Table_1_Impact of Human Genetic Variation on C-Reactive Protein Concentrations and Acute Appendicitis.xlsx

BackgroundAcute 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.
MethodsCRP 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.
ResultsThirteen 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 (HLX) gene, which is involved in blood cell differentiation, and liver and gut organogeneses. The expression of HLX is increased in the appendix of appendicitis patients compared to controls. The locus at 8p23.1 contains multiple genes, including cathepsin B (CTSB), which is overexpressed in appendix tissue from appendicitis patients. The risk allele of the top SNP in this locus also increases CTSB expression in the sigmoid colon of healthy individuals. CTSB is involved in collagen degradation, MHC class II antigen presentation, and neutrophil degranulation.
ConclusionsThe results of this study prioritize HLX and CTSB as potential causal genes for appendicitis and suggest a shared genetic mechanism between appendicitis and CRP concentrations.

研究背景
急性阑尾炎是全球范围内最常见的腹部急症之一，环境与遗传因素均参与其发病过程。C反应蛋白（C-reactive protein, CRP）是急性阑尾炎诊断中的重要生物标志物，其循环水平可受遗传变异的显著影响。然而，此类遗传变异是否与阑尾炎发病风险存在因果关联，目前仍不明确。本研究旨在探究与循环CRP水平相关的单核苷酸多态性（single-nucleotide polymorphisms, SNPs）与急性阑尾炎发病风险及病情严重程度之间的因果关联。

研究方法
本研究检测了325例阑尾炎患者的血清CRP水平，并将阑尾炎划分为复杂型/单纯型以及坏疽型/非坏疽型。随后生成了287份样本的基因型填充单核苷酸多态性数据，开展了针对CRP水平与阑尾炎严重程度的全基因组关联研究（genome-wide association study, GWAS）。将本研究GWAS结果与泛英国生物库（Pan-UKBB）队列中与阑尾炎及CRP相关的基因座进行交集共定位分析，并采用功能基因组学方法对候选基因进行优先级排序。

研究结果
本研究的小样本患者队列中，可重复出既往在大型健康人群队列中鉴定出的13%的显著性CRP数量性状基因座（quantitative trait loci, QTLs），且观察到与阑尾炎相关的CRP-QTLs存在显著富集现象。在这些共享基因座中，本研究对位于1号染色体1q41区域与8号染色体8p23.1区域的两个最显著基因座进行了深入分析：位于1q41区域的最显著SNP位点定位于H2.0样同源框（H2.0 Like Homeobox, HLX）基因的启动子区内，该基因参与血细胞分化以及肝脏与肠道的器官发生过程；与对照组相比，阑尾炎患者阑尾组织中HLX的表达水平显著升高。8p23.1区域的基因座包含多个基因，其中包括组织蛋白酶B（cathepsin B, CTSB），该基因在阑尾炎患者的阑尾组织中呈过表达状态；该基因座中最显著SNP的风险等位基因同时可升高健康个体乙状结肠中CTSB的表达水平，而CTSB参与胶原蛋白降解、MHC II类抗原呈递以及中性粒细胞脱颗粒过程。

研究结论
本研究结果将HLX与CTSB列为阑尾炎潜在的因果关联基因，并提示阑尾炎与CRP水平之间存在共同的遗传调控机制。