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Constant-severe pain in chronic pancreatitis is associated with genetic loci for major depression in the NAPS2 cohort

  • Original Article―Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

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.

Study

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.

Results

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 < 2.2 × 10− 16). Fifteen loci associated with constant-severe pain (p < 0.00001) were found to be in or near depression-associated genes including ROBO2, CTNND2, SGCZ, CNTN5 and BAIAP2. Three of these genes respond to antidepressant use (SGCZ, ROBO2, and CTNND2).

Conclusion

Depression is a major co-factor in the pain experience. This genetic predisposition to depression may have utility in counseling patients and in instituting early antidepressant therapy for pain management of pancreatitis patients. Prospective randomized trials are warranted.

Clinical trials registration

Clinicaltriasl.gov.# NCT01545167

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Abbreviations

AP:

Acute pancreatitis

BAIAP2-AS1 :

The BAIAP2 divergent transcript gene (or BAIAP2-DT)

BMI:

Body mass index

CMH:

Cochran–Mantel–Haenszel statistic

CP:

Chronic pancreatitis

CRF:

Case report form

CTNND2 :

The catenin delta 2 gene (or GT24; NPRAP)

DM:

Diabetes mellitus

EPI:

Exocrine pancreatic insufficiency

EA:

European ancestry

GWAS:

Genome-wide association study

LD:

Linkage disequilibrium

MAF:

Minor allele frequency

MCS:

Mental component summary

NAPS2:

North American Pancreatitis Study II

NDRI:

Antidepressant drug class of norepinephrine-dopamine reuptake inhibitors

OR:

Odds ratio

QOL:

Quality of life

RAP:

Recurrent acute pancreatitis

ROBO2 :

The roundabout guidance receptor 2 gene (or SAX3)

SGCZ :

The sarcoglycan zeta gene (or ZSG1)

SF-12:

Short form 12

SNP:

Single-nucleotide polymorphism

SSNRI:

Antidepressant drug class of serotonin and norepinephrine reuptake inhibitors

TIGAR-O:

Common risk and etiology list for pancreatitis including Toxic, Idiopathic, Genetic, Autoimmune, Recurrent Acute and Severe Acute pancreatitis, and Obstructive

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Acknowledgements

This research was partly supported by the NIDDK T32 DK063922-17 (DCW), NIH DK061451 (DCW), R21 DK098560 (DCW), U01 DK108306 (DCW, DY). This publication was also made possible in part by Grant Number UL1 RR024153 and UL1TR000005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research (University of Pittsburgh. PI, Steven E Reis, MD). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or NIH. The genotyping of the samples in this study were previously completed with the assistance of M. Michael Barmada PhD (deceased), additional phenotyped samples contributions by NAPS2 centers led by Michelle Anderson MD MS, Frank Burton MD (deceased), John Baillie MD MS (deceased), Peter Banks MD, Darwin Conwell MD, MS James DiSario MD, and Robert Hawes MD. Laboratory assistance of Kimberly Stello, Danielle Dwyer and staff of the Whitcomb Core laboratory was appreciated. Data collection was done with the assistance of the Epidemiology Data Center of the University of Pittsburgh (Stephen R. Wisniewski, PhD, director).

Author information

Author notes

  1. Gregory A. Coté

    Present address: Department of Medicine, Medical University of South Carolina, Charleston, SC, USA

  2. Samer Alkaade

    Present address: Mercy Clinic Gastroenterology, St. Louis, MO, USA

  3. Andres Gelrud

    Present address: GastroHealth, Miami, FL, USA

  4. Jessica LaRusch

    Present address: Ariel Precision Medicine, Pittsburgh, PA, USA

  5. Jorge D. Machicado

    Present address: Division of Gastroenterology and Hepatology, Mayo Clinic Health System, Eau Claire, WI, USA

  6. Thiruvengadam Muniraj

    Present address: Department of Medicine, Yale University Medical Center, New Haven, CT, USA

  7. Georgios I. Papachristou

    Present address: Department of Medicine, The Ohio State University, Columbus, OH, USA

  8. Joseph Romagnuolo

    Present address: Ralph H. Johnson VAMC, Charleston, SC, USA

  9. Bimaljit S. Sandhu

    Present address: St Mary’s Hospital, Richmond, VA, USA

Authors and Affiliations

  1. Department of Medicine, University of Pittsburgh, Room 401.4, 3708 Fifth Ave, Pittsburgh, PA, 15213, USA

    Ellyn Dunbar, Phil J. Greer, Randall Brand, Andres Gelrud, Jessica LaRusch, Jorge D. Machicado, Thiruvengadam Muniraj, Georgios I. Papachristou, Dhiraj Yadav & David C. Whitcomb

  2. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Ellyn Dunbar & David C. Whitcomb

  3. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Nadine Melhem

  4. Department of Medicine, St. Louis University, St. Louis, MO, USA

    Samer Alkaade

  5. North Mississippi Medical Center, Tupelo, MS, USA

    Stephen T. Amann

  6. Indiana University School of Medicine, Indianapolis, IN, USA

    Gregory A. Coté & Stuart Sherman

  7. Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA

    Christopher E. Forsmark

  8. Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

    Timothy B. Gardner

  9. Department of Medicine, University of Cincinnati, Cincinnati, OH, USA

    Andres Gelrud

  10. GI Associates, Milwaukee, WI, USA

    Nalini M. Guda

  11. Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA

    Michele D. Lewis

  12. Department of Medicine, Medical University of South Carolina, Charleston, SC, USA

    Joseph Romagnuolo

  13. Department of Medicine, Medical College of Virginia, Richmond, VA, USA

    Bimaljit S. Sandhu

  14. Department of Medicine, University of Alabama At Birmingham, Birmingham, AL, USA

    Charles M. Wilcox

  15. Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Vikesh K. Singh

  16. Department of Cell Biology and Molecular Physiology, University of Pittsburgh, Pittsburgh, PA, USA

    David C. Whitcomb

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  1. Ellyn Dunbar
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  2. Phil J. Greer
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Consortia

For the NAPS2 study group

Contributions

Conceptualization: ED, PJG, DCW; Methodology: ED, PJG, JL, DCW, DY; Formal analysis and investigation: ED, PJG, NM, SA, STA, RB, GAC, CEF, TBG, AG, NMG, JL, MDL, JDM, TM, GIP, JR, BSS, SS, CMW, DY, DCW; Writing—original draft preparation: ED, DCW; Writing—review and editing: all authors; Funding acquisition: DCW; Resources: Supervision: DCW.

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Correspondence to David C. Whitcomb.

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Supplementary Digital Content 1 Table S1: Drug Names; 2–6 Figs. 1–5: Zoom Plots; 7 Information: Depression Gene Information; 8 Table S2: Duration and Felt Blue (DOCX 6611 kb)

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Dunbar, E., Greer, P.J., Melhem, N. et al. Constant-severe pain in chronic pancreatitis is associated with genetic loci for major depression in the NAPS2 cohort. J Gastroenterol 55, 1000–1009 (2020). https://doi.org/10.1007/s00535-020-01703-w

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