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Title: | Impact of Human Genetic Variation on C-Reactive Protein Concentrations and Acute Appendicitis | Authors: | Ricano-Ponce, Isis PEETERS, Toon Matzaraki, Vasiliki Houben, Bert ACHTEN, Ruth Cools, Peter Netea, Mihai G. GYSSENS, Inge Kumar, Vinod |
Issue Date: | 2022 | Publisher: | FRONTIERS MEDIA SA | Source: | FRONTIERS IN IMMUNOLOGY, 13 (Art N° 862742) | Abstract: | 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. | Notes: | Kumar, V (corresponding author), Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, Nijmegen, Netherlands.; Kumar, V (corresponding author), Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.; Kumar, V (corresponding author), Nitte, Nitte Univ Ctr Sci Educ & Res, Mangalore, India.; Kumar, V (corresponding author), Radboud Univ Nijmegen, Radboud Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands. V.Kumar@radboudumc.nl |
Keywords: | C-reactive protein (CRP); appendicitis; functional genetics; biomarker;;quantitative trait | Document URI: | http://hdl.handle.net/1942/37585 | ISSN: | 1664-3224 | e-ISSN: | 1664-3224 | DOI: | 10.3389/fimmu.2022.862742 | ISI #: | WOS:000808451400001 | Rights: | This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2023 |
Appears in Collections: | Research publications |
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