Genome-wide Association Analysis for Organ Failure in Acute Pancreatitis.

Abstract

Background: Patients with acute pancreatitis (AP) develop widely variable severity of organ failure. We hypothesized that genetic factors may influence the development of organ failure in AP. In this study, we identify candidate loci associated with organ failure in AP using genome-wide association analyses (GWAS) and transcriptomic analyses.

Methods: Subjects enrolled in the Mass General Brigham Biobank were retrospectively queried to determine those with a history of AP. Patients with AP were categorized according to the presence of respiratory or renal failure during the first week of AP. Patients were further divided into 2 groups based on the etiology of AP (ie, biliary AP and AP of all other etiologies) and analyzed separately. Meta-analysis of the 2 groups identified candidate loci with P <1e-05. Genes with eQTLs (expression quantitative trait loci) in candidate loci in immune cells were selected. The differential expression of these genes in AP was assessed using transcriptomic data from the Gene Expression Omnibus (GEO) database.

Results: Overall, 665 patients were identified, of which 211 had biliary AP (199 mild, 12 severe) and 454 had AP of other etiologies (428 mild, 26 severe). Nine candidate loci were identified, with rs12185172 on chromosome 16 having the highest association among all SNPs (beta=1.46, P =1.13e-06). Five genes had eQTLs in the candidate loci. CHD9 (adj. P =5.64e-04) , FYB (adj. P =5.09e-03), and MMADHC (adj. P =2.44e-03) were differentially expressed in AP.

Conclusions: We performed a GWAS examining organ failure in AP and identified 9 candidate loci, which did not pass the genome-wide significance threshold. Three candidate genes, CHD9 , FYB , and MMADHC , were identified through eQTL and differential gene expression analyses. These may represent novel therapeutic targets for organ failure in AP.