Dataset Information

Genetic association and differential expression of PITX2 with acute appendicitis.

ABSTRACT: Appendicitis affects 9% of Americans and is the most common diagnosis requiring hospitalization of both children and adults. We performed a genome-wide association study of self-reported appendectomy with 18,773 affected adults and 114,907 unaffected adults of European American ancestry. A significant association with appendectomy was observed at 4q25 near the gene PITX2 (rs2129979, p value?=?8.82?×?10-14) and was replicated in an independent sample of Caucasians (59 affected, 607 unaffected; p value?=?0.005). Meta-analysis of the associated variant across our two cohorts and cohorts from Iceland and the Netherlands (in which this association had previously been reported) showed strong cumulative evidence of association (OR?=?1.12; 95% CI 1.09-1.14; p value?=?1.81?×?10-23) and some evidence for effect heterogeneity (p value?=?0.03). Eight other loci were identified at suggestive significance in the discovery GWAS. Associations were followed up by measuring gene expression across resected appendices with varying levels of inflammation (N?=?75). We measured expression of 27 genes based on physical proximity to the GWAS signals, evidence of being targeted by eQTLs near the signals according to RegulomeDB (score?=?1), or both. Four of the 27 genes (including PITX2) showed significant evidence (p values?

SUBMITTER: Orlova E

PROVIDER: S-EPMC6514078 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Genetic association and differential expression of PITX2 with acute appendicitis.

Orlova Ekaterina E Yeh Andrew A Shi Min M Firek Brian B Ranganathan Sarangarajan S Whitcomb David C DC Finegold David N DN Ferrell Robert E RE Barmada M Michael MM Marazita Mary L ML Hinds David A DA Shaffer John R JR Morowitz Michael J MJ

Human genetics 20181103 1

Appendicitis affects 9% of Americans and is the most common diagnosis requiring hospitalization of both children and adults. We performed a genome-wide association study of self-reported appendectomy with 18,773 affected adults and 114,907 unaffected adults of European American ancestry. A significant association with appendectomy was observed at 4q25 near the gene PITX2 (rs2129979, p value = 8.82 × 10<sup>-14</sup>) and was replicated in an independent sample of Caucasians (59 affected, 607 una ...[more]

PMID: 30392061

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Project description:ImportanceThe familial aspect of acute appendicitis (AA) has been proposed, but its hereditary basis remains undetermined.ObjectiveTo identify genomic variants associated with AA.Design, setting, and participantsThis 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 measuresSingle-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.ResultsA 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 relevanceThis 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.

Project description:ImportanceSome studies based on proportions of patients with perforated appendicitis (PA) among all patients with acute appendicitis (AA) have found an association between socioeconomic status (SES) and risk of perforation. A potential limitation is their use of proportions, which assumes that incidence of AA is evenly distributed across populations at risk. This assumption may be invalid, and SES may have a more complex association with both AA and PA.ObjectiveTo generate population-based incidences of AA and PA and to examine geographic patterns of incidence alongside geographic patterns of SES.Design, setting, and participantsRetrospective study of data from Washington's Comprehensive Hospital Abstract Reporting System and the 2010 US census. Geographic methods were used to identify patterns of age- and sex-standardized incidence in Washington State between 2008 and 2012. The study included all patients discharged with International Classification of Diseases, Ninth Revision codes for AA or PA. Data were analyzed between November 2016 and December 2018.ExposuresLocation of primary residence.Main outcomes and measuresAge- and sex-standardized incidence for AA and PA was generated for each census tract (CT). Global spatial autocorrelation was examined using Moran index (0.0?=?completely random incidence; 1.0?=?fully dependent on location). Clusters of low-incidence CTs (cold spots) and high-incidence CTs (hot spots) were identified for AA. Census-based SES data were aggregated for hot spots and cold spots and then compared.ResultsStatewide, over the 5-year study period, there were 35?730 patients with AA (including 9780 cases of PA), of whom 16?574 were women (46.4%). Median age of the cohort was 29 years (IQR, 16-48 years). Statewide incidence of AA and PA was 106 and 29 per 100?000 person-years (PY), respectively. Crude incidence was higher within the male population and peaked at age 10 to 19 years. Age- and sex-standardized incidence of AA demonstrated significant positive spatial autocorrelation (Moran index, 0.30; P?<?.001), but autocorrelation for PA was only half as strong (0.16; P?<?.001). Median incidence of AA was 118.1 per 100?000 PY among hot spots vs 86.2 per 100?000 PY among cold spots (P?<?.001). Socioeconomic status was higher in cold spots vs hot spots: mean proportion of college-educated adults was 56% vs 26% (P?<?.001), and mean per capita income was $44?691 vs $30?027 (P?<?.001).Conclusions and relevanceAge- and sex-standardized incidence of appendicitis is not randomly distributed across geographic subunits, and geographic clustering of AA is twice as strong as PA. Socioeconomic advantages, such as higher income and secondary education, are strongly associated with lower incidence of AA. These findings challenge conventional views that AA occurs randomly and has no predisposing characteristics beyond age/sex. Socioeconomic status, and likely other geographically circumscribed factors, are associated with incidence of AA.

Dataset Information

Genetic association and differential expression of PITX2 with acute appendicitis.

Publications

Genetic association and differential expression of PITX2 with acute appendicitis.

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