Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis

Abstract

ObjectiveAlcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.Design1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.ResultsWe replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.ConclusionAn inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.

The CTRB1-CTRB2 risk allele for chronic pancreatitis discovered in European populations does not contribute to disease risk variation in the Chinese population due to near allele fixation

“…The aforementioned new discovery was made from the analysis of European subjects 1. Herein, we attempted to confirm this discovery in a cohort of Chinese patients with idiopathic chronic pancreatitis (ICP).…”

“…Finally, they provided in vitro evidence that CTRB1 was less efficient in degrading anionic trypsinogen (PRSS2) than CTRB2 (note that rapid degradation of PRSS2 conferred by a PRSS2 missense variant protects against CP) 3. Taking together, Rosendahl and colleagues concluded that the major inversion allele increases the risk of pancreatitis by negatively affecting protective trypsinogen degradation 1. Indeed, this new finding further strengthens the pivotal role of the trypsin-dependent pathway in the aetiology of CP 4 5…”

“…We read with great interest the article by Rosendahl et al 1 reporting the identification of CTRB1-CTRB2 (chymotrypsin B1 and chymotrypsin B2) as a new chronic pancreatitis (CP) risk locus by means of genome-wide association study, with the lead single nucleotide polymorphism (SNP) rs8055167 having an OR of 1.35. Moreover, they found that a previously reported 16.6 kb inversion in the CTRB1-CTRB2 locus2 was in linkage disequilibrium with the CP-associated SNPs and optimally tagged by rs8048956.…”

Etiology and Risk Factors of Acute and Chronic Pancreatitis

“…A few genome-wide association studies have been performed to date, mainly in chronic pancreatitis and recurrent acute pancreatitis patients. Studies by Whitcomb et al [55] and Rosendahl et al [65] were able to identify new susceptibility loci in the claudin-2 gene ( CLDN2 ), as well as a gene conversion event in the chymotrypsin B CTRB1–2 locus, which modifies the risk for alcoholic and nonalcoholic chronic pancreatitis [65]. …”

Endoscopic and Conservative Management of Chronic Pancreatitis and Its Complications

“…Genetic causes are less frequent and include mutations in cationic trypsinogen 1 and 2 (PRSS1/2), serine protease inhibitor Kazal-type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin C (CTRC), carboxypeptidase A1 (CPA1), carboxyl ester lipase (CEL), and calcium-sensing receptor (CASR) [14-16]. In their pangenetic association study, Rosendahl et al [17] identified a variety of other genetic loci that alter susceptibility to CP, supporting the concept of multiple factors engaging in promoting the disease with a clinically almost stochastically appearing risk. Rare causes include primary hyperparathyroidism as well as posttraumatic states.…”