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

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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

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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

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

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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.}",

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year = "2023",

month = dec,

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

language = "English (US)",

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

Abstract

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