Variants at the MHC Region Associate With Susceptibility to Clostridioides difficile Infection: A Genome-Wide Association Study Using Comprehensive Electronic Health Records
| Autor: | Vida Abedi, Ming Ta Michael Lee, Marc S. Williams, Josep Bassaganya-Riera, Amy Kolinovsky, Harshit S. Khara, Yanfei Zhang, Alexandria L. Jilg, Jiang Li, Donna M. Wolk, David D. K. Rolston, Raquel Hontecillas |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Adult
Male lcsh:Immunologic diseases. Allergy 0301 basic medicine medicine.drug_class Immunology Antibiotics Genome-wide association study Major histocompatibility complex Polymorphism Single Nucleotide 03 medical and health sciences 0302 clinical medicine HLA Antigens NOTCH4 medicine Genetic predisposition Electronic Health Records Humans GWAS Immunology and Allergy Genetic Predisposition to Disease 030212 general & internal medicine Receptor Notch4 Gene Enterocolitis Pseudomembranous Original Research Aged Aged 80 and over C4a biology Clostridioides difficile business.industry Histocompatibility Antigens Class I C4A Complement C4a Middle Aged Diarrhea 030104 developmental biology MICA biology.protein Female medicine.symptom lcsh:RC581-607 business Clostridioides Genome-Wide Association Study |
| Zdroj: | Frontiers in Immunology, Vol 12 (2021) Frontiers in Immunology |
| ISSN: | 1664-3224 1147-5102 |
| Popis: | BackgroundClostridioides 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.MethodsA 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.ResultsNo 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.ConclusionsLeveraging 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|