Nonalcoholic Chronic Pancreatitis Research Articles

A study on fibro-calculous pancreatic diabetes conducted in a tertiary medical institution in Northern Bihar

Fibro-calculous pancreatic diabetes (FCPD), which is seen in tropical areas and is caused by idiopathic nonalcoholic chronic pancreatitis, is characterized by pancreatic calcification and stomach pain. One female patient and nine male patients were identified as having FCPD. Half of the patients were under 30 years old, with an average age of 28.44±7.07. Seven individuals had diabetes for a shorter period of time than five years. Four patients reported with problems related to various infections, while six patients had osmotic complaints due to uncontrolled diabetes. With a mean waist-hip ratio of 0.89 and a mean BMI of 19.42, all of the patients were thinly built. With mean FBS of 231 mg/dl, PPBS of 469 mg/dl, and HbA1c of 11.96, all patients had uncontrolled diabetes. Microvascular issues affected 30% of the patients, while none of the patients experienced macrovascular complications. A rare type of secondary diabetes called FCPD is becoming more widespread in northern states like Bihar.

Exploring the role of TLK2 mutation in tropical calcific pancreatitis: an in silico and molecular dynamics simulation study

Tropical calcific pancreatitis (TCP) is a juvenile form of non-alcoholic chronic pancreatitis seen exclusively in tropical countries. The disease poses a high risk of complications, including pancreatic diabetes and cancer, leading to significant mortality due to poor diagnosis and ineffective treatments. This study employed whole exome sequencing (WES) of 5 TCP patient samples to identify genetic variants associated with TCP. Advanced computational techniques were used to gain atomic-level insights into disease progression, including microsecond-scale long MD simulations and essential dynamics. In silico virtual screening was performed to identify potential therapeutic compounds targeting the mutant protein using the Asinex and DrugBank compound library. WES analysis predicted several single nucleotide variants (SNVs) associated with TCP, including a novel missense variant (c.T1802A or p.V601E) in the TLK2 gene. Computational analysis revealed that the p.V601E mutation significantly affected the structure of the TLK2 kinase domain and its conformational dynamics, altering the interaction profile between ATP and the binding pocket. These changes could impact TLK2's kinase activity and functions, potentially correlating with TCP progression. Promising lead compounds that selectively bind to the TLK2 mutant protein were identified, offering potential for therapeutic interventions in TCP. These findings hold great potential for future research. Communicated by Ramaswamy H. Sarma

Genetic and functional analysis of chymotrypsin-like protease (CTRL) in chronic pancreatitis

BackgroundGenetic predisposition is crucial in the pathogenesis of early-onset chronic pancreatitis (CP). So far, several genetic alterations have been identified as risk factors, predominantly in genes encoding digestive enzymes. However, many early-onset CP cases have no identified underlying cause. Chymotrypsins are a family of serine proteases that can cleave trypsinogen and lead to its degradation. Because genetic alterations in the chymotrypsins CTRC, CTRB1, and CTRB2 are associated with CP, we genetically and functionally investigated chymotrypsin-like protease (CTRL) as a potential risk factor. MethodsWe screened 1005 non-alcoholic CP patients and 1594 controls for CTRL variants by exome sequencing. We performed Western blots and activity assays to analyse secretion and proteolytic activity. We measured BiP mRNA expression to investigate the potential impact of identified alterations on endoplasmic reticulum (ER) stress. ResultsWe identified 13 heterozygous non-synonymous CTRL variants: five exclusively in patients and three only in controls. Functionality was unchanged in 6/13 variants. Four alterations showed normal secretion but reduced (p.G20S, p.G56S, p.G61S) or abolished (p.S208F) activity. Another three variants (p.C201Y, p.G215R and p.C220G) were not secreted and already showed reduced or no activity intracellularly. However, intracellular retention did not lead to ER stress. ConclusionWe identified several CTRL variants, some showing potent effects on protease function and secretion. We observed these effects in variants found in patients and controls, and CTRL loss-of-function variants were not significantly more common in patients than controls. Therefore, CTRL is unlikely to play a relevant role in the development of CP.

1262-P: Circulating Lysophosphatidic Acid Levels Suggest a Metabolic Pathway in T3cDM and Distinguish It from T2DM

Introduction: Diabetes associated with chronic pancreatitis (T3cDM) has distinct clinical features. We investigated metabolomics signature to distinguish T3cDM from T2DM. Methods: Study participants (n=200); treatment naïve nonalcoholic calcific chronic pancreatitis [CP] patients (n=106, age 34.4±11.1 years, BMI 20.9±2.8), T2DM patients (n=68, age 46±10.7 years BMI 27.0±5.8), healthy controls (n=26, age 31.0±5.3 years, BMI 25.0±2.8) were recruited prospectively. OGTT was performed to define diabetes (ADA criteria) with 60% CP patients being normoglycemic, 19% having prediabetes and 21% with diabetes. Metabolomics was done on fasting plasma samples using liquid chromatography/mass spectrometry and quantifications were measured on tandem mass spectrometry. Student’s t-test, PLS-DA, ROCs were used to compare and compute to assess the performance of identified metabolites in distinguishing diabetes subtypes (T3cDM and T2DM). Regression analysis was employed to develop a prediction model. Results: A total of 5493 and 4104 metabolites were detected in T3cDM and T2DM respectively. Untargeted metabolome profiling identified significant differences in fatty acid conjugates in CP. Fatty acid conjugates were 28% in normoglycemic CP, 60% in prediabetic CP, 13% in T3cDM as compared to 42% in controls. Among them, 57 fatty acid conjugates showed increased peak intensities. Comparison of absolute quantifications identified higher lysophosphatidic acid (LPA) in T3cDM 40.50±6.55, T2DM 21.65 ± 1.75; p=0.01 in comparison to controls 16.20±3.4 ng/ml. Sensitivity and specificity for LPA were 81.8%, 78.6% with AUC 80% (p<0.0001), 95% CI (70.6-87.8). Prediction model (null and full model p<0.0001) and its performance (Hosmer-Lemeshow test p=0.9) indicated high accuracy (AUC 87%; 95% CI, 77.8-92.7). Conclusion: Increased Lysophosphatidic acid levels implicate glycerolipid pathway in the pathogenesis of T3cDM and can be used to distinguish T3cDM from T2DM. Disclosure V. Ketavarapu: None. M. Aslam: None. R. Talukdar: None. R. Amanchy: None. P. Sripadi: None. A.C. Powers: None. K. Narayan: None. K.C. Coate: None. L.R. Staimez: None. R. Jagannathan: None. N. D: None. M. Sasikala: None. Funding Science and Engineering Research Board, India Project (CRG/2019/005125)

Heterogeneous Comorbidity in Individuals With Different Phenotypes of Obesity.

Introduction The prevalence of obesity is steadily increasing worldwide. Obesity is one of the most potent risk factors for various diseases and is simultaneously a heterogeneous condition. Different types of obesity could be identified according to body mass index (BMI), waist circumference, and visceral fat level; these conditions may present individually or in combination and pose a risk of developing certain comorbidities. However, the current obesity classification systems do not allow for accurate diagnosis and prediction of the comorbidity risk of patients, which is crucial for their clinical management. This points to the importance of studying obesity phenotyping in the context of body composition. Our study aimed to determine the contribution of obesity phenotypes in forming various comorbidities. Materials and methods This case-control study was conducted at the Clinical and Diagnostic Center of the Aviastroitelny District, Kazan. Patients were selected based on BMI per inclusion and exclusion criteria. A total of 151 patients with a median age of 43 [34.5-50] years were included in the study. The participants were distributed into six groups according to BMI and a combination of abdominal obesity (AO) and excess visceral fat. Results The participants were distributed in the following phenogroups: The first group - normal BMI without AO and excess visceral fat (n=47; 31.1%); the second group - overweight without AO and excess visceral fat (n=26; 17.2%); the third group - normal BMI with AO and without excess visceral fat (n=11; 7.3%); fourth group - overweight with AO and without excess visceral fat (n=34; 22.5%); fifth group - general obesity with AO and without excess visceral fat (n=20; 13.2%); sixth group - general obesity with AO and excess visceral fat (n=13; 8.6%). The five most frequently observed conditions in the general cohort were dyslipidemia (71.5%; n=108), disorders of the gastrointestinal tract (53.0%; n=80), cardiovascular disease (46.4%; n=70), musculoskeletal diseases (40.4%; n=61) and impaired carbohydrate metabolism (25.2%; n=38). The median number of pathological combinations in the general cohort was 5 [IQR: 3-7]. As the group number increased, the median number of comorbidities also increased. While BMI was significantly associated only with arterial hypertension, the level of visceral fat was associated with most comorbidities (obstructive sleep apnea syndrome, non-alcoholic fatty liver disease, chronic pancreatitis, hypertriglyceridemia, and prediabetes), followed by abdominal obesity (gastroesophageal reflux disease, hypertriglyceridemia, arterial hypertension, hypercholesterolemia). Conclusions In working-age people, group 1 and 4 phenotypes were more frequent than others. Abdominal obesity and visceral fat were associated with the most comorbid conditions. However, the individual types of these comorbidities were not the same.

A case of early-onset idiopathic chronic pancreatitis associated with a loss-of-function TRPV6 p.R483Q variant successfully treated by pancreatic duct stenting.

Several pancreatitis-related genetic variants have been identified. Recently, the association of loss-of-function variants in the transient receptor potential cation channel subfamily V member 6 (TRPV6) gene and early-onset non-alcoholic chronic pancreatitis (CP) has been reported. However, detailed clinical presentation of the cases carrying TRPV6 variants remains largely unknown. We report a case of early CP carrying a TRPV6 variant in which recurrent attacks of pancreatitis were successfully managed by pancreatic duct stenting. A 12-year-old boy with CP was referred to our hospital for further investigation. He had experienced recurrent pancreatitis attacks since he was 11years old. Pancreatic ductal anomalies were not identified on magnetic resonance cholangiopancreatography. Genetic analysis revealed that the patient had a loss-of-function TRPV6 c.1448G > A (p.R483Q) variant in a heterozygous form. Conservative treatments were not effective; thus, we placed pancreatic duct stent by endoscopic intervention, and the frequency of relapses have dramatically decreased. We present the first pediatric report of early CP associated with the TRPV6 variant that was successfully treated with pancreatic duct stenting. This case suggests that pancreatic duct stenting is effective in preventing the relapse of pancreatitis related to the TRPV6 variant.

Quality of Life in Patients With Definite Chronic Pancreatitis: A Nationwide Longitudinal Cohort Study.

Chronic pancreatitis (CP) has a negative impact on quality of life (QoL). Because CP is a chronic condition, multiple assessments of QoL are required to obtain a thorough understanding of its impact on patients. Such studies are currently lacking. This study aims to gain insight into the course and predictors of QoL in patients with CP using prospective longitudinal data from a large cohort of patients. Post hoc analysis of consecutive patients with definite CP registered in a prospective database between 2011 and 2019 in the Netherlands. Patient and disease characteristics, nutritional status, pain severity, medication usage, pancreatic function, and pancreatic interventions were assessed from medical records and through standard follow-up questionnaires. The physical and mental component summary scales of the Short-Form 36 were used to assess physical and mental QoL at baseline and during follow-up. The course of both physical and mental QoL and their associated factors were longitudinally assessed by using generalized linear mixed models. Overall, 1,165 patients with definite CP were included for this analysis. During 10-year follow-up, generalized linear mixed model analyses revealed improvements in both physical (41.6-45.2, P < 0.001) and mental (45.9-46.6, P = 0.047) QoL. Younger age, current alcohol consumption, employment, no need for dietetic consultation, no steatorrhea, lower Izbicki pain score, and pain coping mechanism were positively associated with physical QoL ( P < 0.05). For mental QoL, a positive correlation was found between employment, nonalcoholic CP, no need for dietetic consultation, no steatorrhea, lower Izbicki pain score, pain coping mechanism, and surgical treatment. No association was observed between disease duration and longitudinal QoL per patient. This nationwide study provides insight into the dynamics of physical and mental QoL in patients with CP over time. Important and potentially influenceable factors to improve QoL are nutritional status, exocrine pancreatic function, employment status, and patients' coping strategy.

Altered MANF Expression in Pancreatic Acinar and Ductal Cells in Chronic Alcoholic Pancreatitis: A Cross-Sectional Study

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress response protein that plays an important role in pancreatic functions. As both alcohol and ER stress response proteins are involved in the pathogenesis of pancreatitis, we sought to investigate the expression of MANF in chronic alcoholic pancreatitis (CAP) and chronic non-alcoholic pancreatitis (CNP). A cohort of chronic pancreatitis tissues was gathered from routine surgical pathology (n = 77) and autopsy (n = 10) cases and tissue microarrays were created. Sampled tissues were reviewed and designated as representing CAP (n = 15), CNP (n = 58), or normal pancreatic tissue (NPT) (n = 27). MANF immunohistochemistry (IHC) and digital image analysis were performed to obtain an estimation of tissue fibrosis and an optical density (OD) of MANF IHC in ducts and acini for each case. The averaged values for these variables among histologic designations were compared. The amount of fibrous tissue of the combined CAP and CNP group (chronic alcoholic and non-alcoholic pancreatitis, CANP) exceeded that of the NPT group (70% vs. 34%, p < 0.0001). The MANF OD in ducts of CANP was significantly higher than that of NPT (0.19 vs. 0.10, p < 0.05). The MANF OD in ducts of CAP was significantly higher than that of CNP (0.27 vs. 0.17, p < 0.05). The MANF OD in acini of CAP was significantly lower than that in CNP (0.81 vs. 1.05, p < 0.05). Finally, there was a statistically significant positive relationship between the amount of fibrosis and MANF OD in ducts (p < 0.001). MANF expression was higher in ducts of CAP than CNP. In contrast, MANF expression in acini was lower in CAP than CNP and NPT. There was a positive correlation between fibrosis and MANF levels in the ducts.

Colocalization of risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS with eQTL signals indicates candidate disease causing mechanisms

Colocalization of risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS with eQTL signals indicates candidate disease causing mechanisms

Molecular dynamics study of tropical calcific pancreatitis (TCP) associated calcium-sensing receptor single nucleotide variation.

Tropical Calcific Pancreatitis (TCP) is a chronic non-alcoholic pancreatitis characterised by extensive calcification. The disease usually appears at a younger age and is more common in tropical regions. This disease’s progression can lead to pancreatic diabetes, which can subsequently lead to pancreatic cancer. The CASR gene encodes a calcium-sensing receptor (CaSR), which is a GPCR protein of class C. It is expressed in the islets of Langerhans, the parathyroid gland, and other tissues. It primarily detects small gradients in circulating calcium concentrations and couples this information to intracellular signalling, which helps to regulate PTH (parathyroid hormone) secretion and mineral ion homeostasis. From co-leading insulin release, CaSR modulates ductal HCO3− secretion, Ca2+ concentration, cell-cell communication, β-cell proliferation, and intracellular Ca2+ release. In pancreatic cancer, the CaSR limits cell proliferation. TCP-related four novel missense mutations P163R, I427S, D433H and V477A, found in CaSR extracellular domain (ECD) protein, which were reported in the mutTCPdb Database (https://lms.snu.edu.in/mutTCPDB/index.php). P163R mutation occurs in ligand-binding domain 1 (LBD-1) of the CaSR ECD. To investigate the influence of these variations on protein function and structural activity multiple in-silico prediction techniques such as SIFT, PolyPhen, CADD scores, and other methods have been utilized. A 500 ns molecular dynamic simulation was performed on the CaSR ECD crystal structure and the corresponding mutated models. Furthermore, Principal Component Analysis (PCA) and Essential Dynamics analysis were used to forecast collective motions, thermodynamic stabilities, and the critical subspace crucial to CaSR functions. The results of molecular dynamic simulations showed that the mutations P163R, I427S, D433H, and V477A caused conformational changes and decreased the stability of protein structures. This study also demonstrates the significance of TCP associated mutations. As a result of our findings, we hypothesised that the investigated mutations may have an effect on the protein’s structure and ability to interact with other molecules, which may be related to the protein’s functional impairment.

Genetic Analysis of the ATG16L1 c.898A>G (p.T300A) Variant in Acute and Chronic Pancreatitis.

Human and animal studies suggest an important role of autophagy in the pathogenesis of pancreatitis. ATG16L1 (autophagy-related 16 like 1) is part of a protein complex that is involved in the formation of autophagosomes. The c.898A > G (p.T300A) variant of ATG16L1 is associated with Crohn disease. In this study, we analyzed ATG16L1 c.898A > G (p.T300A) for an association with pancreatitis. We genotyped 777 patients and 551 control subjects of German origin by melting curve analysis using fluorescence resonance energy transfer probes. The patient group included 429 patients with nonalcoholic chronic pancreatitis (CP), 141 patients with alcoholic CP, and 207 patients with acute pancreatitis (AP). We classified AP by severity according to the Atlanta symposium 1992. Allele and genotype frequencies of ATG16L1 c.898A > G (p.T300A) did not differ significantly between patients and controls (G allele frequencies: nonalcoholic CP, 49.9%; alcoholic CP, 48.2%; AP, 49.5%; controls, 52.7%). We found no significant association with the severity of AP either. Our data do not support a role of ATG16L1 c.898A > G (p.T300A) in the pathogenesis of AP or CP or an influence on the severity of AP.

Genetic analysis of the aquaporin water channels AQP12A and AQP12B in patients with chronic pancreatitis

BackgroundAlterations in genes specifically expressed in the pancreas have been associated with chronic pancreatitis (CP). A significant percentage of patients with non-alcoholic CP, however, do not have mutations in known risk genes, suggesting the existence of further susceptibility genes. Four aquaporins are expressed in the exocrine pancreas: AQP1, AQP5, AQP8 and AQP12, the latter being found exclusively in this organ. Therefore, we investigated the two AQP12 genes, AQP12A and AQP12B, in CP patients. MethodsWe analyzed all exons and adjacent intronic regions of AQP12A and AQP12B in 292 German patients with non-alcoholic CP and 143 control subjects by direct DNA sequencing. ResultsIn total, we discovered 41 non-synonymous changes, three of which were nonsense variants. Genotype and allele frequencies of these variants did not differ significantly between patients and controls (all p-values >0.05). Remarkably, we found a common nonsense variant in AQP12B, p.S152Tfs∗24, with an allele frequency of 15.7% in controls, including 2.8% homozygous subjects. This finding suggests that AQP12B is physiologically dispensable for normal pancreatic function. ConclusionsOur results suggest that genetic alterations in AQP12A and AQP12B do not predispose to the development of non-alcoholic CP.

Loss-of-function variant in chymotrypsin like elastase 3B (CELA3B) is associated with non-alcoholic chronic pancreatitis

BackgroundGenetic alterations in digestive enzymes have been associated with chronic pancreatitis (CP). Recently, chymotrypsin like elastase 3B (CELA3B) emerged as a novel risk gene. Thus, we evaluated CELA3B in two European cohorts with CP. MethodsWe analyzed all 8 CELA3B exons in 550 German non-alcoholic CP (NACP) patients and in 241 German controls by targeted DNA sequencing. In addition, we analyzed exons 6 and 7 by Sanger sequencing and the c.129+1G>A variant by melting curve analysis in 1078 further German controls. As replication cohort, we investigated up to 243 non-German European NACP patients and up to 1665 controls originating from Poland, Hungary, and Sweden. We assessed the cellular secretion and the elastase activity of recombinant CELA3B variants. ResultsIn the German discovery cohort, we detected a splice-site variant in intron 2, c.129+1G>A, in 9/550 (1.64%) CP patients and in 5/1319 (0.38%) controls (P=0.007, OR=4.4, 95% CI=1.5–13.0). In the European replication cohort, this variant was also enriched in patients (9/178 [5.06%]) versus controls (13/1247 [1.04%]) (P=0.001, OR=5.1, 95% CI=2.1–12.0). We did not find the two previously reported codon 90 variants, p.R90C and p.R90L. ConclusionsOur data indicate that CELA3B is a susceptibility gene for CP. In contrast to previous reports suggesting that increased CELA3B activity is associated with CP risk, the splice-site variant identified here is predicted to cause diminished CELA3B expression. How reduced CELA3B function predisposes to pancreatitis remains to be elucidated.

Tobacco, alcohol and pancreatic disease: key findings from global consortia

(RR) were 1.74 (95% confidence interval, CI, 1.39-2.13) for current and 1.32 (95% CI 1.03-1.71) for former smokers [2, 3]. Chronic pancreatitis is associated to heavy alcohol drinking, though the risk estimates remain open to discussion. Epidemiological data are limited, but consistent with clinical ones to indicate that (heavy) drinking is related to chronic pancreatitis [2]. There is consistent evidence that tobacco is also a major factor for chronic pancreatitis. With reference to tobacco, the RRs from a meta-analysis were 2.8 (95% CI 1.7-4.8) for current and 1.4 (95% CI 1.1-1.9) for former smokers and these associations were not totally accounted for by heavy alcohol drinking [4]. Tobacco is responsible for 10 to 20% of all chronic pancreatitis. In non-alcoholic idiopathic chronic pancreatitis, smoking is associated with disease progression [5]. Cigarette smoking is the major risk factor for pancreatic cancer. In the Pancreatic Cancer Consortium (PanScan; 1481 cases, 1539 controls) the pooled RR was 1.77 (95% CI 1.38-2.26) for current and 1.09 (95% CI 0.91-1.30) for former smokers [6]. In the International Pancreatic Cancer Case-Control Consortium (PanC4; 6507 cases, 12,890 controls), the RR was 2.20 (95% CI 1.71-2.83) for current smokers and rose to 3.39 (95% CI 2.36-1.86) for heavy smokers; the RR was 1.17 (95% CI 1.02-2.83) for former smokers [7]. Cigar smoking was also associated with pancreatic cancer (RR 1.62, 95% CI 1.15-2.29), whereas no consistent association was found for smokeless tobacco, nor for pipe smoking [8]. A meta-analysis of 21 case-control and 11 cohort studies provided conclusive evidence that moderate drinking was unrelated to pancreatic cancer, but heavy drinking (3 or more drinks/day) gave a RR of 1.22 (95% CI 1.12-1.34) [9]. In the PanScan collaborative re-analysis of cohort studies (1530 cases, 1520 controls), there was no overall association with total alcohol intake, but the RR was 1.38 (95% CI 0.9-2.3) for drinking ≥60g day and rose to 2.23 (95% CI 1.0-4.9) for male heavy liquors drinkers [10]. In a pooled analysis of 14 cohort studies (2187 cases) the RR for >30g day was 1.22 (95% CI 1.031.45) [11]. In the PanC4 study (5585 cases, 11,822 controls), the RR was 1.46 (95% CI 1.16-1.83) for ≥6 drinks day; no association was observed with moderate drinking [12]. Possible mechanisms of action of alcohol include acetaldehyde, fatty acid ethyl esters, free radicals, DNA damage and inflammation [12]. Possible mechanisms of action of smoking include tobacco specific nitrosamines (NKK), polycyclic aromatic hydrocarbons (PAH) and other smoking-associated chemicals, and smoking as an inflammatory agent and a progressor in carcinogenesis [7].

Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms

BackgroundPrevious genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions. MethodsWe conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants. ResultsVariants at the CTRC (p = 1.22 × 10−21) and SPINK1 (p = 6.59 × 10−47) risk loci reached genome-wide significance in NACP. CTRC risk variants colocalized with CTRC eQTLs in ACP (PP4 = 0.99, PP4/PP3 = 95.51) and NACP (PP4 = 0.99, PP4/PP3 = 95.46). For both diseases, the 95% credible set of shared causal variants consisted of rs497078 and rs545634. CLDN2-MORC4 risk variants colocalized with CLDN2 eQTLs in ACP (PP4 = 0.98, PP4/PP3 = 42.20) and NACP (PP4 = 0.67, PP4/PP3 = 7.18), probably driven by the shared causal variant rs12688220. ConclusionsA shared causal CTRC risk variant might unfold its pathogenic effect in ACP and NACP by reducing CTRC expression, while the CLDN2-MORC4 shared causal variant rs12688220 may modify ACP and NACP risk by increasing CLDN2 expression.

Genetic analysis of pancreatic phospholipase A2 (PLA2G1B) in patients with chronic pancreatitis

BackgroundGenetic mutations in various pancreatic enzymes or their counteracting proteins have been linked to chronic pancreatitis. In particular, variants in the genes encoding pancreatic lipase (PNLIP) and carboxyl ester lipase (CEL) have been associated with pancreatitis. Therefore, we investigated pancreatic phospholipase A2 (PLA2G1B) as a promising candidate gene in patients with chronic pancreatitis. MethodsWe analyzed all coding exons and adjacent intronic regions of PLA2G1B in 416 German patients with non-alcoholic chronic pancreatitis (NACP) and 186 control subjects by direct DNA sequencing. ResultsWe detected 2 frequent synonymous variants in exon 3: c.222T>C (p.Y74 = ) and c.294G>A (p.S98 = ). The genotype and allele frequencies of these variants were similar between patients and controls (c.222 TC: 9.6% in NACP vs. 9.7% in controls; c.222CC: 0.2% in NACP vs. 0% in controls; c.294 GA: 31.3% in NACP vs. 28.0% in controls; c.294AA: 2.4% in NACP vs. 1.1% in controls). All p-values were non-significant. In addition, we found one synonymous variant, c.138C>T (p.N46 = ) and one non-synonymous variant, c.244A>G (p.S82G), in a single case each. ConclusionsOur results suggest that genetic alterations in PLA2G1B do not predispose to the development of non-alcoholic chronic pancreatitis.

Loss of function TRPV6 variants are associated with chronic pancreatitis in nonalcoholic early-onset Polish and German patients

PurposeLoss of function variants of the transient receptor potential cation channel, subfamily V, member 6 (TRPV6) have been recently associated with chronic pancreatitis (CP) in Japanese, German and French patients. Here, we investigated the association of TRPV6 variants with CP in independent European cohorts of early-onset CP patients from Poland and Germany. Patients and methodsWe enrolled 152 pediatric CP patients (median age 8.6 yrs) with no history of alcohol/smoking abuse and 472 controls from Poland as well as 157 nonalcoholic young CP patients (median age 20 yrs) and 750 controls from Germany. Coding regions of TRPV6 were screened by Sanger and next generation sequencing. Selected, potentially pathogenic TRPV6 variants were expressed in HEK293T cells and TRPV6 activity was analyzed using ratiometric Ca2+ measurements. ResultsOverall, we identified 10 novel (3 nonsense and 7 missenses) TRPV6 variants in CP patients. TRPV6 p.V239SfsX53 nonsense variant and the variants showing significant decrease in intracellular Ca2+ concentration in HEK293T cells (p.R174X, p.L576R, p.R342Q), were significantly overrepresented in Polish patients as compared to controls (6/152, 3.9% vs. 0/358, 0%; P = 0,0007). Nonsense TRPV6 variants predicted as loss of function (p.V239SfsX53 and p.R624X) were also significantly overrepresented in German patients (3/157; 2.0% vs 0/750; 0%, P = 0.005). ConclusionsWe showed that TRPV6 loss of function variants are associated with elevated CP risk in early-onset Polish and German patients confirming that TRPV6 is a novel CP susceptibility gene.

Genetic Risk Factors in Early-Onset Nonalcoholic Chronic Pancreatitis: An Update.

Chronic pancreatitis (CP) is a progressive, irreversible inflammatory disorder of the pancreas, which results from interrelations between different genetic and environmental factors. Genetic variants are the primary cause of the disease in early-onset nonalcoholic CP patients. Novel CP-associated genes are continuously emerging from genetic studies on CP cohorts, providing important clues for distinct mechanisms involved in CP development. On the basis of functional studies, the genetic alterations have been sub-grouped into CP-driving pathological pathways. This review focuses on the concept of CP as a complex disease driven by multiple genetic factors. We will discuss only well-defined genetic risk factors and distinct functional pathways involved in CP development, especially in the context of the early-onset nonalcoholic CP group. The diagnostic implications of the genetic testing will be addressed as well.

Regional Variations in Distribution, Diagnosis and Treatment of Chronic Pancreatitis in Mainland China: A Systematic Review of Case Articles Over 40 Years

Background: Epidemiological data regarding the regional differences in chronic pancreatitis (CP) from the mainland of China is lacking. We aimed to gather and combine the information concerning the regional distribution, diagnosis and treatment of CP, in addition to the risk factors associated with pancreatic cancer (PaCa) and death from published articles. Methods: Case articles on CP published in three English and four Chinese databases from January 1979 to December 2018 were analysed. Findings: A total of 4,452 cases articles (containing 161,243 CP cases) were included. Almost all relevant departments of 1,557 hospitals participated in the writing of CP articles and approximately 67.2% of hospitals wrote only one article. The etiologies, symptoms, treatments, and number of cases with PaCa varied from region to region. Surgical treatment was more common in underdeveloped areas. Endoscopic therapy was mainly concentrated in developed areas and was also associated with non-alcoholic CP. PaCa detected during hospitalization was mainly related to jaundice (r = 0.35, P = 0.000), pain (r = 0.31, P = 0.000), diabetes (r = 0.20, P = 0.000), biliary diseases (r = 0.36, P = 0.000), alcoholic CP (r = 0.30, P = 0.000), conservative treatment (r = 0.37, P = 0.000) and surgical treatment (r = 0.21, P = 0.000). PaCa detected during follow-up was primarily associated with idiopathic CP (r = 0.26, P = 0.000), alcoholic CP (r = 0.23, P = 0.000), endoscopy therapy (r = 0.3, P = 0.000) and surgical treatment (r = 0.24, P = 0.000). Death during hospitalization was only related to surgery. Interpretation: Many regions have gradually formed their own unique characteristics in terms of the diagnosis and treatment of CP. However, the level of diagnosis and treatment of CP in many areas still needs to be improved. The problem of uneven distribution of medical resources needs to be resolved. Funding Statement: None. Declaration of Interests: The authors declare that there are no competing interests associated with the manuscript.

Role of the Common PRSS1-PRSS2 Haplotype in Alcoholic and Non-Alcoholic Chronic Pancreatitis: Meta- and Re-Analyses.

The association between a common PRSS1-PRSS2 haplotype and alcoholic chronic pancreatitis (ACP), which was revealed by the first genome-wide association study of chronic pancreatitis (CP), has been consistently replicated. However, the association with non-ACP (NACP) has been controversial. Herein, we sought to clarify this basic issue by means of an allele-based meta-analysis of currently available studies. We then used studies informative for genotype distribution to explore the biological mechanisms underlying the association data and to test for gene-environment interaction between the risk haplotype and alcohol consumption by means of a re-analysis. A literature search was conducted to identify eligible studies. A meta-analysis was performed using the Review Manager software. The association between the risk genotypes and NACP or ACP was tested for the best-fitting genetic model. Gene-environment interaction was estimated by both case-only and multinomial approaches. Five and eight studies were employed for the meta-analysis of ACP and NACP findings, respectively. The risk allele was significantly associated with both ACP (pooled odds ratio (OR) 1.67, 95% confidence interval (CI) 1.56–1.78; p < 0.00001) and NACP (pooled OR 1.28, 95% CI 1.17–1.40; p < 0.00001). Consistent with a dosage effect of the risk allele on PRSS1/PRSS2 mRNA expression in human pancreatic tissue, both ACP and NACP association data were best explained by an additive genetic model. Finally, the risk haplotype was found to interact synergistically with alcohol consumption.