Pancreatitis Risk Genes Play a Major Role in Pediatric Pancreatitis: Insights From the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE

Background & Aims Clinical data show that genetic variants are significant risk factors for acute recurrent pancreatitis and chronic pancreatitis. To expand the understanding of the role of genetics in acute recurrent pancreatitis and chronic pancreatitis, high-throughput next-generation sequencing of 14 genes was completed in a multicenter pediatric cohort. Methods A cross-sectional study involving 944 pediatric patients with acute recurrent pancreatitis or chronic pancreatitis was conducted. CASR, CEL, CFTR, CLDN2, CPA1, CTRC, GGT1, PRSS1, PRSS2, PRSS3, SBDS, SLC26A9, SPINK1, and UBR1 were sequenced. The frequencies of identified variants were compared with frequencies in the genome aggregation database. Group differences were calculated by odd ratios, relative risks, and 1-tailed Fisher exact test with false discovery rate adjusted P values. Results A total of 120 variants, including 79 never previously reported to be associated with pancreatitis, had an increased odds, with odds ratio >1, (false discovery rate ≤0.01) compared with the genome aggregation database. Of these, 38 focused variants found in CFTR (10 variants), PRSS1 (6), CTRC (6), SPINK1 (5), PRSS3 (3), GGT1 (3), CASR (2), CPA1 (2), and PRSS2 (1) were included for further analysis. Seventy-four percent of children with acute recurrent pancreatitis or chronic pancreatitis carried at least 1 genetic risk variant. In the acute recurrent pancreatitis group, CASR ( P = .005) and CPA1 ( P < .001) contained the most prevalent variants. In chronic pancreatitis, CTRC ( P = .012) and PRSS1 ( P < .001) variants were most common. The presence of any genetic risk variant was associated with faster disease progression from acute pancreatitis to chronic pancreatitis compared with none ( P = .014). Variants in PRSS1, CTRC, and SPINK1 significantly increased progression to chronic pancreatitis. Conclusions Our findings highlight the importance of assessing genetic risk variants in children with pancreatitis.