Ellyn K Dunbar1,2, Phil J Greer1,3, Stephen T Amann4, Samer Alkaade5,6, Peter Banks7, Randall Brand1, Darwin L Conwell7,8, Christopher E Forsmark9, Timothy B Gardner10, Nalini M Guda11,12, Michele D Lewis13, Jorge D Machicado1,14, Thiruvengadam Muniraj1,15, Georgios I Papachristou1,8, Joseph Romagnuolo16,17, Bimaljit S Sandhu18,19, Stuart Sherman20, Adam Slivka1, C Mel Wilcox21, Dhiraj Yadav1, David C Whitcomb1,2,22. 1. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 2. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 3. Current Address: Ariel Precision Medicine, Pittsburgh, Pennsylvania, USA. 4. North Mississippi Medical Center, Tupelo, Mississippi, USA. 5. Department of Medicine, St. Louis University, St. Louis, Missouri, USA. 6. Current affiliation: Mercy Clinic Gastroenterology St. Louis, Missouri, USA. 7. Department of Medicine, Harvard University, Brigham and Woman's Hospital, Boston, Massachusetts, USA. 8. Current address: Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA. 9. Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA. 10. Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA. 11. Aurora St. Luke's Medical Center, GI Associates, Milwaukee, Wisconsin, USA. 12. Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA. 13. Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA. 14. Current address: Division of Gastroenterology and Hepatology, Mayo Clinic Health System, Eau Claire, Wisconsin, USA. 15. Current address: Department of Medicine, Yale University, New Haven, Connecticut, USA. 16. Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA. 17. Current address: Ralph H. Johnson VAMC, Charleston, South Carolina, USA. 18. Department of Medicine, Medical College of Virginia, Richmond, Virginia, USA. 19. Current address: St. Mary's Hospital, Richmond, Virginia, USA. 20. Department of Medicine, Indiana University, Indianapolis, Indiana, USA. 21. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. 22. Department of Cell Biology & Molecular Physiology, and Center for Pain Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Abstract
INTRODUCTION: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are progressive inflammatory syndromes with variable features. Pain is the primary feature that contributes to low physical and mental quality of life with a third of patients reporting severe pain. Pain experience is worsened by depression. Here, we tested the hypothesis that genetic risk of the psychiatric conditions of anxiety and post-traumatic stress disorder (PTSD) is associated with pain in CP and RAP + CP subjects. METHODS: The study cohort included phenotyped and genotyped RAP and CP patients from the North American Pancreatitis Study II of European Ancestry. Candidate genetic association studies were based on the absence of pain vs pain that is constant, constant-severe, or severe. Twenty-eight candidate genetic loci for anxiety and PTSD risk were identified in the literature and were the focus of this study. RESULTS: We identified 24 significant pain-associated single nucleotide polymorphisms within 13 loci across the 3 pain patterns in CP and RAP + CP (P < 0.002). Thirteen anxiety or PTSD genes were within these pain loci indicating nonrandom associations (P < 4.885 × 10-23). CTNND2 was associated with all pain categories and all pancreatitis etiologies. Implicated systems include neuronal signaling (HTR2A, DRD3, NPY, and BDNF), hypothalamic-pituitary-adrenal axis (NR3C1 and FKBP5), and cell-cell interaction (CTNND2 and THBS2). DISCUSSION: A component of constant and severe pain in patients with RAP and CP is associated with genetic predisposition to anxiety and PTSD. Identification of patients at risk eligible for trials of targeted treatment as a component of a multidisciplinary pain management strategy should be formally evaluated.
INTRODUCTION: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are progressive inflammatory syndromes with variable features. Pain is the primary feature that contributes to low physical and mental quality of life with a third of patients reporting severe pain. Pain experience is worsened by depression. Here, we tested the hypothesis that genetic risk of the psychiatric conditions of anxiety and post-traumatic stress disorder (PTSD) is associated with pain in CP and RAP + CP subjects. METHODS: The study cohort included phenotyped and genotyped RAP and CP patients from the North American Pancreatitis Study II of European Ancestry. Candidate genetic association studies were based on the absence of pain vs pain that is constant, constant-severe, or severe. Twenty-eight candidate genetic loci for anxiety and PTSD risk were identified in the literature and were the focus of this study. RESULTS: We identified 24 significant pain-associated single nucleotide polymorphisms within 13 loci across the 3 pain patterns in CP and RAP + CP (P < 0.002). Thirteen anxiety or PTSD genes were within these pain loci indicating nonrandom associations (P < 4.885 × 10-23). CTNND2 was associated with all pain categories and all pancreatitis etiologies. Implicated systems include neuronal signaling (HTR2A, DRD3, NPY, and BDNF), hypothalamic-pituitary-adrenal axis (NR3C1 and FKBP5), and cell-cell interaction (CTNND2 and THBS2). DISCUSSION: A component of constant and severe pain in patients with RAP and CP is associated with genetic predisposition to anxiety and PTSD. Identification of patients at risk eligible for trials of targeted treatment as a component of a multidisciplinary pain management strategy should be formally evaluated.
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