Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Am J Gastroenterol. 2021 Oct 1;116(10):2128-2136. doi: 10.14309/ajg.0000000000001366.
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.
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.
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).
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.
复发性急性胰腺炎（RAP）和慢性胰腺炎（CP）是具有不同特征的进行性炎症综合征。疼痛是导致生活质量下降的主要特征，其中三分之一的患者报告有严重疼痛。疼痛体验会因抑郁而恶化。在这里，我们检验了这样一个假设，即焦虑和创伤后应激障碍（PTSD）的精神疾病的遗传风险与 CP 和 RAP+CP 患者的疼痛有关。
该研究队列包括来自欧洲裔的北美胰腺炎研究 II 中表型和基因分型的 RAP 和 CP 患者。候选基因关联研究是基于是否存在疼痛与持续疼痛、持续严重疼痛或严重疼痛的区别。在文献中确定了 28 个与焦虑和 PTSD 风险相关的候选遗传位点，是本研究的重点。
我们在 CP 和 RAP+CP 中发现了 24 个与 3 种疼痛模式相关的显著单核苷酸多态性（P<0.002）。13 个焦虑或 PTSD 基因位于这些疼痛位点内，表明存在非随机关联（P<4.885×10-23）。CTNND2 与所有疼痛类别和所有胰腺炎病因均相关。涉及的系统包括神经元信号（HTR2A、DRD3、NPY 和 BDNF）、下丘脑-垂体-肾上腺轴（NR3C1 和 FKBP5）和细胞-细胞相互作用（CTNND2 和 THBS2）。
RAP 和 CP 患者持续和严重疼痛的一个因素与焦虑和 PTSD 的遗传易感性有关。应正式评估确定有风险的患者，使他们有资格参加靶向治疗试验，作为多学科疼痛管理策略的一部分。
