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

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. CrenshawDavid Carrell, Yuan Luo, Ozan Dikilitas, Joshua C. Denny, Gail P. Jarvik, David R. Crosslin^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Article number	18532
Journal	Scientific reports
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41598-023-45649-4
State	Published - Dec 2023

Funding

The authors would like to thank all of the research participants and scientific staff of the eMERGE consortium. This study was supported by the following U01 grants from the National Human Genome Research Institute (NHGRI), a component of the National Institutes of Health (NIH), Bethesda, MD, USA: 1. U01HG8684 (The Children’s Hospital of Philadelphia); 2. U01HG8666 (Cincinnati Children’s Medical Hospital); 3. U01HG8680 (Columbia University); 4. U01HG006382 (Geisinger Health System); 5. U01HG008685 (Mass General Brigham); 6. U01HG006375 (Kaiser/Group Health/University of Washington); 7. U01HG006389 (Essentia Health & Marshfield Clinic Research Foundation); 8. U01HG006379 (Mayo Clinic); 9. U01HG006378, U01HG006385 (Vanderbilt University); 10. U01HG006380 (The Mt. Sinai Hospital); and 11. U01HG006388 (Northwestern University). The authors would like to thank all of the research participants and scientific staff of the eMERGE consortium. This study was supported by the following U01 grants from the National Human Genome Research Institute (NHGRI), a component of the National Institutes of Health (NIH), Bethesda, MD, USA: 1. U01HG8684 (The Children’s Hospital of Philadelphia); 2. U01HG8666 (Cincinnati Children’s Medical Hospital); 3. U01HG8680 (Columbia University); 4. U01HG006382 (Geisinger Health System); 5. U01HG008685 (Mass General Brigham); 6. U01HG006375 (Kaiser/Group Health/University of Washington); 7. U01HG006389 (Essentia Health & Marshfield Clinic Research Foundation); 8. U01HG006379 (Mayo Clinic); 9. U01HG006378, U01HG006385 (Vanderbilt University); 10. U01HG006380 (The Mt. Sinai Hospital); and 11. U01HG006388 (Northwestern University).

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Ferar, K., Hall, T. O., Crawford, D. C., Rowley, R., Satterfield, B. A., Li, R., Gragert, L., Karlson, E. W., de Andrade, M., Kullo, I. J., McCarty, C. A., Kho, A., Hayes, M. G., Ritchie, M. D., Crane, P. K., Mirel, D. B., Carlson, C., Connolly, J. J., Hakonarson, H., ... Crosslin, D. R. (2023). Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection. Scientific reports, 13(1), Article 18532. https://doi.org/10.1038/s41598-023-45649-4

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title = "Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41598-023-45649-4",

language = "English (US)",

volume = "13",

journal = "Scientific reports",

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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 2023, 'Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection', Scientific reports, vol. 13, no. 1, 18532. https://doi.org/10.1038/s41598-023-45649-4

TY - JOUR

T1 - Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection

AU - Ferar, Kathleen

AU - Hall, Taryn O.

AU - Crawford, Dana C.

AU - Rowley, Robb

AU - Satterfield, Benjamin A.

AU - Li, Rongling

AU - Gragert, Loren

AU - Karlson, Elizabeth W.

AU - de Andrade, Mariza

AU - Kullo, Iftikhar J.

AU - McCarty, Catherine A.

AU - Kho, Abel

AU - Hayes, M. Geoffrey

AU - Ritchie, Marylyn D.

AU - Crane, Paul K.

AU - Mirel, Daniel B.

AU - Carlson, Christopher

AU - Connolly, John J.

AU - Hakonarson, Hakon

AU - Crenshaw, Andrew T.

AU - Carrell, David

AU - Luo, Yuan

AU - Dikilitas, Ozan

AU - Denny, Joshua C.

AU - Jarvik, Gail P.

AU - Crosslin, David R.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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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U2 - 10.1038/s41598-023-45649-4

DO - 10.1038/s41598-023-45649-4

M3 - Article

C2 - 37898691

AN - SCOPUS:85175185956

SN - 2045-2322

VL - 13

JO - Scientific reports

JF - Scientific reports

IS - 1

M1 - 18532

ER -

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

Abstract

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UN SDGs

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