PMID- 32376702 OWN - NLM STAT- MEDLINE DCOM- 20210715 LR - 20210715 IS - 2379-5042 (Electronic) IS - 2379-5042 (Linking) VI - 5 IP - 3 DP - 2020 May 6 TI - Genetic Association Reveals Protection against Recurrence of Clostridium difficile Infection with Bezlotoxumab Treatment. LID - 10.1128/mSphere.00232-20 [doi] LID - e00232-20 AB - 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-DRB1*07:01 and HLA-DQA1*02:01, 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).IMPORTANCEClostridium 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. CI - Copyright (c) 2020 Shen et al. FAU - Shen, Judong AU - Shen J AD - Merck & Co., Inc., Kenilworth, New Jersey, USA. FAU - Mehrotra, Devan V AU - Mehrotra DV AD - Merck & Co., Inc., Kenilworth, New Jersey, USA. FAU - Dorr, Mary Beth AU - Dorr MB AD - Merck & Co., Inc., Kenilworth, New Jersey, USA. FAU - Zeng, Zhen AU - Zeng Z AD - Merck & Co., Inc., Kenilworth, New Jersey, USA. FAU - Li, Junhua AU - Li J AD - BGI-Shenzhen, Shenzhen, China. AD - Shenzhen Key Laboratory of Unknown Pathogen Identification, Shenzhen, China. AD - School of Bioscience and Biotechnology, South China University of Technology, Guangzhou, China. FAU - Xu, Xun AU - Xu X AD - BGI-Shenzhen, Shenzhen, China. AD - Shenzhen Key Laboratory of Unknown Pathogen Identification, Shenzhen, China. FAU - Nickle, David AU - Nickle D AD - Merck & Co., Inc., Kenilworth, New Jersey, USA. FAU - Holzinger, Emily R AU - Holzinger ER AD - Merck & Co., Inc., Kenilworth, New Jersey, USA. FAU - Chhibber, Aparna AU - Chhibber A AD - Merck & Co., Inc., Kenilworth, New Jersey, USA. FAU - Wilcox, Mark H AU - Wilcox MH AD - Leeds Teaching Hospital and University of Leeds, Leeds, United Kingdom. FAU - Blanchard, Rebecca L AU - Blanchard RL AD - Merck & Co., Inc., Kenilworth, New Jersey, USA. FAU - Shaw, Peter M AU - Shaw PM AD - Merck & Co., Inc., Kenilworth, New Jersey, USA peter_shaw3@merck.com. LA - eng SI - ClinicalTrials.gov/NCT01241552 SI - ClinicalTrials.gov/NCT01513239 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20200506 PL - United States TA - mSphere JT - mSphere JID - 101674533 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Neutralizing) RN - 0 (Broadly Neutralizing Antibodies) RN - 0 (HLA-D Antigens) RN - 4H5YMK1H2E (bezlotoxumab) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Alleles MH - Antibodies, Monoclonal/*therapeutic use MH - Antibodies, Neutralizing/blood MH - Broadly Neutralizing Antibodies/*therapeutic use MH - Clostridioides difficile/*drug effects MH - Clostridium Infections/*drug therapy/*genetics MH - Female MH - Genome-Wide Association Study MH - Genotype MH - HLA-D Antigens/genetics MH - Humans MH - Male MH - Middle Aged MH - Polymorphism, Single Nucleotide MH - Recurrence MH - Young Adult PMC - PMC7203456 OTO - NOTNLM OT - Clostridium difficile OT - antibacterials OT - bezlotoxumab OT - genomics EDAT- 2020/05/08 06:00 MHDA- 2021/07/16 06:00 PMCR- 2020/05/06 CRDT- 2020/05/08 06:00 PHST- 2020/05/08 06:00 [entrez] PHST- 2020/05/08 06:00 [pubmed] PHST- 2021/07/16 06:00 [medline] PHST- 2020/05/06 00:00 [pmc-release] AID - 5/3/e00232-20 [pii] AID - mSphere00232-20 [pii] AID - 10.1128/mSphere.00232-20 [doi] PST - epublish SO - mSphere. 2020 May 6;5(3):e00232-20. doi: 10.1128/mSphere.00232-20.