Infection Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Sci Rep. 2022 Feb 16;12(1):2582. doi: 10.1038/s41598-022-05838-z.
There is limited data on host-specific genetic determinants of susceptibility to bacterial and viral infections. Genome-wide association studies using large population cohorts can be a first step towards identifying patients prone to infectious diseases and targets for new therapies. Genetic variants associated with clinically relevant entities of bacterial and viral infections (e.g., abdominal infections, respiratory infections, and sepsis) in 337,484 participants of the UK Biobank cohort were explored by genome-wide association analyses. Cases (n = 81,179) were identified based on ICD-10 diagnosis codes of hospital inpatient and death registries. Functional annotation was performed using gene expression (eQTL) data. Fifty-seven unique genome-wide significant loci were found, many of which are novel in the context of infectious diseases. Some of the detected genetic variants were previously reported associated with infectious, inflammatory, autoimmune, and malignant diseases or key components of the immune system (e.g., white blood cells, cytokines). Fine mapping of the HLA region revealed significant associations with HLA-DQA1, HLA-DRB1, and HLA-DRB4 locus alleles. PPP1R14A showed strong colocalization with abdominal infections and gene expression in sigmoid and transverse colon, suggesting causality. Shared significant loci across infections and non-infectious phenotypes in the UK Biobank cohort were found, suggesting associations for example between SNPs identified for abdominal infections and CRP, rheumatoid arthritis, and diabetes mellitus. We report multiple loci associated with bacterial and viral infections. A better understanding of the genetic determinants of bacterial and viral infections can be useful to identify patients at risk and in the development of new drugs.
关于宿主特异性遗传决定因素对细菌和病毒感染易感性的研究数据有限。使用大型人群队列进行全基因组关联研究可以作为鉴定易患传染病患者和新疗法靶点的第一步。通过对英国生物库队列的 337484 名参与者进行全基因组关联分析，探讨了与细菌和病毒感染（如腹部感染、呼吸道感染和败血症）相关的临床相关实体的遗传变异。病例（n=81179）根据医院住院和死亡登记处的 ICD-10 诊断代码确定。使用基因表达（eQTL）数据进行功能注释。发现了 57 个独特的全基因组显著位点，其中许多在传染病方面是新颖的。一些检测到的遗传变异以前曾报道与传染病、炎症、自身免疫和恶性疾病或免疫系统的关键组成部分（如白细胞、细胞因子）有关。HLA 区域的精细映射显示与 HLA-DQA1、HLA-DRB1 和 HLA-DRB4 基因座等位基因显著相关。PPP1R14A 与腹部感染和乙状结肠和横结肠的基因表达强烈共定位，提示存在因果关系。在英国生物库队列中发现了感染和非传染性表型之间的共享显著位点，表明例如腹部感染确定的 SNPs 与 CRP、类风湿关节炎和糖尿病之间存在关联。我们报告了多个与细菌和病毒感染相关的基因座。更好地了解细菌和病毒感染的遗传决定因素，有助于识别高危患者和开发新药。
