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
References
Mullady DK, Yadav D, Amann ST, et al. Type of pain, pain-associated complications, quality of life, disability and resource utilisation in chronic pancreatitis: a prospective cohort study. Gut. 2011;60:77–84.
Whitcomb DC, Larusch J, Krasinskas AM, et al. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet. 2012;44:1349–54.
Whitcomb DC, Frulloni L, Garg P, et al. Chronic pancreatitis: an international draft consensus proposal for a new mechanistic definition. Pancreatology. 2016;16:218–24.
Amann ST, Yadav D, Barmada MM, et al. Physical and mental quality of life in chronic pancreatitis: a case-control study from the North American Pancreatitis Study 2 cohort. Pancreas. 2013;42:293–300.
Cote GA, Yadav D, Abberbock JA, et al. Recurrent acute pancreatitis significantly reduces quality of life even in the absence of overt chronic pancreatitis. Am J Gastroenterol. 2018;113:906–12.
Machicado JD, Amann ST, Anderson MA, et al. Quality of life in chronic pancreatitis is determined by constant pain, disability/unemployment, current smoking, and associated co-morbidities. Am J Gastroenterol. 2017;112:633–42.
Whitcomb DC, North American Pancreatitis Study G. Pancreatitis: TIGAR-O version 2 risk/etiology checklist with topic reviews, updates, and use primers. Clin Transl Gastroenterol. 2019;10:e00027.
Zator Z, Whitcomb DC. Insights into the genetic risk factors for the development of pancreatic disease. Therap Adv Gastroenterol. 2017;10:323–36.
Masamune A, Kotani H, Sorgel FL, et al. Variants that affect function of calcium channel TRPV6 are associated with early-onset chronic pancreatitis. Gastroenterology. 2020;158:1626–41.
Goodarzi MO, Nagpal T, Greer P, et al. Genetic risk score in diabetes associated with chronic pancreatitis versus type 2 diabetes mellitus. Clin Transl Gastroenterol. 2019;10:e00057.
Bellin MD, Whitcomb DC, Abberbock J, et al. Patient and disease characteristics associated with the presence of diabetes mellitus in adults with chronic pancreatitis in the United States. Am J Gastroenterol. 2017;112:1457–65.
Rickels MR, Bellin M, Toledo FG, et al. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest 2012. Pancreatology. 2013;13:336–42.
Klein AP, Wolpin BM, Risch HA, et al. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. Nature communications. 2018;9:556.
Chen F, Childs EJ, Mocci E, et al. Analysis of heritability and genetic architecture of pancreatic cancer: a PanC4 study. Cancer Epidemiol Biomarkers Prev. 2019;28:1238–45.
Stoffel EM, McKernin SE, Brand R, et al. Evaluating susceptibility to pancreatic cancer: ASCO provisional clinical opinion. J Clin Oncol. 2019;37:153–64.
Shelton CA, Grubs RE, Umapathy C, et al. Impact of hereditary pancreatitis on patients and their families. J Genet Couns. 2020. https://doi.org/10.1002/jgc4.1221.
Whitcomb DC, Shelton C, Brand RE. Genetics and genetic testing in pancreatic cancer. Gastroenterology. 2015;149:1252–64.
Navratilova E, Morimura K, Xie JY, et al. Positive emotions and brain reward circuits in chronic pain. J Comp Neurol. 2016;524:1646–52.
Singh VV, Toskes PP. Medical therapy for chronic pancreatitis pain. Curr Gastroenterol Rep. 2003;5:110–6.
WHO. Depression [Web]. World Health Organization (2018). Available from: https://www.who.int/news-room/fact-sheets/detail/depression. Accessed 22 March 2018;2019
Otte C, Gold SM, Penninx BW, et al. Major depressive disorder. Nat Rev Dis Primers. 2016;2:16065.
Sullivan PF, Geschwind DH. Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders. Cell. 2019;177:162–83.
Howard DM, Adams MJ, Clarke TK, et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat Neurosci. 2019;22:343–52.
Postolache TT, Del Bosque-Plata L, Jabbour S, et al. Co-shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome. Am J Med Genet B Neuropsychiatr Genet. 2019;180:186–203.
Lee CH, Giuliani F. The role of inflammation in depression and fatigue. Front Immunol. 2019;10:1696.
Whitcomb DC, Yadav D, Adam S, et al. Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2). Pancreatology. 2008;8:520–31.
Yadav D, Hawes RH, Brand RE, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med. 2009;169:1035–45.
Wilcox CM, Sandhu BS, Singh V, et al. Racial differences in the clinical profile, causes, and outcome of chronic pancreatitis. Am J Gastroenterol. 2016;111:1488–96.
Conwell DL, Banks PA, Sandhu BS, et al. Validation of demographics, etiology, and risk factors for chronic pancreatitis in the usa: a report of the North American Pancreas Study (NAPS) Group. Dig Dis Sci. 2017;62:2133–40.
Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology. 2001;120:682–707.
Whitcomb DC. Hereditary pancreatitis: new insights into acute and chronic pancreatitis. Gut. 1999;45:317–22.
Stevens T, Conwell DL, Zuccaro G. Pathogenesis of chronic pancreatitis: an evidence-based review of past theories and recent developments. Am J Gastroenterol. 2004;99:2256–70.
Jeon CY, Whitcomb DC, Slivka A, et al. Lifetime drinking history of persons with chronic pancreatitis. Alcohol Alcohol. 2019;54:615–24.
Coté GA, Yadav D, Slivka A, Hawes RH, Anderson MA, Burton FR, Brand RE, Banks PA, Lewis MD, Disario JA, Gardner TB, Gelrud A, Amann ST, Baillie J, Money ME, O'Connell M, Whitcomb DC, Sherman S. Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis. Clin Gastroenterol Hepatol. 2011;9(3):266–73.
Wilcox CM, Yadav D, Tian Y, et al. Chronic pancreatitis pain pattern and severity are independent of abdominal imaging findings. Clin Gastroenterol Hepatol. 2015;13(3):552–e29.
Romagnuolo J, Talluri J, Kennard E, et al. Clinical profile, etiology, and treatment of chronic pancreatitis in North American women: analysis of a large multicenter cohort. Pancreas. 2016;45:934–40.
Phillips AE, LaRusch J, Greer P, et al. Known genetic susceptibility factors for chronic pancreatitis in patients of European ancestry are rare in patients of African ancestry. Pancreatology. 2018;18:528–35.
LaRusch J, Jung J, General IJ, et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014;10:e1004376.
Schneider A, Larusch J, Sun X, et al. Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis. Gastroenterology. 2011;140:162–71.
LaRusch J, Lozano-Leon A, Stello K, et al. The common chymotrypsinogen C (CTRC) variant G60G (C.180T) increases risk of chronic pancreatitis but not recurrent acute pancreatitis in a North American population. Clin Transl Gastroenterol. 2015;6:e68.
Lowe ME, Andersen DK, Caprioli RM, et al. Precision medicine in pancreatic disease-knowledge gaps and research opportunities: summary of a National institute of diabetes and digestive and kidney diseases workshop. Pancreas. 2019;48:1250–8.
Whitcomb DC. Primer on precision medicine for complex chronic disorders. Clin Transl Gastroenterol. 2019;10:e00067.
Shelton CA, Whitcomb DC (2020) Precision medicine for pancreatic diseases. Curr Opin Gastroenterol (in press).
McCarthy S, Das S, Kretzschmar W, et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016;48:1279–83.
Loh PR, Danecek P, Palamara PF, et al. Reference-based phasing using the haplotype reference consortium panel. Nat Genet. 2016;48:1443–8.
Durbin R. Efficient haplotype matching and storage using the positional Burrows-Wheeler transform (PBWT). Bioinformatics. 2014;30:1266–72.
Gill SC, Butterworth P, Rodgers B, et al. Validity of the mental health component scale of the 12-item Short-Form Health Survey (MCS-12) as measure of common mental disorders in the general population. Psychiatry Res. 2007;152:63–71.
Vilagut G, Forero CG, Pinto-Meza A, et al. The mental component of the short-form 12 health survey (SF-12) as a measure of depressive disorders in the general population: results with three alternative scoring methods. Value Health. 2013;16:564–73.
R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2019.
Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.
Buniello A, MacArthur JAL, Cerezo M, et al. The NHGRI-EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 2019;47:D1005–D10121012.
Pruim RJ, Welch RP, Sanna S, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336–7.
Imanishi M. Gapplin. 1.6.2 ed2019.
Bair MJ, Robinson RL, Katon W, et al. Depression and pain comorbidity: a literature review. Arch Intern Med. 2003;163:2433–45.
McIntosh AM, Hall LS, Zeng Y, et al. Genetic and environmental risk for chronic pain and the contribution of risk variants for major depressive disorder: a family-based mixed-model analysis. PLoS Med. 2016;13:e1002090.
Sheng J, Liu S, Wang Y, et al. The Link between Depression and Chronic Pain: Neural Mechanisms in the Brain. Neural Plast. 2017;2017:9724371-.
Balliet WE, Edwards-Hampton S, Borckardt JJ, et al. Depressive symptoms, pain, and quality of life among patients with nonalcohol-related chronic pancreatitis. Pain Res Treat. 2012;2012:978646.
Shah R, Haydek C, Mulki R, et al. Incidence and predictors of 30-day readmissions in patients hospitalized with chronic pancreatitis: a nationwide analysis. Pancreatology. 2018;18:386–93.
Fadista J, Manning AK, Florez JC, et al. The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants. Eur J Hum Genet. 2016;24:1202–5.
McIntosh AM, Sullivan PF, Lewis CM. Uncovering the genetic architecture of major depression. Neuron. 2019;102:91–103.
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).
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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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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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DOI: https://doi.org/10.1007/s00535-020-01703-w