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 < 0.0033) of differential expression across categories of appendix inflammation. An additional ten genes showed nominal evidence ( p value < 0.05) of differential expression, which, together with the significant genes, is more than expected by chance ( p value = 6.6 × 10 −12 ). PITX2 impacts morphological development of intestinal tissue, promotes an anti-oxidant response, and its expression correlates with levels of intestinal bacteria and colonic inflammation. Further studies of the role of PITX2 in appendicitis are warranted. Electronic supplementary material The online version of this article (10.1007/s00439-018-1956-2) contains supplementary material, which is available to authorized users.

MIR31 May Mediate Multiple Biology Processes To Promote Vocal Fold Wound Healing

“…1a. Upregulated MIR31 has been reported to alleviate in ammation in colon injury (Orlova et al, 2019) and cardiac injury (Miguel et al, 2018). At the early stage of wound healing, in ammation is the initial response to cellular injuries and is the key process in wound healing (Meng X.M., 2019).…”

Simultaneous acute appendicitis in identical twin boys

“…Basta et al performed a comprehensive segregation analysis of 80 consecutive families affected by acute appendicitis that suggested a polygenic or multifactorial mode of inheritance with total heritability of 56% 13. More recently, two groups have discovered an association between appendicitis and a specific genetic variant close to the PITX2 gene, a locus responsible for levels of intestinal bacteria and colonic inflammation 19 20…”

Appendicitis in Low-Resource Settings

“…Immune alterations also correlate with appendicitis. Differential expression of human genes, including paired like homeodomain 2 (PITX2), have been linked to appendicitis [10], while temporal and spatial clustering of appendicitis cases suggests an infectious etiology for the disease [11][12][13]. However, researchers have been unable to identify specific inciting agents [13].…”