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

frontiers in immunology

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