Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis

Abstract

Objectives. Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intra-pancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase (CEL) emerged as a trypsin-independent risk gene. Here, we evaluated PNLIP encoding pancreatic lipase as a potential novel susceptibility gene for CP. Methods. We analyzed all 13 PNLIP exons in 429 German non-alcoholic CP patients and in 600 German control subjects, in 632 patients and 957 controls from France, and in 223 patients and 1070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 CP patients and 1849 controls originating from Germany, USA and India. We assessed the cellular secretion, lipase activity and proteolytic stability of recombinant PNLIP variants. Results. In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P=0.02, OR=5.7, 95% CI=1.1–38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) versus controls (1/957 [0.1%]) (P=0.04, OR=7.6, 95% CI=0.9–172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1163 cases (1.1%) and in 3/3000 controls (0.1%) (OR=11.3, 95% CI=3.0–49.9, P<0.0001). Conclusions. Our data indicate that protease-sensitive PNLIP variants are novel genetic risk factors for the development of chronic pancreatitis.

TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population

“…Three recently discovered CP‐predisposing genes or alleles, CPA1 (Witt et al, 2013), CEL‐HYB (Fjeld et al, 2015), and CTRB1‐CTRB2 (Rosendahl et al, 2018), have not been replicated in the Chinese population (Tang et al, 2018; Wu et al, 2017; Zou et al, 2016). More recently, rare protease‐sensitive variants in the PNLIP gene were reported to be associated with early‐onset CP in German and French patients but not in American, Japanese, and Indian patients (Lasher et al, 2019; also not in Chinese patients; our unpublished data). The consistent association between functionally deficient TRPV6 variants and CP across two Asian populations (Japanese and Chinese) and two European populations (French and German) thus indicates that TRPV6 is a new major susceptibility gene for CP.…”

Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis

“…3 Several pancreatitis susceptibility genes have been identified, including cationic trypsinogen (PRSS1), 4 cystic fibrosis transmembrane conductance regulator (CFTR), 5,6 serine protease inhibitor Kazal type 1 (SPINK1), 7 trypsin-degrading enzyme chymotrypsin C (CTRC), 8 carboxypeptidase A1 (CPA1), 9 carboxyl ester lipase (CEL), 10 and pancreatic lipase (PNLIP). 11 Except for CFTR, these gene products act as components of the pancreatic digestive enzyme/enzyme inhibitor system. The underlying pathogenic mechanisms of mutations in these susceptibility genes include an imbalance of trypsin and its counterparts or endoplasmic reticulum stress in pancreatic acinar cells.…”

“…The underlying pathogenic mechanisms of mutations in these susceptibility genes include an imbalance of trypsin and its counterparts or endoplasmic reticulum stress in pancreatic acinar cells. [4][5][6][7][8][9][10][11][12] However, in many patients with hereditary or early-onset idiopathic CP, no pathogenic mutation in any of the known pancreatitis susceptibility genes can be detected, 13 suggesting the presence of yet-unknown inherited factors.…”

Genetic Abnormalities in Pancreatitis: An Update on Diagnosis, Clinical Features, and Treatment

“…In 2000, a mutation in the serine protease inhibitor gene ( Kazal type 1: SPINK1 ) was reported to be related to chronic idiopathic pancreatitis of unknown cause [ 13 ]. Since then, genetic causes of pancreatitis, calcium-sensing receptor ( CASR ) in 2003 [ 14 , 15 , 16 , 17 ], chymotrypsin C in 2008 ( CTRC ) [ 18 ], claudin-2 ( CLDN2 ) in 2012 [ 19 ], carboxypeptidase A1 ( CPA1 ) in 2013 [ 20 ], carboxyl ester lipase ( CEL ) in 2015 [ 21 ], chymotrypsin B1 and B2 ( CTRB1 / CTRB2 ) in 2017 [ 22 ], pancreatic lipase ( PNLIP ) in 2019 [ 23 ], and transient receptor cation channel subfamily V member 6 gene ( TRPV6 ) in 2020 [ 24 ] have also been reported to play key roles in the etiology of APR and CP. With respect to these genes, p.C563fsX673 and p.C596fsX695 in CEL gene [ 25 ], and p.S282P in CAP1 gene [ 26 ] have also been determined as causative factors of HP, together with PRSS1 gene.…”

“…The changes in the balance of chymotrypsin isoforms, namely inversion at the CTRB1 and CTRB2 locus, that affect trypsin degradation slightly increased the risk of alcoholic and non-alcoholic CP [ 22 , 67 ]. In addition, several variants of PNLIP gene, particularly p.F300L, were associated with early onset and non-alcoholic CP in the European population, but the mechanism remains unclear [ 23 ].…”