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Background & Aims Idiopathic chronic pancreatitis (ICP) is the second most common subtype of CP. In 1994, researchers reported the bimodal age at onset of ICP symptoms: early onset ICP (EO-ICP; median age, 19.2 y) and late-onset ICP (LO-ICP; median age, 56.2 y). Ages of onset and clinical features of ICP differed from those of alcohol-related CP (ACP). However, variants in PRSS1 had not yet been associated with ICP. We reexamined ages of onset of ICP in a large, North American cohort of patients, and investigated the effects of genetic factors and alcohol use in patients with EO-ICP, LO-ICP, and ACP. Methods We performed a cross-sectional analysis of patients with CP of European ancestry enrolled in the North American Pancreatitis Study 2, a prospective study of 1195 patients with CP from 26 centers in the United States from August 2000 through December 2014. We compared age at onset of symptoms for 130 patients with CP who were lifetime abstainers from alcohol (61 patients with early onset and 69 patients with late onset), 308 light to moderate alcohol drinkers with CP, and 225 patients with ACP and heavy to very heavy alcohol use. DNA from available patients was analyzed for variants associated with CP in SPINK1, CFTR, and CTRC. The Kruskal–Wallis test was used to compare continuous variables across groups and based on genetic variants. Results Median ages at onset of symptoms were 20 years for patients with EO-ICP and no alcohol use, 58 years for patients with LO-ICP and no alcohol use, 47 years for light to moderate alcohol drinkers with CP, and 44 years for patients with ACP. A higher proportion of patients with EO-ICP had constant pain (65%) than patients with LO-ICP (31%) (P = .04). A higher proportion of patients with ACP had pseudocysts (43%) than patients with EO-ICP (11%) (P = .001). A higher proportion of patients with EO-ICP had pathogenic variants in SPINK1, CFTR, or CTRC (49%) than patients with LO-ICP (23%), light to moderate alcohol drinking with CP (26%), or ACP (23%) (P = .001). Among patients with variants in SPINK1, those with EO-ICP had onset of symptoms at a median age of 12 years, and light to moderate alcohol drinkers with CP had an age at onset of 24 years. Among patients with variants in CFTR, light to moderate alcohol drinkers had an age at onset of symptoms of 41 years, but this variant did not affect age at onset of EO-ICP or ACP. Conclusions We confirmed previously reported ages at onset of symptoms for EO-ICP and LO-ICP in a North American cohort. We found differences in clinical features among patients with EO-ICP, LO-ICP, and ACP. Almost half of patients with EO-ICP have genetic variants associated with CP, compared with approximately one quarter of patients with LO-CP or ACP. Genetic variants affect ages at onset of symptoms in some groups.

Pain is the most debilitating symptom of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) and often requires chronic opioids or total pancreatectomy with islet autotransplantation to manage. Pain is a complex experience that can be exacerbated by depression and vice versa. Our aim was to test the hypothesis that depression-associated genes are associated with a constant-severe pain experience in RAP/CP patients. A retrospective study was done using North American Pancreatitis Study II (NAPS2) genotyped RAP and CP patients with completed case report forms (n = 1,357). Subjects were divided based on pattern of pain and pain severity as constant-severe pain (n = 787) versus not constant-severe pain (n = 570) to conduct a nested genome-wide association study. The association between reported antidepressant medication use and depression gene loci was tested. Constant-severe pain was reported in 58% (n = 787) of pancreatitis patients. No differences in sex or alcohol consumption were found based on pain severity. Antidepressant use was reported in 28% (n = 223), and they had lower SF-12 mental quality of life (MCS, p

BACKGROUND: Multiple pathogenic genetic variants are associated with pancreatitis in patients of European (EA) and Asian ancestries, but studies on patients of African ancestry (AA) are lacking. We evaluated the prevalence of known genetic variations in African-American subjects in the US. METHODS: We studied prospectively enrolled controls (n = 238) and patients with chronic (CP) (n = 232) or recurrent acute pancreatitis (RAP) (n = 45) in the NAPS2 studies from 2000–2014 of self-identified AA. Demographic and phenotypic information was obtained from structured questionnaires. Ancestry and admixture were evaluated by principal component analysis (PCA). Genotyping was performed for pathogenic genetic variants in PRSS1, SPINK1, CFTR and CTRC. Prevalence of disease-associated variants in NAPS2 subjects of AA and EA was compared. RESULTS: When compared with CP subjects of EA (n = 862), prevalence of established pathogenic genetic variants was infrequent in AA patients with CP, overall (29 vs. 8.19%, OR 4.60, 95% CI 2.74–7.74, p < 0.001), and after stratification by alcohol etiology (p < 0.001). On PCA, AA cases were more heterogeneous but distinct from EA subjects; no difference was observed between AA subjects with and without CP-associated variants. Of 19 A A patients with CP who had pathogenic genetic variants, 2 had variants in PRSS1 (R122H, R122C), 4 in SPINK1 (all N34S heterozygotes), 12 in CFTR (2 CFTR(sev), 9 CFTR(BD), 1 compound heterozygote with CFTR(sev) and CFTR(BD)), and 1 in CTRC (R254W). CONCLUSION: Pathogenic genetic variants reported in EA patients are significantly less common in AA patients. Further studies are needed to determine the complex risk factors for AA subjects with pancreatitis.

Introduction: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM. We approached this question from a unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM. Methods: We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin. Results: The mean GRS was identical between 321 subjects with CP-DM and 423 subjects with T2DM (66.53 vs 66.42, P = 0.95), and the GRS of both diabetic groups was significantly higher than that of nondiabetic controls (n = 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreas-specific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM. Discussion: Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.

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

OBJECTIVES A risk association has been observed between non-O blood groups and pancreatic adenocarcinoma. Chronic pancreatitis also increases risk for pancreatic cancer, raising questions as to whether non-O blood groups are a risk for chronic pancreatitis and whether the pathophysiologic pathways are linked. Our goal was to determine whether ABO blood group may affect the risk of chronic pancreatitis. METHODS The study cohort included chronic pancreatitis patients (n = 499) and healthy controls (n = 631) from the North American Pancreatitis Study 2 study. Genotyping was performed using Sequenom assay of rs8176746 A/C and rs505922 C/T to classify participants into ABO blood groups. RESULTS O blood group was nonsignificantly more common among cases (44.7% vs 42.0%; P = 0.36), particularly among cases with alcohol-related chronic pancreatitis (49.3% vs 42%; P = 0.060). Alcoholic patients without coexisting high-risk PRSS1, CFTR, or SPINK1 variants had a significant overrepresentation of O blood type when compared with controls (odds ratio, 1.54; 95% confidence interval, 1.09-2.17; P = 0.01). CONCLUSIONS A, B, and AB blood groups were not associated with a greater likelihood of having chronic pancreatitis and may decrease the risk of chronic pancreatitis in individuals who are very heavy drinkers. These results suggest that the mechanism linking non-O blood type with pancreatic pathology is specific to carcinogenesis.

Background:Etiologies of recurrent pancreatitis include anatomical anomalies, hereditary, metabolic and autoimmune disorders. A significant number of patients remain with a diagnosis of idiopathic pancreatitis. The advent of genetic analysis and electrophysiologic testing may further assist in the diagnostic process. Evidence has shown that specific genetic mutations in the cationic trypsinogen gene PRSS1 and the SPINK1 gene for pancreatic secretory trypsin inhibitor cause pancreatitis; furthermore cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations have been associated with pancreatitis. Aims :To present the work-up of patients with recurrent pancreatitis referred for genetic analysis and electrophysiological testing. Methods : Patients with recurrent, acute pancreatitis with no known etilology were referred to the Electrophysiology Laboratory, Division of Pediatric GI at Hadassah University Hospital for PRSS1 and SPINK1 gene mutations as well as evaluation of CFTR function by Nasal Potential Difference (NPD) testing. Results: A total of 42 patients with recurrent pancreatitis were evaluated; the mean age was 21 years ±14.9 years (range 2-54 yrs). A third (33%) of the patients was of Ashkenazi ancestry, 41% of mainly Sephardic ancestry, 24% of Arab ancestry and the remaining 2% of other ethnic background. There was a family history in 8 patients. The patients had a mean of 4 episodes (range 1-25). 6 (14%) patients showed PRSS1 genemutation (p.R112H and p.K23R) including 2 sets of siblings of Georgian Jewish ancestry with p.K23R. No SPINK1 mutation was found in the 26 patients submitted for testing. 3 patients out of 21 submitted for CFTR gene testing showed mutations (5T, F508del/p.L997F and D1152H/5T). 26 (61%) patients underwent sweat testing, with 13 patients with results >40 mmol/L. 35 (83%) patients had Nasal Potential Difference testing, 4 (11.5%) with abnormal results: 3 had sweat chloride>60mmol/L with no CFTR mutations found but one patient with D1152H/5T had a sweat test of 30 mmol/L. None of the 6 patients with PRSS1 gene mutation showed any concomitant CFTR dysfunction (by NPD or sweat testing) or gene mutation.Conclusion:This is the first study on recurrent pancreatitis in Israel examining both the presence of susceptibility gene mutations for pancreatitis and CFTR dysfunction. A prospective study with a larger number of patients may further clarify the impact of genetic mutations and CFTR dysfunction on the clinical presentation and outcome of recurrent pancreatitis.

Background:Etiologies of recurrent pancreatitis include anatomical anomalies, hereditary, metabolic and autoimmune disorders. A significant number of patients remain with a diagnosis of idiopathic pancreatitis. The advent of genetic analysis and electrophysiologic testing may further assist in the diagnostic process. Evidence has shown that specific genetic mutations in the cationic trypsinogen gene PRSS1 and the SPINK1 gene for pancreatic secretory trypsin inhibitor cause pancreatitis; furthermore cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations have been associated with pancreatitis. Aims :To present the work-up of patients with recurrent pancreatitis referred for genetic analysis and electrophysiological testing. Methods : Patients with recurrent, acute pancreatitis with no known etilology were referred to the Electrophysiology Laboratory, Division of Pediatric GI at Hadassah University Hospital for PRSS1 and SPINK1 gene mutations as well as evaluation of CFTR function by Nasal Potential Difference (NPD) testing. Results: A total of 42 patients with recurrent pancreatitis were evaluated; the mean age was 21 years ±14.9 years (range 2-54 yrs). A third (33%) of the patients was of Ashkenazi ancestry, 41% of mainly Sephardic ancestry, 24% of Arab ancestry and the remaining 2% of other ethnic background. There was a family history in 8 patients. The patients had a mean of 4 episodes (range 1-25). 6 (14%) patients showed PRSS1 genemutation (p.R112H and p.K23R) including 2 sets of siblings of Georgian Jewish ancestry with p.K23R. No SPINK1 mutation was found in the 26 patients submitted for testing. 3 patients out of 21 submitted for CFTR gene testing showed mutations (5T, F508del/p.L997F and D1152H/5T). 26 (61%) patients underwent sweat testing, with 13 patients with results >40 mmol/L. 35 (83%) patients had Nasal Potential Difference testing, 4 (11.5%) with abnormal results: 3 had sweat chloride>60mmol/L with no CFTR mutations found but one patient with D1152H/5T had a sweat test of 30 mmol/L. None of the 6 patients with PRSS1 gene mutation showed any concomitant CFTR dysfunction (by NPD or sweat testing) or gene mutation.Conclusion:This is the first study on recurrent pancreatitis in Israel examining both the presence of susceptibility gene mutations for pancreatitis and CFTR dysfunction. A prospective study with a larger number of patients may further clarify the impact of genetic mutations and CFTR dysfunction on the clinical presentation and outcome of recurrent pancreatitis.

Background:Etiologies of recurrent pancreatitis include anatomical anomalies, hereditary, metabolic and autoimmune disorders. A significant number of patients remain with a diagnosis of idiopathic pancreatitis. The advent of genetic analysis and electrophysiologic testing may further assist in the diagnostic process. Evidence has shown that specific genetic mutations in the cationic trypsinogen gene PRSS1 and the SPINK1 gene for pancreatic secretory trypsin inhibitor cause pancreatitis; furthermore cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations have been associated with pancreatitis. Aims :To present the work-up of patients with recurrent pancreatitis referred for genetic analysis and electrophysiological testing. Methods : Patients with recurrent, acute pancreatitis with no known etilology were referred to the Electrophysiology Laboratory, Division of Pediatric GI at Hadassah University Hospital for PRSS1 and SPINK1 gene mutations as well as evaluation of CFTR function by Nasal Potential Difference (NPD) testing. Results: A total of 42 patients with recurrent pancreatitis were evaluated; the mean age was 21 years ±14.9 years (range 2-54 yrs). A third (33%) of the patients was of Ashkenazi ancestry, 41% of mainly Sephardic ancestry, 24% of Arab ancestry and the remaining 2% of other ethnic background. There was a family history in 8 patients. The patients had a mean of 4 episodes (range 1-25). 6 (14%) patients showed PRSS1 genemutation (p.R112H and p.K23R) including 2 sets of siblings of Georgian Jewish ancestry with p.K23R. No SPINK1 mutation was found in the 26 patients submitted for testing. 3 patients out of 21 submitted for CFTR gene testing showed mutations (5T, F508del/p.L997F and D1152H/5T). 26 (61%) patients underwent sweat testing, with 13 patients with results >40 mmol/L. 35 (83%) patients had Nasal Potential Difference testing, 4 (11.5%) with abnormal results: 3 had sweat chloride>60mmol/L with no CFTR mutations found but one patient with D1152H/5T had a sweat test of 30 mmol/L. None of the 6 patients with PRSS1 gene mutation showed any concomitant CFTR dysfunction (by NPD or sweat testing) or gene mutation.Conclusion:This is the first study on recurrent pancreatitis in Israel examining both the presence of susceptibility gene mutations for pancreatitis and CFTR dysfunction. A prospective study with a larger number of patients may further clarify the impact of genetic mutations and CFTR dysfunction on the clinical presentation and outcome of recurrent pancreatitis.