Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection

Kathleen Ferar¹, Taryn O Hall², Dana C Crawford^{3

4}, Robb Rowley⁵, Benjamin A Satterfield⁶, Rongling Li⁵, Loren Gragert⁷, Elizabeth W Karlson⁸, Mariza de Andrade⁹, Iftikhar J Kullo⁶, Catherine A McCarty^{10

11}, Abel Kho¹², M Geoffrey Hayes¹³, Marylyn D Ritchie¹⁴, Paul K Crane¹⁵, Daniel B Mirel¹⁶, Christopher Carlson¹⁷, John J Connolly¹⁸, Hakon Hakonarson¹⁹, Andrew T Crenshaw²⁰, David Carrell²¹, Yuan Luo²², Ozan Dikilitas⁶, Joshua C Denny²³, Gail P Jarvik²⁴, David R Crosslin²⁵

Affiliations

¹ Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, USA. kmuenzen@uw.edu.
² Optum Genomics, UnitedHealth Group, Minnetonka, MN, USA.
³ Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
⁴ Department of Genetics and Genome Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
⁵ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
⁷ Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
⁸ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁹ Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
¹⁰ University of Minnesota Medical School, Duluth, MN, USA.
¹¹ Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
¹² Divisions of General Internal Medicine and Preventive Medicine, Northwestern University, Chicago, IL, USA.
¹³ Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹⁴ Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, PA, USA.
¹⁵ Division of General Internal Medicine, University of Washington, Seattle, WA, USA.
¹⁶ Scilligence Corp., Cambridge, MA, USA.
¹⁷ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹⁸ Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁹ Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²⁰ The Broad Institute of Harvard-MIT, Cambridge, MA, USA.
²¹ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
²² Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
²³ Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
²⁴ Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA, USA.
²⁵ Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA. crosslin@tulane.edu.

PMID: 37898691
PMCID: PMC10613277
DOI: 10.1038/s41598-023-45649-4

Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection

Kathleen Ferar et al. Sci Rep. 2023.

. 2023 Oct 28;13(1):18532.

doi: 10.1038/s41598-023-45649-4.

Authors

Affiliations

¹ Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, USA. kmuenzen@uw.edu.
² Optum Genomics, UnitedHealth Group, Minnetonka, MN, USA.
³ Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
⁴ Department of Genetics and Genome Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
⁵ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
⁷ Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
⁸ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁹ Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
¹⁰ University of Minnesota Medical School, Duluth, MN, USA.
¹¹ Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
¹² Divisions of General Internal Medicine and Preventive Medicine, Northwestern University, Chicago, IL, USA.
¹³ Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹⁴ Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, PA, USA.
¹⁵ Division of General Internal Medicine, University of Washington, Seattle, WA, USA.
¹⁶ Scilligence Corp., Cambridge, MA, USA.
¹⁷ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹⁸ Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁹ Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²⁰ The Broad Institute of Harvard-MIT, Cambridge, MA, USA.
²¹ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
²² Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
²³ Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
²⁴ Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA, USA.
²⁵ Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA. crosslin@tulane.edu.

PMID: 37898691
PMCID: PMC10613277
DOI: 10.1038/s41598-023-45649-4

Erratum in

Author Correction: Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection.
Ferar K, Hall TO, Crawford DC, Rowley R, Satterfield BA, Li R, Gragert L, Karlson EW, de Andrade M, Kullo IJ, McCarty CA, Kho A, Hayes MG, Ritchie MD, Crane PK, Mirel DB, Carlson C, Connolly JJ, Hakonarson H, Crenshaw AT, Carrell D, Luo Y, Dikilitas O, Denny JC, Jarvik GP, Crosslin DR. Ferar K, et al. Sci Rep. 2023 Nov 15;13(1):19972. doi: 10.1038/s41598-023-47359-3. Sci Rep. 2023. PMID: 37968452 Free PMC article. No abstract available.

Abstract

Clostridioides difficile (C. diff.) infection (CDI) is a leading cause of hospital acquired diarrhea in North America and Europe and a major cause of morbidity and mortality. Known risk factors do not fully explain CDI susceptibility, and genetic susceptibility is suggested by the fact that some patients with colons that are colonized with C. diff. do not develop any infection while others develop severe or recurrent infections. To identify common genetic variants associated with CDI, we performed a genome-wide association analysis in 19,861 participants (1349 cases; 18,512 controls) from the Electronic Medical Records and Genomics (eMERGE) Network. Using logistic regression, we found strong evidence for genetic variation in the DRB locus of the MHC (HLA) II region that predisposes individuals to CDI (P > 1.0 × 10^-14; OR 1.56). Altered transcriptional regulation in the HLA region may play a role in conferring susceptibility to this opportunistic enteric pathogen.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Figure 1**
Manhattan plot of P-values generated using logistic regression analysis in the European ancestry sample (n = 14,620). An additive model was used to assess the disease susceptibility impact of the minor (coded) allele at each position, while controlling for age, BMI, sex, ancestry, nursing home status, chemotherapy, diabetes, HIV, transplant medications, corticosteroids, and medium or high-risk antibiotic exposure as covariates. Genomic coordinates are displayed along the X-axis, and the negative logarithm of logistic regression P-values are displayed on the Y-axis. Each dot represents a SNV in the regression model, with associated P-values plotted accordingly, while the triangle represents the most significantly associated SNV. The dotted line represents the negative logarithm of the genome-wide significance threshold (P < 5 × 10^–8). Colors are used to distinguish between SNVs in adjacent chromosomes.

**Figure 2**
Regional LD plot of SNVs evaluated in the European-ancestry logistic regression analysis, using the European 1000 Genomes superpopulation as a reference group. Genomic coordinates spanning the HLA-DRB region and surrounding genes are shown on the X-axis in both subplots. Negative logarithms of P-values from the European-ancestry logistic regression analysis are shown on the Y-axis in the upper sublot, and annotated gene transcripts are distributed along the Y-axis in the lower subplot. Each dot represents a SNV in the regression model, with associated P-values plotted accordingly. SNVs in highest LD with reference to the index SNV (rs68148149) are colored in red. The LD plot was generated with the LocusZoom tool using default parameters and the 1000 Genomes Project 2014 EUR reference panel.

**Figure 3**
eMERGE *Clostridiodes difficile* phenotyping algorithm flowchart.

See this image and copyright information in PMC

References

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Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection

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Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection

Authors

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