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Original Investigation
July 28, 2021

Association Between NEDD4L Variation and the Genetic Risk of Acute Appendicitis: A Multi-institutional Genome-Wide Association Study

Author Affiliations
  • 1Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, Boston
  • 2Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts
  • 3Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston
JAMA Surg. 2021;156(10):917-923. doi:10.1001/jamasurg.2021.3303
Key Points

Question  What genetic loci are associated with acute appendicitis (AA)?

Findings  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.

Meaning  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.


Importance  The familial aspect of acute appendicitis (AA) has been proposed, but its hereditary basis remains undetermined.

Objective  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.

Results  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.

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