIFY I/II phase 3 clinical trials, we identified three genetic variants associated with reduced rates of C. difficile infection recurrence in bezlotoxumab-treated participants. The effects were most pronounced in participants at high risk of C. difficile infection recurrence. All three variants are located in the extended major histocompatibility complex on chromosome 6, suggesting the involvement of a host-driven immunological mechanism in the prevention of C. difficile infection recurrence.
format	article
author	Judong Shen Devan V. Mehrotra Mary Beth Dorr Zhen Zeng Junhua Li Xun Xu David Nickle Emily R. Holzinger Aparna Chhibber Mark H. Wilcox Rebecca L. Blanchard Peter M. Shaw
author_facet	Judong Shen Devan V. Mehrotra Mary Beth Dorr Zhen Zeng Junhua Li Xun Xu David Nickle Emily R. Holzinger Aparna Chhibber Mark H. Wilcox Rebecca L. Blanchard Peter M. Shaw
author_sort	Judong Shen
title	Genetic Association Reveals Protection against Recurrence of <italic toggle="yes">Clostridium difficile</italic> Infection with Bezlotoxumab Treatment
title_short	Genetic Association Reveals Protection against Recurrence of <italic toggle="yes">Clostridium difficile</italic> Infection with Bezlotoxumab Treatment
title_full	Genetic Association Reveals Protection against Recurrence of <italic toggle="yes">Clostridium difficile</italic> Infection with Bezlotoxumab Treatment
title_fullStr	Genetic Association Reveals Protection against Recurrence of <italic toggle="yes">Clostridium difficile</italic> Infection with Bezlotoxumab Treatment
title_full_unstemmed	Genetic Association Reveals Protection against Recurrence of <italic toggle="yes">Clostridium difficile</italic> Infection with Bezlotoxumab Treatment
title_sort	genetic association reveals protection against recurrence of <italic toggle="yes">clostridium difficile</italic> infection with bezlotoxumab treatment
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/adb561e16b8649aeaf98ce58ff6ef478
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Genetic Association Reveals Protection against Recurrence of <italic toggle="yes">Clostridium difficile</italic> Infection with Bezlotoxumab Treatment

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