Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.

Background Chronic pancreatitis (CP) has a profound independent effect on quality of life (QOL). Our aim was to identify factors that impact the QOL in CP patients. Methods We used data on 1,024 CP patients enrolled in the three NAPS2 studies. Information on demographics, risk factors, co-morbidities, disease phenotype and treatments was obtained from responses to structured questionnaires. Physical (PCS) and mental (MCS) component summary scores generated using responses to the Short Form-12 (SF-12) survey were used to assess QOL at enrollment. Multivariable linear regression models determined independent predictors of QOL. Results Mean PCS and MCS scores were 36.7±11.7 and 42.4±12.2, respectively. Significant (p<0.05) negative impact on PCS scores in multivariable analyses was noted due to constant mild-moderate pain with episodes of severe pain or constant severe pain (10 points), constant mild-moderate pain (5.2), pain-related disability/unemployment (5.1), current smoking (2.9 points) and medical co-morbidities. Significant (p<0.05) negative impact on MCS scores was related to constant pain irrespective of severity (6.8-6.9 points), current smoking (3.9 points) and pain-related disability/unemployment (2.4 points). In women, disability/unemployment resulted in an additional reduction 3.7 point reduction in MCS score. Final multivariable models explained 27% and 18% of the variance in PCS and MCS scores, respectively. Etiology, disease duration, pancreatic morphology, diabetes, exocrine insufficiency and prior endotherapy/pancreatic surgery had no significant independent effect on QOL. Conclusion Constant pain, pain-related disability/unemployment, current smoking, and concurrent co-morbidities significantly affect the QOL in CP. Further research is needed to identify factors impacting QOL not explained by our analyses.

CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<<0.0001). WNK1-SPAK pathway-activated increases in CFTR bicarbonate permeability are altered by CFTRBD variants through multiple mechanisms. CFTRBD variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.

Background & Aims Chronic pancreatitis is characterized by inflammation, atrophy, fibrosis with progressive ductal changes, and functional changes that include variable exocrine and endocrine insufficiency and multiple patterns of pain. We investigated whether abdominal imaging features accurately predict patterns of pain. Methods We collected data from participants in North American Pancreatitis Study 2 Continuation and Validation, a prospective multicenter study of patients with chronic pancreatitis performed at 13 expert centers in the United States from July 2008 through March 2012. Chronic pancreatitis was defined based on detection of characteristic changes by cross-sectional abdominal imaging, endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography, or histology analyses. Patients were asked by a physician or trained clinical research coordinator if they had any abdominal pain in the year before enrollment; those that responded “yes” were asked to select from a list of 5 pain patterns. Using these patterns, we classified patients’ pain based on timing and severity. Abnormal pancreatitis-associated features on abdominal imaging were recorded using standardized case report forms. Results Data were collected from 518 patients (mean age, 52±14.6 years; 55% male; and 87.6% white). The most common physician-identified etiologies were alcohol (45.8%) and idiopathic (24.3%); 15.6% of patients reported no abdominal pain in the year before enrollment. The most common individual pain pattern was described as constant mild pain with episodes of severe pain, reported in 45% of patients. The most common imaging findings included pancreatic ductal dilatation (68%), atrophy (57%), and calcifications (55%). Imaging findings were categorized as obstructive for 20% and inflammatory for 25% of cases. The distribution of individual imaging findings was similar among patients with different patterns of pain. The distribution of pain patterns did not differ among clinically relevant groups of imaging findings. Conclusions Mechanisms that determine patterns and severity of pain in patients with chronic pancreatitis are largely independent of structural variants observed by abdominal imaging techniques. Pancreas-relevant quantitative and qualitative pain measures should be included in the evaluation of patients with chronic pancreatitis, to assess pain severity independently of imaging findings.

OBJECTIVES: Diabetes mellitus (DM) is a common complication of chronic pancreatitis (CP). Past studies for DM risk factors in CP have been limited to single centers or highly focused on a single etiology such as alcoholic or hereditary disease. We studied risk factors for DM in a large population of patients with CP of all etiologies enrolled in the North American Pancreatitis 2 studies. METHODS: Participants (1,171) with CP (n =383 with DM, n =788 without DM) were enrolled prospectively from 26 participating centers. Questionnaires were completed by patients and physicians in a cross-sectional assessment. Patient demographics and disease characteristics were compared for CP with DM vs. without DM. Logistic regression was performed to assess the variables associated with DM diagnosis in a multivariable model. RESULTS: Diabetics were more likely to be black (P =0.02), overweight, or obese (P <0.001), and with a family history of DM (P =0.0005). CP patients with DM were more likely to have pancreatic calcifications (63% vs. 54%, P =0.002), atrophy (44% vs. 32%, P <0.0001), and prior pancreas surgery (26.9% vs. 16.9%, P <0.0001). In multivariate logistic regression modeling, the strongest risk factors for DM were obesity (odds ratio (OR) 2.8, 95% confidence interval (CI) 1.9, 4.2) and exocrine insufficiency (OR 2.4, 95% CI 1.8, 3.2). CONCLUSIONS: In this large multicenter cohort of patients with CP, exocrine insufficiency, calcifications, and pancreas surgery conveyed higher odds of having DM. However, the traditional ‘type 2 DM’ risk factors of obesity and family history were similarly important in conveying risk for DM.