Pain Experience in Pancreatitis: Strong Association of Genetic Risk Loci for Anxiety and PTSD in Patients With Severe, Constant, and Constant-Severe Pain

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.

Acute and Chronic Pancreatitis Disease Prevalence, Classification, and Comorbidities: A Cohort Study of the UK BioBank

“…Most other conditions strongly associated with AP and CP are either symptoms (R10.X), treatments (Y83.6), complications (N17.9), or sequela (E10, E11) of the conditions. Recent studies from the NAPS2 ( 45 , 46 ) and multicenter CP pain study ( 47 ) cohorts demonstrated a strong association with depression and anxiety in patients with pancreatitis, especially those with pain. A striking but not surprising finding was the relative high risk of intentional self-harm ( ICD-10 X60-X65 family; e.g.…”

Response to Liu et al.

“…We thank Liu et al for their letter in reference to our recent paper by Dunbar et al (1,2). We will address the 4 points sequentially.Cohort numbers vary between comparisons.…”

“…To further clarify the first contention, see the “Variables” subsection of our “Methods” section in our paper (1) where we specify that we are using the same pool of patients with pancreatitis from the NAPS2 in 2 groups to account for similarities between CP and RAP. Similarly, we did group patients by pain category in such a way that some patients may overlap between the groups (see “Pain categories and quality of life” (1)). However, we do not believe that the genetic association seen with CTNND2 across all 3 pain categories is only due to an association with constant-severe pain.…”

Psychiatric Disease Susceptibility and Pain in Chronic Pancreatitis: Association or Causation?

“…In this issue of The American Journal of Gastroenterology , Dunbar et al (22) evaluated patients with CP and recurrent acute pancreatitis (RAP) from the North American Pancreatitis Study II (NAPS2) to determine whether there are associations between pain and SNPs related to anxiety and/or PTSD. The patients were classified into 3 pain phenotypes categories: constant, severe, and constant-severe pain.…”