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

Kathleen Ferar; Taryn O Hall; Dana C Crawford; Robb Rowley; Benjamin A Satterfield; Rongling Li; Loren Gragert; Elizabeth W Karlson; Mariza de Andrade; Iftikhar J Kullo; Catherine A McCarty; Abel Kho; M Geoffrey Hayes; Marylyn D Ritchie; Paul K Crane; Daniel B Mirel; Christopher Carlson; John J Connolly; Hakon Hakonarson; Andrew T Crenshaw; David Carrell; Yuan Luo; Ozan Dikilitas; Joshua C Denny; Gail P Jarvik; David R Crosslin

doi:10.1038/s41598-023-45649-4

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

Sci Rep. 2023 Oct 28;13(1):18532. doi: 10.1038/s41598-023-45649-4.

Authors

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.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Clostridium Infections* / genetics
Diarrhea
Genetic Variation
Genome-Wide Association Study*
HLA Antigens / genetics
Histocompatibility Antigens
Histocompatibility Antigens Class II
Humans

Substances

Histocompatibility Antigens
HLA Antigens
Histocompatibility Antigens Class II

Abstract

Publication types

MeSH terms

Substances

Grants and funding