Risk Of Chronic Pancreatitis Research Articles

Six Types of Pancreatitis Risk Factors in the Trypsinogen Gene Loci (PRSS1-PRSS2-TRB).

Trypsin dysregulation is central to acute pancreatitis (AP) and contributes to chronic pancreatitis (CP). Genetic variants within the T Cell receptor beta chain (TRB) locus, that includes the trypsinogen genes (PRSS1 and PRSS2) affect risks of AP and CP. Hereditary pancreatitis is caused by rare gain-of-function variants (e.g. PRSS1 p.N29I, p.R122H), while other common and rare variants alter risk for AP and/or CP through 5 other mechanisms, including altering the TRB gene receptor repertoire. Here we provide a brief primer of genetic risk for AP and CP using examples of variants within the TRB locus and the PRSS1 and PRSS2 genes

Effect analysis of trimethylamine N-oxide and its precursors on susceptibility to pancreatic diseases

To investigate the causal relationship between trimethylamine N-oxide (TMAO) and its precursors (betaine, carnitine, and choline) and pancreatic diseases based on the Mendelian randomization (MR) method. Genome-wide association study data of TMAO, betaine, carnitine, choline, acute pancreatitis (AP), chronic pancreatitis (CP), pancreatic cancer (PC), and circulating immune cell characteristics (white blood cell, lymphocyte, monocyte, neutrophil, eosinophil and basophil) were collected. According to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)-MR reporting guidelines, the available genetic variants [single nucleotide polymorphism (SNP)] were strictly screened. The causal relationship between exposure (TMAO and its precursors) and outcomes (pancreatic diseases and circulating immune cell characteristics) was evaluated using inverse variance weighting (IVW), MR-Egger regression and weighted median. The reliability of the results was evaluated by sensitivity analysis based on MR-Egger regression, MR-PRESSO, Cochrane's Q test and leave-one-out method. A total of 36 SNP associated with TMAO and its precursors were included. Five of these were associated with TMAO, 13 with betaine, 12 with carnitine, and 6 with choline. (1) MR analysis showed that TMAO may increase the risk of AP [odds ratio (OR) = 1.100, 95% confidence interval (95%CI) was 1.008-1.200, P = 0.032], and choline may reduce the risk of alcoholic acute pancreatitis (AAP; OR = 0.743, 95%CI was 0.585-0.944, P = 0.015). The analysis results of MR-Egger regression and weighted median were consistent with the IVW results. There is no evidence to support a causal relationship between TMAO and its precursors and the risk of CP and PC. Sensitivity analysis indicated that SNP analyzed by MR showed no heterogeneity and low pleiotropy. The leave-one-out method analysis determined that after excluding any SNP, the effect intervals of the remaining SNP on the results were similar to the overall effect intervals, which suggested the robustness of MR results. (2) There was a positive causal relationship between plasma TMAO level and circulating monocyte count (OR = 1.017, 95%CI was 1.000*-1.034, P = 0.048, * represented that the data was obtained by correcting to 3 decimal places from 1.000 1). The causal effect obtained by MR-Egger regression and weighted median analysis was consistent with the results of IVW. Sensitivity analysis illustrated SNP analyzed by MR showed no heterogeneity and pleiotropy. The leave-one-out method analysis determined that after excluding any SNP, the effect intervals of the remaining SNP on the results were similar to the overall effect intervals, which suggested the robustness of MR results. TMAO and choline may change the risk of AP, and TMAO may contribute to the increase of circulating monocyte count in AP.

Immune Checkpoint Inhibitors in Cancer Treatment and Incidence of Pancreatitis.

Immune checkpoint inhibitors (ICIs) are an approved therapy for the management of various advanced neoplasms. Limited reviews focus on the influence of this therapy resulting in pancreatitis. This review discusses the relationship between ICIs and their effects on the pancreas, including the incidence of pancreatitis, immunotherapy, programmed cell death 1 (PD-1) receptors, driver mutations, programmed death ligand 1 (PD-L1), and immune-related adverse events. Additionally, it focuses on the clinical presentations, diagnosis, case studies, and mechanisms by which ICIs activate different pathways to cause pancreatitis. We conducted a comprehensive literature search using PubMed, Cochrane Library, and Google Scholar databases to identify relevant studies on ICI-associated pancreatitis. The review explores the incidence and epidemiology of ICI-induced pancreatitis, its clinical presentation, diagnostic criteria, and management strategies.The overall incidence of ICI-induced pancreatitis is estimated at 1-2%, with higher rates observed in combination therapy. Clinical presentations range from asymptomatic enzyme elevations to severe pancreatitis. Diagnosis relies on a combination of clinical symptoms, elevated pancreatic enzymes, and imaging findings, with MRI and endoscopic ultrasound showing promise in early detection. Management strategies include IV fluid administration, pain control, and nutritional support. The efficacy of corticosteroids remains controversial, and alternative immunosuppressants are being explored for steroid-refractory cases. Long-term monitoring is crucial due to the risk of chronic pancreatitis and pancreatic insufficiency. This review highlights the need for further research to elucidate the exact mechanisms of ICI-associated pancreatic injury, develop predictive biomarkers, and refine treatment protocols. As ICI use continues to expand, a thorough understanding of this adverse event is essential for optimizing patient care and outcomes in cancer immunotherapy.

Novel chymotrypsin C (CTRC) variants from real-world genetic testing of pediatric chronic pancreatitis cases

BackgroundChymotrypsin C (CTRC) protects the pancreas against unwanted intrapancreatic trypsin activity through degradation of trypsinogen. Loss-of-function CTRC variants increase the risk for chronic pancreatitis (CP). The aim of the present study was to characterize novel CTRC variants found during genetic testing of CP cases at a pediatric pancreatitis center. MethodsWe used next-generation sequencing to screen patients. We analyzed the functional effects of CTRC variants in HEK 293T cells and using purified enzymes. ResultsIn 5 separate cases, we detected 5 novel heterozygous CTRC variants: c.407C>T (p.Thr136Ile), c.550G>A (p.Ala184Thr), c.627Cdup (p.Ser210Leufs∗?, where the naming indicates a frame shift with no stop codon), c.628T>C (p.Ser210Pro), and c.779A>G (p.Asp260Gly). Functional studies revealed that with the exception of p.Ser210Leufs∗?, the CTRC variants were secreted normally from transfected cells. Enzyme activity of purified variants p.Thr136Ile, p.Ala184Thr, and p.Asp260Gly was similar to that of wild-type CTRC, whereas variant p.Ser210Pro was inactive. The frame-shift variant p.Ser210Leufs∗? was not secreted but accumulated intracellularly, and induced endoplasmic reticulum stress, as judged by elevated mRNA levels of HSPA5 and DDIT3, and increased mRNA splicing of XBP1. ConclusionsCTRC variants p.Ser210Pro and p.Ser210Leufs∗? abolish CTRC function and should be classified as pathogenic. Mechanistically, variant p.Ser210Pro directly affects the amino acid at the bottom of the substrate-binding pocket while the frame-shift variant promotes misfolding and thereby blocks enzyme secretion. Importantly, 3 of the 5 novel CTRC variants proved to be benign, indicating that functional analysis is indispensable for reliable determination of pathogenicity and the correct interpretation of genetic test results.

Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression

Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.

Alcohol Exposure and Disease Associations: A Mendelian Randomization and Meta-Analysis on Weekly Consumption and Problematic Drinking.

Alcohol consumption significantly impacts disease burden and has been linked to various diseases in observational studies. However, comprehensive meta-analyses using Mendelian randomization (MR) to examine drinking patterns are limited. We aimed to evaluate the health risks of alcohol use by integrating findings from MR studies. A thorough search was conducted for MR studies focused on alcohol exposure. We utilized two sets of instrumental variables-alcohol consumption and problematic alcohol use-and summary statistics from the FinnGen consortium R9 release to perform de novo MR analyses. Our meta-analysis encompassed 64 published and 151 de novo MR analyses across 76 distinct primary outcomes. Results show that a genetic predisposition to alcohol consumption, independent of smoking, significantly correlates with a decreased risk of Parkinson's disease, prostate hyperplasia, and rheumatoid arthritis. It was also associated with an increased risk of chronic pancreatitis, colorectal cancer, and head and neck cancers. Additionally, a genetic predisposition to problematic alcohol use is strongly associated with increased risks of alcoholic liver disease, cirrhosis, both acute and chronic pancreatitis, and pneumonia. Evidence from our MR study supports the notion that alcohol consumption and problematic alcohol use are causally associated with a range of diseases, predominantly by increasing the risk.

Exploring the casual association between gut microbiome, circulating inflammatory cytokines and chronic pancreatitis: A Mendelian randomization analysis.

It has been established that gut dysbiosis contributed to the pathogenesis of digestive disorders. We aimed to explore the causal relationships between intestinal microbiota, circulating inflammatory cytokines and chronic pancreatitis (CP). Summary statistics of genome-wide association studies (GWAS) of intestinal microbiome was retrieved from the MiBioGen study and the GWAS data of 91 circulating inflammatory cytokines and CP were obtained from the GWAS catalog. The 2-sample bidirectional Mendelian randomization (MR) analysis was performed between gut microbiota, circulating inflammatory cytokines and CP, in which the inverse variance weighted (IVW) method was regarded as the primary analysis approach. To prove the reliability of the causal estimations, multiple sensitivity analyses were utilized. IVW results revealed that genetically predicted 2 genera, including Sellimonas and Eubacteriumventriosumgroup, and plasm C-C motif chemokine 23 (CCL23) level were positively associated with CP risk, while genus Escherichia Shigella, Eubacteriumruminantiumgroup and Prevotella9, and plasma Caspase 8, Adenosine Deaminase (ADA), and SIR2-like protein 2 (SIRT2) level, demonstrated an ameliorative effect on CP. Leave-one-out analysis confirmed the robustness of the aforementioned causal effects and no significant horizontal pleiotropy or heterogeneity of the instrumental variables was detected. However, no association was found from the identified genera to the CP-related circulating inflammatory cytokines. Besides, the reverse MR analysis demonstrated no causal relationship from CP to the identified genera and circulating inflammatory cytokines. Taken together, our comprehensive analyses offer evidence in favor of the estimated causal connections from the 5 genus-level microbial taxa and 4 circulating inflammatory cytokines to CP risk, which may help to reveal the underlying pathogenesis of CP.

Exploring the enigmatic association between PNLIP variants and risk of chronic pancreatitis in a large Chinese cohort

Background & AimsProtease-sensitive PNLIP variants were recently associated with chronic pancreatitis (CP) in European populations. The pathological mechanism yet remains elusive. Herein, we performed a comprehensive genetic and functional analysis of PNLIP variants found in a large Chinese cohort, aiming to further unravel the enigmatic association of PNLIP variants with CP. MethodsAll coding and flanking intronic regions of the PNLIP gene were analyzed for rare variants by targeted next-generation sequencing in 1082 Chinese CP patients and 1196 controls. All novel missense variants were subject to analysis of secretion, lipase activity, and proteolytic degradation. One variant was further analyzed for its potential to misfold and induce endoplasmic reticulum (ER) stress. p.F300L, the most common PNLIP variant associated with CP, was used as a control. ResultsWe identified 12 rare heterozygous PNLIP variants, with 10 being novel. The variant carrier frequency did not differ between the groups. Of them, only the variant p.A433T found in a single patient was considered pathologically relevant. p.A433T exhibited increased susceptibility to proteolytic degradation, which was much milder than p.F300L. Interestingly, both variants exhibited an increased tendency to misfold, leading to intracellular retention as insoluble aggregates, reduced secretion, and elevated ER stress. ConclusionsOur genetic and functional analysis of PNLIP variants identified in a Chinese CP cohort suggests that the p.A433T variant and the previously identified p.F300L variant are not only protease-sensitive but also may be potentially proteotoxic. Mouse studies of the PNLIP p.F300L and p.A433T variants are needed to clarify their role in CP.

Adherence to the Mediterranean diet is associated with reduced chronic pancreatitis risk: a longitudinal cohort study.

Background: The role of diet on the risk of chronic pancreatitis (CP) is understudied. The health benefits of the Mediterranean diet (MedDiet) pattern have long been recognized, but its association with CP risk is unclear. We aimed to investigate the association between adherence to MedDiet and the incidence of CP in a large-scale cohort. Methods: 190 790 participants from the UK Biobank were involved, all free of CP and with typical diet recall data at recruitment. The diagnosis of CP was ascertained by the combination of hospital inpatient data, primary care data, and death registry data. Multivariable Cox regression models were used to evaluate the associations between MedDiet adherence, measured by the Mediterranean Diet Adherence Screener (MEDAS) continuous score, and the incidence of CP. The mediating role of inflammation (assessed by C-reactive protein) and metabolic status between MedDiet adherence and CP risk was also investigated. Results: During a mean of 10.8 years of follow-up, 214 participants developed CP. Individuals with the highest adherence to MedDiet, defined by continuous MEDAS scores, exhibited significantly lower risk of developing CP (hazard ratio [HR] = 0.57, 95% confidence interval [CI]: 0.40-0.82; p = 0.002) compared to those in the lowest tertiles. Metabolic status mediated 4.74% of the association between MedDiet adherence and CP risk, while the mediating role of C-reactive protein was not significant. Conclusion: Greater Mediterranean diet adherence is associated with reduced chronic pancreatitis risk.

Heterozygous Spink1 Deficiency Promotes Trypsin-dependent Chronic Pancreatitis in Mice

Heterozygous SPINK1 mutations are strong risk factors for chronic pancreatitis in humans, yet heterozygous disruption of mouse Spink1 yielded no pancreatic phenotype. To resolve this contradiction, we usedCRISPR/Cas9-mediated genome editing to generate heterozygous Spink1-deleted mice (Spink1-KOhet) in the C57BL/6N strain and studied the effect of this allele in trypsin-independent and trypsin-dependent pancreatitis models. We investigated severity of acute pancreatitis and progression to chronic pancreatitis in Spink1-KOhet mice after transient (10 injections) and prolonged (2× 8 injections) cerulein hyperstimulation. We crossed Spink1-KOhet mice with T7D23A and T7D22N,K24R mice that carry strongly autoactivating trypsinogen mutants and exhibit spontaneous chronic pancreatitis. Prolonged but not transient cerulein stimulation resulted in increased intrapancreatic trypsin activity and more severe acute pancreatitis in Spink1-KOhet mice relative to the C57BL/6N control strain. After the acute episode, Spink1-KOhet mice developed progressive disease with chronic pancreatitis-like features, whereas C57BL/6N mice recovered rapidly. Trypsinogen mutant mice carrying the Spink1-KOhet allele exhibited strikingly more severe chronic pancreatitis than the respective parent strains. Heterozygous Spink1 deficiency caused more severe acute pancreatitis after prolonged cerulein stimulation and promoted chronic pancreatitis after the cerulein-induced acute episode, and in two strains of trypsinogen mutant mice with spontaneous disease. In contrast, acute pancreatitis induced with limited cerulein hyperstimulation was unaffected by heterozygous Spink1 deletion, in agreement with recent observations that trypsin activity does not mediate pathologic responses in this model. Taken together, the findings strongly support the notion that loss-of-function SPINK1 mutations inhumans increase chronic pancreatitis risk in a trypsin-dependent manner.

Analysis of the selenoprotein P (rs7579) gene polymorphism and expression in patients with chronic pancreatitis combined with hypothyroidism

Background. The specific role and place of genetic factors in the development of chronic pancreatitis and hypothyroidism, which determine the activity of glutathione antioxidant protection, have not been clarified. They are interconnected with changes in the fat and carbohydrate metabolism, and also affect the transport and signaling pathways of key nutrients for the work of the immune, endocrine and nervous systems. The purpose of the study is to investigate the selenoprotein P (SEPP1) (rs7579) gene polymorphism and expression in patients with chronic pancreatitis combined with hypothyroidism. Materials and methods. Forty-nine patients with chronic pancreatitis and hypothyroidism and 30 practically healthy individuals passed the screening stage. The SEPP1 (rs7579) gene polymorphism was determined by the polymerase chain reaction. Results. The study showed that out of 98 isolated alleles in patients with chronic pancreatitis and hypothyroidism and 60 alleles of the control group, the G allele of the SEPP1 gene (rs7579, 25191G/A) dominated over the A allele: in the examined patients — by 34.7 % (χ2 = 23.59; p < 0.001), in the practically healthy group — by 53.34 % (χ2 = 34.13; p < 0.001). At the same time, the relative frequency of individual genotypes, as well as wild-type and mutant alleles, probably did not differ between the experimental and control groups. The A allele of the SEPP1 gene (rs7579) slightly increases the risk of chronic pancrea­titis in the studied population, but non-significantly [risk ratio (RR) = 1.43; RR 95% CI (confidence interval): 0.91–2.26; odds ratio (OR) = 1.65; OR 95% CI: 0.88–3.08; p = 0.115]. Conclusions. In patients with chronic pancreatitis who are residents of Northern Bukovyna, mutation of the SEPP1 gene (rs7579, 25191G/A) in the homozygous state occurs with a frequency of 10.2 %, while it is absent in practically healthy people. In both groups, the G allele dominates over the A allele: in the examined patients — by 34.7 % (χ2 = 23.59; p < 0.001), in controls — by 53.34 % (χ2 = 34.13; p < 0.001). SEPP1 gene polymorphism (rs7579, 25191G/A) does not determine the risk of chronic pancreatitis in the population. However, the A allele increases the risk of hypothyroidism in chro­nic pancreatitis patients twice [OR = 2.0; OR 95% CI: 1.09–3.66; p = 0.023], with the lowest chances of its appearance in carriers of the G allele [OR = 0.50; OR 95% CI: 0.27–0.91; p = 0.023]. Mapping of the expression quantitative trait loci on both sides of the SEPP1 gene (rs7579) transcription start site evidenced 152 statistically significant cis-variants of rs7579 of the SEPP1 gene (SELENOP) associations with the expression of 20 genes in 35 different organs and tissues and 22 phenotypic traits.

Multistate Model of the Natural History of Inflammatory Pancreatic Diseases: A Nationwide Population-based Cohort Study

Understanding the nature of inflammatory pancreatic diseases is essential for planning health care system requirements and interventions. The aim of this study was to quantify the trajectories of inflammatory pancreatic diseases and their association with pancreatic cancer in a population-based setting. National health registries were used to identify all Danish residents (18 years or older) in the period from 2000 through 2018 with incident cases of acute pancreatitis (AP), recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), and pancreatic cancer. We used a multistate model to examine transitions from a healthy state to intermediate states of acute pancreatic inflammation (AP and RAP) to chronic states (CP and pancreatic cancer) and, ultimately, death. Results were reported as transition incidence rates per 1000 person-years with 95% CIs. There were 4,663,864 individuals included (mean age, 46 years; 51% were women). During a mean follow-up of 16.8 years, 31,396 individuals were diagnosed with incident AP, 5546 with RAP, 8898 with CP, and 18,182 with pancreatic cancer. The cumulative incidence of pancreatitis (acute and chronic) during the study period was 0.80% (95% CI, 0.79%-0.80%). The transition incidence rates to CP were 12.1 (95% CI, 8.1-18.1) from AP, 46.8 (95% CI, 31.6-69.3) from RAP, and 0.07 (95% CI, 0.04-0.13) from a healthy state. Similar patterns were observed for transitions to pancreatic cancer. Most patients diagnosed with CP (64.2%) and pancreatic cancer (96.4%) transitioned directly from a healthy state. Among patients with pancreatitis, 41.0% (95% CI, 40.5%-41.5%) died during follow-up. The study findings revealed an increased risk of CP and pancreatic cancer in patients with a history of AP. However, most patients with CP and pancreatic cancer transitioned directly from a healthy state.

Risk of chronic pancreatitis in carriers of the c.180C>T (p.Gly60=) CTRC variant: case-control studies and meta-analysis

Chymotrypsin C (CTRC) is a digestive serine protease produced by the pancreas that regulates intrapancreatic trypsin activity and provides a defensive mechanism against chronic pancreatitis (CP). CTRC exerts its protective effect by promoting degradation of trypsinogen, the precursor to trypsin. Loss-of-function missense and microdeletion variants of CTRC are found in around 4% of CP cases and increase disease risk by approximately 3-7-fold. In addition, a commonly occurring synonymous CTRC variant c.180C>T (p.Gly60=) was reported to increase CP risk in various cohorts but a global analysis of its impact has been lacking. Here, we analyzed the frequency and effect size of variant c.180C>T in Hungarian and pan-European cohorts, and performed meta-analysis of the new and published genetic association data. When allele frequency was considered, meta-analysis revealed an overall frequency of 14.2% in patients and 8.7% in controls (allelic odds ratio (OR) 2.18, 95% confidence interval (CI) 1.72–2.75). When genotypes were examined, c.180TT homozygosity was observed in 3.9% of CP patients and in 1.2% of controls, and c.180CT heterozygosity was present in 22.9% of CP patients and in 15.5% of controls. Relative to the c.180CC genotype, the genotypic OR values were 5.29 (95% CI 2.63–10.64), and 1.94 (95% CI 1.57–2.38), respectively, indicating stronger CP risk in homozygous carriers. Finally, we obtained preliminary evidence that the variant is associated with reduced CTRC mRNA levels in the pancreas. Taken together, the results indicate that CTRC variant c.180C>T is a clinically relevant risk factor, and should be considered when genetic etiology of CP is investigated.

Causal associations between modifiable risk factors and pancreatitis: A comprehensive Mendelian randomization study.

The pathogenesis of pancreatitis involves diverse environmental risk factors, some of which have not yet been clearly elucidated. This study systematically investigated the causal effects of genetically predicted modifiable risk factors on pancreatitis using the Mendelian randomization (MR) approach. Genetic variants associated with 30 exposure factors were obtained from genome-wide association studies. Summary-level statistical data for acute pancreatitis (AP), chronic pancreatitis (CP), alcohol-induced AP (AAP) and alcohol-induced CP (ACP) were obtained from FinnGen consortia. Univariable and multivariable MR analyses were performed to identify causal risk factors for pancreatitis. Genetic predisposition to smoking (OR = 1.314, P = 0.021), cholelithiasis (OR = 1.365, P = 1.307E-19) and inflammatory bowel disease (IBD) (OR = 1.063, P = 0.008) as well as higher triglycerides (OR = 1.189, P = 0.016), body mass index (BMI) (OR = 1.335, P = 3.077E-04), whole body fat mass (OR = 1.291, P = 0.004) and waist circumference (OR = 1.466, P = 0.011) were associated with increased risk of AP. The effect of obesity traits on AP was attenuated after correcting for cholelithiasis. Genetically-driven smoking (OR = 1.595, P = 0.005), alcohol consumption (OR = 3.142, P = 0.020), cholelithiasis (OR = 1.180, P = 0.001), autoimmune diseases (OR = 1.123, P = 0.008), IBD (OR = 1.066, P = 0.042), type 2 diabetes (OR = 1.121, P = 0.029), and higher serum calcium (OR = 1.933, P = 0.018), triglycerides (OR = 1.222, P = 0.021) and waist-to-hip ratio (OR = 1.632, P = 0.023) increased the risk of CP. Cholelithiasis, triglycerides and the waist-to-hip ratio remained significant predictors in the multivariable MR. Genetically predicted alcohol drinking was associated with increased risk of AAP (OR = 15.045, P = 0.001) and ACP (OR = 6.042, P = 0.014). After adjustment of alcohol drinking, genetic liability to IBD had a similar significant causal effect on AAP (OR = 1.137, P = 0.049), while testosterone (OR = 0.270, P = 0.002) a triglyceride (OR = 1.610, P = 0.001) and hip circumference (OR = 0.648, P = 0.040) were significantly associated with ACP. Genetically predicted higher education and household income levels could lower the risk of pancreatitis. This MR study provides evidence of complex causal associations between modifiable risk factors and pancreatitis. These findings provide new insights into potential therapeutic and prevention strategies.

Association between Dietary Habits and Pancreatitis among Individuals of European Ancestry: A Two-Sample Mendelian Randomization Study

Dietary factors are believed to potentially influence the risk of pancreatitis. Here, we systematically investigated the causal relationships between dietary habits and pancreatitis by using two-sample Mendelian randomization (MR). Large-scale genome-wide association study (GWAS) summary statistics for dietary habits were obtained from the UK Biobank. GWAS data for acute pancreatitis (AP), chronic pancreatitis (CP), alcohol-induced AP (AAP) and alcohol-induced CP (ACP) were from the FinnGen consortium. We performed univariable and multivariable MR analyses to evaluate the causal association between dietary habits and pancreatitis. Genetically driven alcohol drinking was associated with increased odds of AP, CP, AAP and ACP (all with p < 0.05). Genetic predisposition to higher dried fruit intake was associated with reduced risk of AP (OR = 0.280, p = 1.909 × 10-5) and CP (OR = 0.361, p = 0.009), while genetic predisposition to fresh fruit intake was associated with reduced risk of AP (OR = 0.448, p = 0.034) and ACP (OR = 0.262, p = 0.045). Genetically predicted higher consumption of pork (OR = 5.618, p = 0.022) or processed meat (OR = 2.771, p = 0.007) had a significant causal association with AP, and genetically predicted higher processed meat intake increased the risk of CP (OR = 2.463, p = 0.043). Our MR study showed that fruit intake may be protective against pancreatitis, whereas dietary intake of processed meat has potential adverse impacts. These findings may inform prevention strategies and interventions directed toward dietary habits and pancreatitis.

The Coexistence of TRPV6 Variants With Other Pancreatitis-Associated Genes Affects Pediatric-Onset Pancreatitis.

Recently, a genetic risk for chronic pancreatitis (CP) was found to be conferred by pathogenic variants in the transient receptor potential cation channel, subfamily V, member 6 ( TRPV6 ). Interestingly, 20%-57% of patients with functionally defective TRPV6 variants have other susceptibility genes such as cationic trypsinogen, serine protease inhibitor Kazal type 1, chymotrypsin C, cystic fibrosis transmembrane conductance regulator, and carboxypeptidase A1. In this study, we focused on pediatric patients with acute recurrent pancreatitis or CP with at least 1 variant in these 5 genes and investigated the presence of coexisting TRPV6 mutations. Ninety Japanese pediatric patients (median age at first onset, 8.0 years) who had at least 1 variant of these 5 genes were enrolled in this study. DNA samples were extracted for analysis from peripheral blood leukocytes. Coding regions of TRPV6 were screened by Sanger sequencing. Regardless of functional defects or non-defects in TRPV6 variants, 14 of the 90 patients (15.6%) were trans-heterozygous for TRPV6 variants [p.A18S (n = 3), p.C197R (n = 3), p.I223T (n = 3), p.D324N (n = 4), p.M418V (n = 3), p.V540F (n = 1), p.A606T (n = 1), and p.M721T (n = 3)] and the 5 susceptibility genes noted above. Of these variants, p.D324N, p.V540F, and p.A606T are associated with pancreatitis. Three patients had the ancestral haplotype [p.C197R + p.M418V + p.M721T]. Overall, 4 of 90 patients (4.4%) had the coexistence of clearly pathogenic TRPV6 variants with pancreatitis-associated variants. The cumulative accumulation of these genetic factors may contribute to the development of pancreatitis at a young age.

Smoking as the most important risk factor for chronic pancreatitis in the general population.

We tested the hypothesis that six toxic risk factors from the TIGAR-O classification system are equally important for risk of chronic pancreatitis, at the level of the individual patient and in the general population. 108,438 women and men aged 20-100years participating in the Copenhagen General Population Study from 2003 to 2015 were included. Associations of smoking, alcohol intake, waist/hip ratio, kidney function, plasma triglycerides, plasma Ca2+, and diseases within the causal pathway with risk of chronic pancreatitis, and corresponding population attributable risks were estimated. Information on chronic pancreatitis was from national Danish health registries. During median 9years (range: 0-15) of follow-up, 313 individuals had a first diagnosis of chronic pancreatitis; the incidence of chronic pancreatitis per 10,000 person-years were 3.1 overall, 2.8 in women, and 3.5 in men. Of the six toxic risk factors and relative to individuals with low values, individuals in the top 5% had hazard ratios for chronic pancreatitis of 3.1(95% CI 2.1-4.5) for pack-years smoked, 2.5(1.5-4.0) for alcohol intake, and 1.6(1.1-2.6) for plasma triglycerides. Corresponding values versus those without the baseline disease were 12.6 (7.9-20.2) for acute pancreatitis, 1.9 (1.2-2.8) for gallstone disease, and 1.9 (1.3-2.7) for diabetes mellitus. The highest population attributable fractions were for women (1) ever smoking (31%), (2) gallstone disease (5%), and (3) diabetes mellitus (4%), and for men (1) ever smoking (38%), (2) acute pancreatitis (7%)/high alcohol intake (7%), and (3) high plasma triglycerides (5%). Smoking is the most important risk factor for chronic pancreatitis in the general population.

The PRSS3P2 and TRY7 deletion copy number variant modifies risk for chronic pancreatitis

BackgroundPRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition. MethodsWe analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction. ResultsWe demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52–0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77–0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression. ConclusionsThe common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection.

Epidemiologic risk factors for patients admitted with chronic pancreatitis and pancreatic ductal adenocarcinoma in the United States

Epidemiological studies of chronic pancreatitis (CP) and its association with pancreatic ductal adenocarcinoma (PDAC) are limited. Understanding demographic and ethno-racial factors may help identify patients at the highest risk for CP and PDAC. To evaluate the ethno-racial risk factors for CP and its association with PDAC. The secondary aim was to evaluate hospitalization outcomes in patients admitted with CP and PDAC. This retrospective cohort study used the 2016 and 2017 National Inpatient Sample databases. Patients included in the study had ICD-10 codes for CP and PDAC. The ethnic, socioeconomic, and racial backgrounds of patients with CP and PDAC were analyzed. Hospital admissions for CP was 29 per 100000, and 2890 (0.78%) had PDAC. Blacks [adjusted odds ratio (aOR) 1.13], men (aOR 1.35), age 40 to 59 (aOR 2.60), and being overweight (aOR 1.34) were significantly associated with CP (all with P < 0.01). In patients with CP, Whites (aOR 1.23), higher income, older age (aOR 1.05), and being overweight (aOR 2.40) were all significantly associated with PDAC (all with P < 0.01). Men (aOR 1.81) and Asians (aOR 15.19) had significantly increased mortality (P < 0.05). Hispanics had significantly increased hospital length of stay (aOR 5.24) (P < 0.05). Based on this large, nationwide analysis, black men between 40-59 years old and overweight are at significantly increased risk for admission with CP. White men older than 40 years old and overweight with higher income were found to have significant associations with CP and PDAC. This discrepancy may reflect underlying differences in healthcare access and utilization among different socioeconomic and ethno-racial groups.

The genetic risk factor CEL-HYB1 causes proteotoxicity and chronic pancreatitis in mice

Background & aimsThe CEL gene encodes the digestive enzyme carboxyl ester lipase. CEL-HYB1, a hybrid allele of CEL and its adjacent pseudogene CELP, is a genetic variant suggested to increase the risk of chronic pancreatitis (CP). Our aim was to develop a mouse model for CEL-HYB1 that enables studies of pancreatic disease mechanisms. MethodsWe established a knock-in mouse strain where the variable number of tandem repeat (VNTR) region of the endogenous mouse Cel gene was substituted with the mutated VNTR of the human CEL-HYB1 allele. Heterozygous and homozygous Cel-HYB1 mice and littermate wildtype controls were characterized with respect to pancreatic pathology and function. ResultsWe successfully constructed a mouse model with pancreatic expression of a humanized CEL-HYB1 protein. The Cel-HYB1 mice spontaneously developed features of CP including inflammation, acinar atrophy and fatty replacement, and the phenotype became more pronounced as the animals aged. Moreover, Cel-HYB1 mice were normoglycemic at age 6 months, whereas at 12 months they exhibited impaired glucose tolerance. Immunostaining of pancreatic tissue indicated the formation of CEL protein aggregates, and electron microscopy showed dilated endoplasmic reticulum. Upregulation of the stress marker BiP/GRP78 was seen in pancreatic parenchyma obtained both from Cel-HYB1 animals and from a human CEL-HYB1 carrier. ConclusionsWe have developed a new mouse model for CP that confirms the pathogenicity of the human CEL-HYB1 variant. Our findings place CEL-HYB1 in the group of genes that increase CP risk through protein misfolding-dependent pathways.