AUTHOR=Li Jiang , Zhang Yanfei , Jilg Alexandria L. , Wolk Donna M. , Khara Harshit S. , Kolinovsky Amy , Rolston David D. K. , Hontecillas Raquel , Bassaganya-Riera Josep , Williams Marc S. , Abedi Vida , Lee Ming Ta Michael 

TITLE=Variants at the MHC Region Associate With Susceptibility to Clostridioides difficile Infection: A Genome-Wide Association Study Using Comprehensive Electronic Health Records

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.638913

DOI=10.3389/fimmu.2021.638913

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p><italic>Clostridioides difficile</italic> is a major cause of healthcare-associated and community-acquired diarrhea. Host genetic susceptibility to <italic>Clostridioides difficile</italic> infection has not been studied on a large-scale.</p></sec><sec><title>Methods</title><p>A total of 1,160 <italic>Clostridioides difficile</italic> infection cases and 15,304 controls were identified by applying the eMERGE <italic>Clostridioides difficile</italic> infection algorithm to electronic health record data. A genome-wide association study was performed using a linear mixed model, adjusted for significant covariates in the full dataset and the antibiotic subgroup. Colocalization and MetaXcan were performed to identify potential target genes in <italic>Clostridioides difficile</italic> infection - relevant tissue types.</p></sec><sec><title>Results</title><p>No significant genome-wide association was found in the meta-analyses of the full <italic>Clostridioides difficile</italic> infection dataset. One genome-wide significant variant, rs114751021, was identified (OR = 2.42; 95%CI = 1.84-3.11; p=4.50 x 10<sup>-8</sup>) at the major histocompatibility complex region associated with <italic>Clostridioides difficile</italic> infection in the antibiotic group. Colocalization and MetaXcan identified <italic>MICA</italic>, <italic>C4A/C4B</italic>, and <italic>NOTCH4</italic> as potential target genes. Down-regulation of <italic>MICA</italic>, upregulation of <italic>C4A</italic> and <italic>NOTCH4</italic> was associated with a higher risk for <italic>Clostridioides difficile</italic> infection.</p></sec><sec><title>Conclusions</title><p>Leveraging the EHR and genetic data, genome-wide association, and fine-mapping techniques, this study identified variants and genes associated with <italic>Clostridioides difficile</italic> infection, provided insights into host immune mechanisms, and described the potential for novel treatment strategies for <italic>Clostridioides difficile</italic> infection. Future replication and functional validation are needed.</p></sec>