What genetic loci are associated with acute appendicitis (AA)?
In this genome-wide association study, a genetic locus at chromosome 18q was found to be associated with AA, located in the NEDD4L gene. NEDD4L was also among the top differentially expressed genes in appendiceal tissue between AA patients and controls.
This study suggests that NEDD4L variations are associated with the development of AA; these findings can improve understanding of the genetic predisposition to and pathogenesis of AA.
The familial aspect of acute appendicitis (AA) has been proposed, but its hereditary basis remains undetermined.
To identify genomic variants associated with AA.
Design, Setting, and Participants
This genome-wide association study, conducted from June 21, 2019, to February 4, 2020, used a multi-institutional biobank to retrospectively identify patients with AA across 8 single-nucleotide variation (SNV) genotyping batches. The study also examined differential gene expression in appendiceal tissue samples between patients with AA and controls using the GSE9579 data set in the National Institutes of Health’s Gene Expression Omnibus repository. Statistical analysis was conducted from October 1, 2019, to February 4, 2020.
Main Outcomes and Measures
Single-nucleotide variations with a minor allele frequency of 5% or higher were tested for association with AA using a linear mixed model. The significance threshold was set at P = 5 × 10−8.
A total of 29 706 patients (15 088 women [50.8%]; mean [SD] age at enrollment, 60.1 [17.0] years) were included, 1743 of whom had a history of AA. The genomic inflation factor for the cohort was 1.003. A previously unknown SNV at chromosome 18q was found to be associated with AA (rs9953918: odds ratio, 0.99; 95% CI, 0.98-1.00; P = 4.48 × 10−8). This SNV is located in an intron of the NEDD4L gene. The heritability of appendicitis was estimated at 30.1%. Gene expression data from appendiceal tissue donors identified NEDD4L to be among the most differentially expressed genes (14 of 22 216 genes; β [SE] = −2.71 [0.44]; log fold change = −1.69; adjusted P = .04).
Conclusions and Relevance
This study identified SNVs within the NEDD4L gene as being associated with AA. Nedd4l is involved in the ubiquitination of intestinal ion channels and decreased Nedd4l activity may be implicated in the pathogenesis of AA. These findings can improve the understanding of the genetic predisposition to and pathogenesis of AA.
Identify all potential conflicts of interest that might be relevant to your comment.
Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.
Err on the side of full disclosure.
If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.
Not all submitted comments are published. Please see our commenting policy for details.
Gaitanidis A, Kaafarani HMA, Christensen MA, et al. Association Between NEDD4L Variation and the Genetic Risk of Acute Appendicitis: A Multi-institutional Genome-Wide Association Study. JAMA Surg. Published online July 28, 2021. doi:10.1001/jamasurg.2021.3303
Coronavirus Resource Center
Customize your JAMA Network experience by selecting one or more topics from the list below.
Create a personal account or sign in to: