Genome Wide Analysis Reveals Host Genetic Variants that Associate with Reduction in Clostridium difficile Infection Recurrence (rCDI) in Patients Treated with Bezlotoxumab
Authors: Shaw Peter , Shen Judong , Dorr Mary Beth , Wilcox Mark , Li Junhua , Mogg Robin , Mehrotra Devan V , Blanchard Rebecca L 
Published: October 2017

Abstract

Background
Bezlotoxumab (BEZ) and actoxumab (ACT) are monoclonal antibodies against C. difficile toxins B and A, respectively. Patients receiving a single infusion of BEZ alone or with ACT in the MODIFY I/II trials showed a consistent reduction in the rate of rCDI over a 12-week period compared with a placebo (PBO) infusion. Exploratory genome wide analyses were conducted to determine whether genetic variants across the genome were associated with treatment response (rCDI).

Methods
DNA was extracted from blood obtained from patients who consented to genetic analysis (PGx population). Genetic data were generated on a commercial Axiom array platform (Affymetrix). Genotype imputation was performed using the 1000 Genomes Phase 3 reference data and Impute2 software after genetic quality control. Data from BEZ and ACT+BEZ arms were combined to provide increased power. The logistic regression with likelihood ratio test was used to search for single nucleotide polymorphisms (SNPs) that were strongly associated with a treatment effect on rCDI.

Results
An SNP rs2516513 located in the extended major histocompatibility complex (xMHC), region with a minor allele frequency of 25% in the general population, was associated with rCDI (P = 3.04E-08) (Figure 1). rCDI rates for the PGx population and in subgroups at high/low risk for rCDI stratified by SNP rs2516513 are shown in Table 1. Carriers of the T allele of SNP rs2516513 were associated with a statistically significant reduction in rCDI in BEZ-treated patients but not in PBO-treated patients (DrCDI = -21.5%). The magnitude of the effect of the T allele on rCDI is most prominent in patients who have ≥1 risk factor for rCDI (DrCDI = -24.6%), but is also present in patients without risk factors (DrCDI = -10.6%). In CC homozygous patients, rCDI rates are similar in both treatment groups and in patients at high and low risk of rCDI.

Conclusion
An SNP variant rs2516513 is associated with a lower rate of rCDI recurrence in patients treated with BEZ. The location of the associated genetic variant on chromosome 6 within xMHC, suggests that a host driven, immunological mechanism may play a role in rCDI and may predict patients most likely to respond to BEZ. As this is an exploratory finding, the results should be replicated in an independent validation study.

Disclosures
P. Shaw, Merck & Co., Inc.: Employee, May own stock/hold stock options in Company; J. Shen, Merck & Co., Inc.: Employee, may hold stock/hold stock options in the Company; M. B. Dorr, Merck & Co., Inc.: Employee and Shareholder, may own stock/hold stock options in the Company; J. Li, BGI-Shenzhen: Employee, Salary; R. Mogg, Merck & Co., Inc.: Employee, May hold stock/stock options in the Company; D. V. Mehrotra, Merck & Co., Inc.: Employee, may own stock/hold stock options in the Company; R. L. Blanchard, Merck & Co., Inc.: Employee, may own stock/hold stock options in the Company