PDF(Pubmed)
Abstract：
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.
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.
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.
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.
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.
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.
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.
摘要：
艰难梭菌是医疗保健相关和社区获得性腹泻的主要原因。宿主对艰难梭菌感染的遗传易感性尚未大规模研究。
通过将eMERGE艰难梭菌感染算法应用于电子健康记录数据，共识别出1,160例艰难梭菌感染病例和15,304例对照。使用线性混合模型进行了全基因组关联研究，在完整数据集和抗生素亚组中调整了显著的协变量。进行共定位和MetaXcan以鉴定艰难梭菌感染相关组织类型中的潜在靶基因。
在完整的艰难梭菌感染数据集的荟萃分析中未发现显著的全基因组关联。一个全基因组的重要变异，在抗生素组中与艰难梭菌感染相关的主要组织相容性复合区域鉴定出rs114751021（OR=2.42；95CI=1.84-3.11；p=4.50x10-8）。协同定位和MetaX可以识别MICA，C4A/C4B,和NOTCH4作为潜在的靶基因。MICA的下调,C4A和NOTCH4的上调与艰难梭菌感染的高风险相关。
利用EHR和遗传数据，全基因组关联，和精细映射技术，这项研究确定了与艰难梭菌感染相关的变异和基因，提供了对宿主免疫机制的见解，并描述了艰难梭菌感染的新治疗策略的潜力。需要将来的复制和功能验证。
通过将eMERGE艰难梭菌感染算法应用于电子健康记录数据，共识别出1,160例艰难梭菌感染病例和15,304例对照。使用线性混合模型进行了全基因组关联研究，在完整数据集和抗生素亚组中调整了显著的协变量。进行共定位和MetaXcan以鉴定艰难梭菌感染相关组织类型中的潜在靶基因。
在完整的艰难梭菌感染数据集的荟萃分析中未发现显著的全基因组关联。一个全基因组的重要变异，在抗生素组中与艰难梭菌感染相关的主要组织相容性复合区域鉴定出rs114751021（OR=2.42；95CI=1.84-3.11；p=4.50x10-8）。协同定位和MetaX可以识别MICA，C4A/C4B,和NOTCH4作为潜在的靶基因。MICA的下调,C4A和NOTCH4的上调与艰难梭菌感染的高风险相关。
利用EHR和遗传数据，全基因组关联，和精细映射技术，这项研究确定了与艰难梭菌感染相关的变异和基因，提供了对宿主免疫机制的见解，并描述了艰难梭菌感染的新治疗策略的潜力。需要将来的复制和功能验证。
