title: Contribution of Clostridium difficile infection to the development of lower gastrointestinal adverse events during autologous stem cell transplantation.
abstract: BACKGROUND
  Lower gastrointestinal (GI) adverse events (LGAE) are common afflictions of patients undergoing stem cell transplantation (SCT). Unfortunately, the pathophysiology remains poorly characterized. Emerging data suggest a prominent role of intestinal microbiota; however, contributions of pathogenic gut microbiota such as Clostridium difficile are not well defined. We performed a genome-wide association study (GWAS) to investigate clinical and genetic factors associated with development of LGAE.
  
  
  METHODS
  A total of 972 patients undergoing autologous SCT were graded for LGAE based on Common Terminology Criteria for Adverse Events (v 4.0). Germline DNA material was obtained from leukapharesis products and genotyped using Illumina(®) Whole Genome Genotyping Infinium chemistry and HumanOmni1-Quad Bead chips containing over 1.1 million single nucleotide polymorphisms (SNPs) (Illumina, San Diego, California, USA). Statistical models incorporating clinical factors, genetic factors, and a combination of clinical plus genetic factors were utilized to compare patients who developed severe LGAE (grade 2 or above) and others.
  
  
  RESULTS
  Among 972 patients, 459 (47.2%) developed severe LGAE. Baseline hemoglobin and hematocrit, estimated glomerular filtration rate, β2-microglobulin, protocol type, and C. difficile infection (CDI) were associated with severe LGAE on univariate analysis, Genomic comparisons between groups did not reveal any SNPs associated with severe LGAE and neither did incorporation of genetic factors into the clinical model. In addition, 11 candidate SNPs associated with upper GI mucositis were evaluated, alongside clinical factors in a multivariate model. Only CDI was found to be associated with severe LGAE in all models.
  
  
  CONCLUSIONS
  CDI is a prominent factor in the development of LGAE in patients undergoing autologous SCT.
authors.affiliation: Division of Infectious Diseases, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: S
authors.identifier: http://orcid.org/0000-0002-3915-5814
authors.initials: S
authors.lastname: Apewokin
authors.affiliation: University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Goodwin
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: J Y
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Erickson
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sanathkumar
authors.affiliation: Department of Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: V R
authors.initials: VR
authors.lastname: Raj
authors.affiliation: Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: McKelvey
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: O
authors.initials: O
authors.lastname: Stephens
authors.affiliation: University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Coleman
mesh_terms: D000328:Adult; D000368:Aged; D016360:Clostridioides difficile / Q000302:isolation & purification; D003015:Clostridium Infections / Q000150:complications* / Q000175:diagnosis; D005260:Female; D005767:Gastrointestinal Diseases / Q000209:etiology / Q000235:genetics / Q000382:microbiology*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012720:Severity of Illness Index; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous
chemical_list: D005819:Genetic Markers
keywords: Clostridium difficile; GI adverse events; GWAS; cancer; chemotherapy; stem cell transplant