The Common Chymotrypsinogen C ( CTRC ) Variant G60G (C.180T) Increases Risk of Chronic Pancreatitis But Not Recurrent Acute Pancreatitis in a North American Population

Abstract

OBJECTIVES:Recurrent acute pancreatitis (RAP) is a complex inflammatory disorder that may progress to fibrosis and other irreversible features recognized as chronic pancreatitis (CP). Chymotrypsinogen C (CTRC) protects the pancreas by degrading prematurely activated trypsinogen. Rare mutations are associated with CP in Europe and Asia. We evaluated the occurrence of CTRC variants in subjects with RAP, CP, and controls from the North American Pancreatitis Study II cohort.METHODS:CP (n=694), RAP (n=448), and controls (n=1017) of European ancestry were evaluated. Subgroup analysis included CFTR and SPINK1 variants, alcohol, and smoking.RESULTS:We identified previously reported rare pathogenic CTRC A73T, R254W, and K247_R254del variants, intronic variants, and G60G (c.180 C>T; rs497078). Compared with controls (minor allele frequency (MAF)=10.8%), c.180T was associated with CP (MAF=16.8%, P<0.00001) but not RAP (MAF=11.9% P=NS). Trend test indicated co-dominant risk for CP (CT odds ratio (OR)=1.36, 95% confidence interval (CI)=1.13–1.64, P=0.0014; TT OR=3.98, 95% CI=2.10–7.56, P<0.0001). The T allele was significantly more frequent with concurrent pathogenic CFTR variants and/or SPINK1 N34S (combined 22.9% vs. 16.1%, OR 1.92, 95% C.I. 1.26–2.94, P=0.0023) and with alcoholic vs. non-alcoholic CP etiologies (20.8% vs. 12.4%, OR=1.9, 95% CI=1.30–2.79, P=0.0009). Alcohol and smoking generally occurred together, but the frequency of CTRC c.180 T in CP, but not RAP, was higher among never drinkers–ever smokers (22.2%) than ever drinker–never smokers (10.8%), suggesting that smoking rather than alcohol may be the driving factor in this association.CONCLUSIONS:The common CTRC variant c.180T acts as disease modifier that promotes progression from RAP to CP, especially in patients with CFTR or SPINK1 variants, alcohol, or smoking.

Genetics and Genetic Testing in Pancreatic Cancer

“…Modifier genes are an important example, as they must be fairly common or they would not be found in combination with susceptibility genes. Risk of progressing from recurrent acute pancreatitis to chronic pancreatitis, for example, is increased by CTRC G60G (113) and the high-risk CLDN2 haplotype (91), both with frequencies in the general population of over 10%.…”

“…Chronic pancreatitis is also a complex disorder, and leading research groups recognize that disease in an individual patient arises from the combination of dozens and dozens of common and rare mutations (78,80,112,113). These advances have not come from traditional clinical sign and symptom-defined hypothesis-null hypothesis significance testing research, dubbed the "scientific method".…”

Epidemiologic and Mechanistic Associations Between Smoking and Pancreatitis

“…[41] It is interesting to speculate that cigarette smoke toxins may reduce pancreatic secretion through a similar mechanism, by disrupting CFTR. [42]…”

Genetic determination of pancreatitis

“…In our study of patients with AP published in 2017, three CTRC mutations were detected in exon 7: p.V235I (c.703 G>A), p.K247_R254del, p.R254W, known to be responsible for CP, and p.I259V, the importance of which has not been sufficiently recognised [87]. The frequent CTRC variant c.180T may exert an effect on the modification of the progression from RAP to CP, especially in patients with CFTR or SPINK1 variant, who consume alcohol and are tobacco smokers [88]. The presence of the SPINK1 and CTRC mutations causes a high risk of contracting pancreatitis and may be responsible for a more severe course of acute pancreatitis [84,87].…”