Pancreatitis is an inflammatory syndrome that can become chronic, resulting in irreversible destruction of the pancreas with variable levels of fibrosis, diabetes mellitus, exocrine pancreatic insufficiency (EPI), and abdominal pain (1–3). The complex etiology of acute pancreatitis (AP), recurrent AP (RAP), and chronic pancreatitis (CP) is associated with metabolic and toxic factors such as smoking, alcohol use, hypertriglyceridemia, hypercalcemia, obstructive etiologies, and genetic factors such as variants in or near CASR, CEL, CFTR, CLDN2, CPA1, CTRC, PRSS1, SPINK1, TRPV6, and UBR1 among other genes (4–6). Additional environmental factors and genetic variants also increase patients' risk of secondary complications such as diabetes (7–9) and pancreatic cancer (10–14). AP and RAP typically occur before progressing to CP (1).
Severe, constant pain, a symptom seen in 1 in 3 CP patients, is the major driver of low quality of life (QOL) in these patients (1,15–18). However, even at the early stages of pancreatitis, pain negatively impacts physical and mental health and QOL (15–17). Thus, the detriment in mental QOL in CP is not fully explained by pain alone and may be related, in part, to psychological determinants. Similarly, the reason for the variability of the pain experience by pancreatitis patients is unknown, but it may be influenced by a genetic predisposition to psychiatric disorders, given that psychiatric disorders and pain disorders often co-occur (19). In fact, depression and anxiety are common in CP patients (18,20).
Both children and adults with chronic abdominal pain commonly report comorbid psychological distress and trauma (21). It is plausible that pain associated with a pancreatitis attack could be a sufficient stressor to induce psychopathology in genetically at-risk patients (18). Existing mental disorders could worsen and be worsened by the pain of the pancreatitis attack in a vicious cycle (19,22,23). We have previously identified depression risk genes in pancreatitis patients with constant-severe pain; therefore, the focus of this investigation was on anxiety and post-traumatic stress disorder (PTSD) (23,24).
The effectiveness of management for pain and poor QOL in patients with pancreatitis is often poor (25–27). Recognition of the role of psychiatric risk in the pain experience may help develop more effective pain management for pancreatitis patients. To test the hypothesis that pain is associated with genetic risk loci for anxiety and PTSD, we investigated patients in the deeply phenotyped and genotyped North American Pancreatitis Study II (NAPS2) cohorts.
The NAPS2 cohort represents 3 sequential, cross-sectional, case-control studies of RAP and CP as previously described (28–30). Standardized questionnaires were used for data collection, and single nucleotide polymorphism (SNP) arrays (Illumina HumanOmniExpress BeadChip and HumanCoreExome) were used for genotyping (2), with supplemental, targeted genotyping as previously described (24,31). The subset of patients used for this analysis from the NAPS2 cohort was CP (N = 818) and RAP + CP (N = 1,277) subjects of European ancestry (EA). To reduce heterogeneity, the small sample of NAPS2 patients not of EA was excluded.
Pain categories and quality of life
Patterns of pancreatitis pain were defined following the Mullady 6-category severity-frequency classification system with O = no pain; A = episodes of mild pain; B = constant mild to moderate pain; C = episodes of severe pain; D = constant mild and episodes of severe pain; and E = constant-severe pain during the year before recruitment (1). Subjects responding with B, D, or E were classified as constant pain, subjects responding with C, D, and E were classified as severe pain, and subjects with D and E were constant-severe pain.
Anxiety and PTSD were not directly measured in the patient questionnaires; however, a mental component summary (MCS) score was calculated using responses from the Short-Form 12 (17). The MCS is defined as a measure of mental QOL, with higher scores correlating with better QOL and a score of 50 representing average health status (1,17). The MCS has previously been used as an indicator of mental health and measure of depressive disorders (24,32,33). Thus, we used a lower than average MCS as a proxy indicator of poor mental health as had been performed previously for depression (24).
Demographic and phenotypic data for patients in each pain category were compiled and analyzed using R version 3.6.2 (34). Univariate comparisons were performed based on demographic variables using the Pearson χ2 test for categorical data and the t test for continuous data. Two-tailed P values < 0.05 were considered statistically significant (Tables 1–6) (34).
Two subsets of patients were tested independently, 1 group labeled RAP + CP, included both RAP patients and CP patients, and the other comprised only patients with CP. All patients were classified as case or control based on the presence or absence of specific pain endophenotypes. A total of 6 studies were conducted looking at each of the 3 pain categories described above within both categories of pancreatitis patients. Both categories were used to compensate for a possible power reduction from assuming similarities of RAP and CP, although RAP is a part of the CP pathogenesis and to increase sample sizes (1,2). A sample of only RAP patients (N = 453) from NAPS2, and used in the RAP + CP group, was used to replicate major gene associations (see Tables S1 and S2, Supplemental Digital Content 1, http://links.lww.com/AJG/C92, which reports results from replication analysis).
A literature search was conducted in the summer of 2020 to compile a noncomprehensive list of candidate, autosomal risk genes for anxiety and PTSD (see Table S3, Supplemental Digital Content 2, http://links.lww.com/AJG/C93 for a list of candidate genes). These are genes implicated in or suggested as being associated with anxiety and/or PTSD, and genes also associated with depression or antidepressant response are labeled in Table S3 (Supplemental Digital Content 2, http://links.lww.com/AJG/C93 for a list of candidate genes). As a supplemental, the same candidate gene approach was repeated using a list of genes reported for anxiety and PTSD in the GWAS Catalog (see Tables S4 and S5, Supplemental Digital Content 3, http://links.lww.com/AJG/C94, which reports gene candidate results using the Genome Wide Association Study [GWAS] Catalog) (35).
Genetic data analysis
The genetic analysis was constructed as a candidate gene review using data from pancreatitis subjects similar to what was performed previously with depression (24). This candidate gene review was conducted using PLINK 1.9 software (36). Quality control methods for SNP data have been previously reported (2,24). Data were fit to a logistic regression to test for associations. The analysis was restricted to the list of candidate genes with a border of 50 kilobases (kb) added to each gene in PLINK 1.9. Because 28 gene regions instead of the whole genome were tested, the level of significance was relaxed to P < 0.002 (37,38). To control for ancestry, the first 4 principal components of ancestry were included as covariates. Additional covariates were age, sex, body mass index, and a variable to control for differences across SNP chips. The minor allele frequency threshold was set to 0.01.
SNPs meeting the required significance threshold were then combined into groups (likely haplotypes) based on linkage disequilibrium (±250 kb from index SNP, r2 > 0.5) in PLINK 1.9 (36). The lead SNPs (P ≤ 0.002) were annotated with genes within the borders of these linkage disequilibrium regions based on genome build GRCh37/hg19.
The minor allele frequency for the lead SNPs was calculated using PLINK 1.9 (Table 7) (36). Finally, GTEx (https://gtexportal.org/home/) was queried to determine whether any of the lead SNPs were also expression quantitative trait loci (eQTLs) (see Table S6, Supplemental Digital Content 4, http://links.lww.com/AJG/C95, which reports eQTLs) (39).
We used an online exact hypergeometric probability calculator to test the probability that the anxiety/PTSD gene loci were associated with pancreatitis pain loci by chance alone (40).
All 6 tested categories of disease status and pain pattern show that higher pain levels are all significantly associated with lower average age (P < 1 × 10−5) (Tables 1–6). In addition, higher pain levels are all significantly associated with lower mental QOL scores (P < 1 × 10−5). Individually, constant pain is associated with smoking (P = 0.0027) and EPI (P = 0.0009) in CP patients and with sex (P = 0.047), smoking (P = 6.13 × 10−5), EPI (P < 1 × 10−5), and diabetes (P = 0.03) in RAP + CP patients. Constant-severe pain is associated with smoking (P = 0.0018) and EPI (P = 0.0085) in CP patients and sex (P = 0.028), smoking (P = 0.0002), and EPI (P = 2.24 × 10−5) in RAP + CP patients. Finally, severe pain in CP is associated only with younger age (P < 1 × 10−5) and MCS (P < 1 × 10−5), while severe pain in RAP + CP patients is associated with smoking (P = 0.0065) and EPI (P = 0.022).
Candidate anxiety/PTSD genes associated with pain in CP/RAP + CP
Candidate gene studies were conducted within CP and RAP + CP patients across the 3 pain phenotypes. Resultant odds ratios (ORs), 95% confidence intervals, standard error, and P values for the 24 unique lead SNPs representing 13 loci across the 6 tested categories are reported in Table 7. The biological function of these known anxiety/PTSD gene products and associated systems is described below.
CTNND2 was the anxiety and/or PTSD candidate gene most commonly associated with the various pain categories and was previously associated with depression (24). In addition, several genes have multiple loci with different effects. The ORs associated with specific SNPs within different loci suggest that some are protective (OR < 1) and others risk (OR > 1) for worse pain experience in pancreatitis, suggesting complex gene expression regulatory mechanism. Pain and anxiety/PTSD risk SNPs in DRD3 are associated with constant pain in the CP category, but we also identified an SNP that was protective for severe pain in the RAP + CP category.
The probability that these loci for psychiatric disorder genes overlapped with loci for severe pancreatic pain was tested. The probability that the loci were shared by chance alone was very low (P < 4.885 × 10−23), indicating a statistically significant association.
Of the 24 lead SNPs, 6 have reported eQTLs from GTEx (39) (Table 7, see Table S6, Supplemental Digital Content 4, http://links.lww.com/AJG/C95, which reports eQTLs). The fact that these SNPs are seen in a variety of tissues indicates that the function of these genes is not pancreas-specific and reflects secondary disorders that make the experience of pancreatic disease worse.
The poor QOL experienced by many patients with pancreatitis is linked to the pain experience, which is affected by pain signaling, central processing, and the emotional response to those signals (1,15–17,41). We previously noted that symptoms of depression in RAP and CP are associated with constant-severe pain and genetic loci containing depression risk genes (24). We extended the findings of genetic predisposition to depression to investigate genetic predisposition to anxiety and PTSD and identified several candidate genes for anxiety and PTSD that deserve further targeted studies.
Both anxiety and PTSD interfere with daily life and relationships. A common model for understanding the variable etiology of these psychiatric disorders is “diathesis-stress” or rather genes and stress (23,42). This model predicts that after a combination of genes and outside stressors reaches a threshold, stress-related psychopathology emerges (23).
Generalized anxiety disorder (GAD) is characterized by excessive and uncontrolled worry that is not appropriate to the actual risk posed by a stimulus or in the absence of the stimulus (42). In addition to exposure to stress early in life, dysregulation of the hypothalamic-pituitary-adrenal axis also plays a role in anxiety disorders (42,43). GAD overlaps phenotypically and is comorbid with other stress-related disorders (such as other anxiety disorders and depression) (42). Twin studies produced a heritability estimate of 30%–50% (23,42). About two-thirds of children experiencing chronic pain also exhibit anxiety, and ∼30%–60% of patients with chronic pain will experience anxiety (22,44). Patients with chronic pain and anxiety tend not to respond well to treatment of their pain (22,44). One study even showed that although children with anxiety and pain were more likely to adhere to cognitive behavioral therapy for their pain, they were less likely to respond to it than other children with pain (44).
Post-traumatic stress disorder typically occurs in some individuals after experiencing traumatic events (23). PTSD is characterized by 4 hallmark symptoms: hyperarousal or reactivity, re-experiencing of the trauma, poor mood and thoughts related to the trauma, and avoidance of stimuli related to the trauma (23). Twin studies have shown that both exposure to trauma (combat) and the symptoms of PTSD are heritable (23). In addition, PTSD can increase pain perception (45).
These findings further expand the opportunities to improve patient care through precision medicine (46). Clinicians typically find it difficult to effectively treat CP pain because of the lack of precise therapies to relieve the different etiologies and severity patterns of pain in pancreatitis patients. In addition, the regulatory pressure to avoid opiates adds another challenge. The possibility of identifying pain-predominant symptoms linked to genetic risk of GAD, PTSD, or depression at the point-of-care (including rural communities) provides a new precision medicine option for selecting specific medications for individual patients, educating them about how these psychological tendencies affect pain perception and QOL, and referring them for adjunctive therapy(ies) such as cognitive behavioral therapy that targets the specific aspect of pain. However, randomized, double blind, placebo-controlled trials are needed to determine the correlation between the genetic predictions and the utility of specific psychotropic medications and the magnitude of the effects, with and without additional psychiatric interventions.
The limitations include relatively small sample size, including only people of EA, and lack of psychiatric phenotypic data (24). An additional limitation of this study may be a nonexhaustive candidate gene list (47). The candidate gene list was intended to capture the more established loci for anxiety and PTSD. However, we used a tool using exact hypergeometric probability to determine that the overlap (n = 15) of our candidate genes (n = 28) with pain genes (n = 315) is not by random chance alone (P < 4.885 × 10−23, 30,000 total genes) (40). Refer to the Tables S4 and S5 (Supplemental Digital Content 3, http://links.lww.com/AJG/C94), which reports gene candidate results using the GWAS Catalog for more exhaustive results using genes reported in the GWAS Catalog as being associated with anxiety and/or PTSD (35).
Several established genes associated with anxiety and PTSD are also associated with pain in pancreatitis. Many of these genes are involved with dopamine biology: DRD3, BDNF, SLC6A3, and NPY. Other pathways that these candidate genes are associated with include neuronal signaling, prepulse inhibition, hypothalamic-pituitary-adrenal axis, G protein–coupled receptor signaling, and cell-cell interaction (see Table 8 and Supplemental Digital Content 5, http://links.lww.com/AJG/C96 for a discussion of the significant candidate genes). The cell-cell interaction gene CTNND2 has shown significant associations across all pain categories in CP and RAP + CP patients. These associations to pain phenotypes were also replicated in our cohort, using only RAP patients (see Tables S1 and S2, Supplemental Digital Content 1, http://links.lww.com/AJG/C92, which reports results from replication analysis). Pain in pancreatitis is subjective and a complex symptom. It is not predictably responsive to current therapies and has a significant impact on QOL. As we showed previously with depression, identifying patients at risk of psychiatric disorders may be beneficial in recommending alternative pain therapies (24). Further studies into genotypic and phenotypic associations of pain and mental health are warranted.
CONFLICTS OF INTEREST
Guarantor of the article: David C. Whitcomb, MD, PhD.
Specific author contributions: conceptualization: E.K.D., P.J.G., and D.C.W. Methodology: E.K.D., P.J.G., D.C.W., and D.Y. Formal analysis and investigation: E.K.D., P.J.G., S.T.A., P.B., R.B., D.L.C., C.E.F., T.B.G., N.M.G., M.D.L., J.D.M., T.M., G.I.P., J.R., B.S.S., S.S., A.S., C.M.W., D.Y., and D.C.W. Writing—original draft preparation: E.K.D. and D.C.W. Writing—review, editing, and approval of final draft: all authors. Funding acquisition: D.C.W. Supervision: D.C.W.
Financial support: This research was partly supported by the NIDDK T32 DK063922-17 (D.C.W. and E.K.D.), NIH DK061451 (D.C.W.), R21 DK098560 (D.C.W.), U01 DK108306 (D.C.W. and D.Y.), U01 DK108327 (D.L.C.). 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.
Potential competing interests: D.C.W. is cofounder of Ariel Precision Medicine, Pittsburgh, PA. He serves as a consultant and may have equity.
Clinical trials registration: Clinicaltrial.gov. NCT01545167.
WHAT IS KNOWN
- ✓ Pancreatitis pain is variable and can be severe, leading to a poor quality of life in some patients.
- ✓ Current pain treatment strategies are often suboptimal or ineffective.
- ✓ Depression risk loci overlap pancreatitis pain loci.
WHAT IS NEW HERE
- ✓ Pancreatitis genetic loci associated with severe pain overlap with generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD) risk loci.
- ✓ GAD and PTSD are pre-existing risk and are not necessarily only a response to chronic pain.
- ✓ Patients who experience constant and severe pancreatic pain may have several overlapping conditions that should be addressed individually as part of a complex disorder.
The authors acknowledge the contributions of the following individuals to the NAPS2 studies: Peter Banks, MD, and Darwin Conwell, MD (Brigham and Women's Hospital, Boston, MA); Simon K. Lo, MD (Cedars-Sinai Medical Center, Los Angeles, CA); Timothy Gardner, MD (Dartmouth-Hitchcock Medical Center, Hanover, NH); Late. John Baillie, MD (Duke University Medical Center, Durham, NC); Christopher E. Forsmark, MD (University of Florida, Gainesville, FL); Thiruvengadam Muniraj, MD, PhD (Griffin Hospital, CT); Stuart Sherman, MD (Indiana University, Indianapolis, IN); Mary Money, MD (Washington County Hospital, Hagerstown, MD); Michele Lewis, MD (Mayo Clinic, Jacksonville, FL); Joseph Romagnuolo, MD, Robert Hawes, MD, Gregory A. Coté, MD, and Christopher Lawrence, MD (Medical University of South Carolina, Charleston, SC); Michelle A. Anderson, MD (University of Michigan, Ann Arbor, MI); Stephen T. Amann, MD (North Mississippi Medical Center, Tupelo, MS); Babak Etemad, MD (Ochsner Medical Center, New Orleans, LA); Mark DeMeo, MD (Rush University Medical Center, Chicago, IL); Michael Kochman, MD (University of Pennsylvania, Philadelphia, PA); Late. M. Michael Barmada, PhD, Jessica LaRusch, PhD, Judah N. Abberbock, PhD, Gong Tang, PhD, Michael O'Connell, PhD, Kimberly Stello, Emil Bauer, Elizabeth Kennard, PhD, Stephen R. Wisniewski, PhD, Adam Slivka, MD, PhD, Dhiraj Yadav, MD, MPH, and David C. Whitcomb, MD, PhD (University of Pittsburgh, Pittsburgh, PA); Late. Frank Burton, MD (St. Louis University, St. Louis, MO); James DiSario, MD, University of Utah Health Science Center, Salt Lake City, UT; William Steinberg, MD (Washington Medical Center, Washington, DC); Samer Alkaade, MD (Mercy Clinic Gastroenterology St. Louis, MO); and Andres Gelrud, MD (GastroHealth, Miami, FL).
Laboratory assistance of Kimberly Stello, Danielle Dwyer, and staff of the Whitcomb Core Laboratory during the NAPS2 studies is appreciated. Data collection was performed with the assistance of the Epidemiology Data Center of the University of Pittsburgh (Stephen R. Wisniewski, PhD, director).
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