Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
Department of Infectious Diseases & Immunity, Jessa Hospital, Hasselt, Belgium.
Front Immunol. 2022 May 25;13:862742. doi: 10.3389/fimmu.2022.862742. eCollection 2022.
Acute appendicitis is one of the most common abdominal emergencies worldwide. Both environmental and genetic factors contribute to the disease. C-reactive protein (CRP) is an important biomarker in the diagnosis of acute appendicitis. CRP concentrations are significantly affected by genetic variation. However, whether such genetic variation is causally related to appendicitis risk remains unclear. In this study, the causal relationship between single-nucleotide polymorphisms (SNPs) associated with circulating CRP concentrations and the risk and severity of acute appendicitis was investigated.
CRP concentrations in serum of appendicitis patients (n = 325) were measured. Appendicitis was categorized as complicated/uncomplicated and gangrenous/non-gangrenous. Imputed SNP data (n = 287) were generated. A genome-wide association study (GWAS) on CRP concentrations and appendicitis severity was performed. Intersection and colocalization of the GWAS results were performed with appendicitis and CRP-associated loci from the Pan-UKBB cohort. A functional-genomics approach to prioritize genes was employed.
Thirteen percent of significant CRP quantitative trait loci (QTLs) that were previously identified in a large cohort of healthy individuals were replicated in our small patient cohort. Significant enrichment of CRP-QTLs in association with appendicitis was observed. Among these shared loci, the two top loci at chromosomes 1q41 and 8p23.1 were characterized. The top SNP at chromosome 1q41 is located within the promoter of H2.0 Like Homeobox () gene, which is involved in blood cell differentiation, and liver and gut organogeneses. The expression of is increased in the appendix of appendicitis patients compared to controls. The locus at 8p23.1 contains multiple genes, including cathepsin B (), which is overexpressed in appendix tissue from appendicitis patients. The risk allele of the top SNP in this locus also increases expression in the sigmoid colon of healthy individuals. is involved in collagen degradation, MHC class II antigen presentation, and neutrophil degranulation.
The results of this study prioritize and as potential causal genes for appendicitis and suggest a shared genetic mechanism between appendicitis and CRP concentrations.
急性阑尾炎是全球最常见的腹部急症之一。环境和遗传因素都促成了这种疾病的发生。C 反应蛋白（CRP）是诊断急性阑尾炎的重要生物标志物。CRP 浓度受遗传变异的显著影响。然而，这种遗传变异是否与阑尾炎风险有因果关系尚不清楚。在这项研究中，我们研究了与循环 CRP 浓度相关的单核苷酸多态性（SNP）与急性阑尾炎风险和严重程度的因果关系。
测量了阑尾炎患者（n=325）血清中的 CRP 浓度。将阑尾炎分为复杂/不复杂和坏疽/非坏疽。生成了 SNP 数据（n=287）的推断。对 CRP 浓度和阑尾炎严重程度进行了全基因组关联研究（GWAS）。与 Pan-UKBB 队列中的阑尾炎和 CRP 相关位点进行了交集和共定位分析。采用功能基因组学方法对基因进行优先级排序。
在一个大型健康人群队列中先前确定的 13%的 CRP 数量性状基因座（QTL）在我们的小患者队列中得到了复制。观察到 CRP-QTL 与阑尾炎显著富集。在这些共享的位点中，染色体 1q41 和 8p23.1 上的两个顶级位点特征明显。染色体 1q41 上的顶级 SNP 位于 H2.0 样同源盒（）基因的启动子内，该基因参与血细胞分化以及肝脏和肠道器官发生。与对照组相比，阑尾炎患者阑尾中的表达增加。8p23.1 位点包含多个基因，包括组织蛋白酶 B（），其在阑尾炎患者阑尾组织中过度表达。该位点的顶级 SNP 的风险等位基因也增加了健康个体乙状结肠中表达。参与胶原降解、MHC Ⅱ类抗原呈递和中性粒细胞脱粒。
这项研究优先考虑和作为阑尾炎的潜在因果基因，并表明阑尾炎和 CRP 浓度之间存在共同的遗传机制。
