Chronic pancreatitis (CP) is a progressive and destructive inflammatory disorder of the pancreas. One of the most distressing features is pain, which occurs in ~90% of patients, about half of whom have constant pain, which is associated with increased hospitalization and lower quality of life. Since there are multiple pain etiologies and since no standardized method exists to assess pain in patients with CP, novel approaches are needed to better understand the mechanisms of pain in CP and how it can be appropriately treated. The North American Pancreatitis Study 2 (NAPS2) recruited, phenotyped, and obtained biospecimens from the largest US cohort of pancreatitis, and we have completed a genome-wide association study (GWAS) that includes 1,171 NAPS2 CP cases for whom detailed phenotypic pain data are available. We propose to analyze the NAPS2 data set and biospecimens (DNA, serum, pancreas tissue) to define genetic risks and potential mechanisms of constant pain, identify markers of inflammatory pain, and characterize clinical pain complexes that can guide patient management. We have already identified through the full and a nested GWAS 8 candidate genes for constant pain.
Aim 1 will determine whether these variants are associated with functional changes in genes associated with the constant pain phenotype. Targeted SNP genotyping and gene expression studies will be conducted, including mRNA studies and immunohistochemical staining in human samples.
Aim 2 will determine whether c-reactive protein (CRP) or cytokine biomarkers correlate with constant pain. Pain is an indicator of active inflammation, with pro-inflammatory cytokines increasing pain, and anti-inflammatory cytokines diminishing pain. We will test 500 NAPS2 samples for elevated CRP and 10 Th1/Th2 cytokines as biomarkers of inflammation. For positive controls we will include blood samples from 40 acute pancreatitis patients who remain hospitalized for > 4 days for pain or inflammation.
Aim 3 will apply machine-learning approaches to test for correlation of genotype, biomarkers, and morphology (obstruction) with quantitative measures of pain pattern, severity, and character as well as SF12 v2 quality of life scores (mental and physical) while controlling for sex, smoking, and alcohol. We anticipate that our machine learning approaches will provide decision rules for the proper classification of pain according to etiology worthy of formal testing in clinical trials. In addition, use of machine learning is anticipated to provide insight into pai mechanism by optimally linking the symptoms signatures, biomarkers, imaging studies, and genetics to complex mechanisms that are seen in patients with painful CP. The goal of this study is to use existing NAPS2 data and biospecimens to construct a framework for future clinical studies that test the effectiveness of personalized pain management based on our machine-learning-predicted etiology rather than symptoms alone.

Public Health Relevance

Chronic pancreatitis is a medical condition that is poorly understood. One of the most distressing factors is severe chronic pain, which develops in about half of all patients for no clear reason. We will carefully analyze all the clinical data, CT scan results, lifestyle factors, and selected genes from the largest study of chronic pancreatitis in th US to better understand the origin of pain in chronic pancreatitis. Identifying the underlying causes is an important step to providing effective treatment.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Serrano, Jose
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Machicado, Jorge D; Amann, Stephen T; Anderson, Michelle A et al. (2017) Quality of Life in Chronic Pancreatitis is Determined by Constant Pain, Disability/Unemployment, Current Smoking, and Associated Co-Morbidities. Am J Gastroenterol 112:633-642
Zator, Zachary; Whitcomb, David C (2017) Insights into the genetic risk factors for the development of pancreatic disease. Therap Adv Gastroenterol 10:323-336
Whitcomb, David C; Frulloni, Luca; Garg, Pramod et al. (2016) Chronic pancreatitis: An international draft consensus proposal for a new mechanistic definition. Pancreatology 16:218-24
Anderson, Michelle A; Akshintala, Venkata; Albers, Kathryn M et al. (2016) Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group. Pancreatology 16:83-94
Wilcox, C Mel; Yadav, Dhiraj; Ye, Tian et al. (2015) Chronic pancreatitis pain pattern and severity are independent of abdominal imaging findings. Clin Gastroenterol Hepatol 13:552-60; quiz e28-9