Evaluation of Pain in Chronic Pancreatitis using the NAPS2 cohorts

使用 NAPS2 队列评估慢性胰腺炎的疼痛

• 批准号: 8638624
• 负责人: DAVID Clement WHITCOMB
• 金额: $ 26.3万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638624
• 关键词: Alcohol consumption; Alcohols; American; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Appearance; Biological; Biological Assay; Biological Markers; Blood specimen; C-reactive protein; Candidate Disease Gene; Categories; Classification; Clinical; Clinical Data; Clinical Research; Clinical Trials; Complex; Complication; DNA; Data; Data Set; Detection; Development; Discrimination; Distress; Effectiveness; Etiology; Evaluation; Failure; Frequencies; Funding; Future; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic Transcription; Genotype; Glycine Receptors; Goals; Hospitalization; Human; Hydroxyprostaglandin Dehydrogenases; Image; Immunohistochemistry; Inflammation; Inflammatory; Intervention; Lead; Link; Machine Learning; Maps; Measures; Medical; Messenger RNA; Methods; Morphology; NTF3 gene; Nature; North America; Obstruction; Outcome; Pain; Pain Map; Pain Origin; Pain management; Pancreas; Pancreatic Diseases; Pancreatitis; Patients; Pattern; Phenotype; Physicians; Predisposition; Preventive; Procedures; Proteins; Psyche structure; Quality of life; Recruitment Activity; Reporting; Research; Research Design; Risk; SNP genotyping; Sampling; Serum; Severities; Smoking; Staining method; Stains; Symptoms; TLR4 gene; Testing; Therapeutic Agents; Tissue Sample; Tissues; Total Pancreatectomy; Validation; Variant; X-Ray Computed Tomography; acute pancreatitis; base; chronic pain; chronic pancreatitis; cohort; cytokine; design; disability; effective therapy; exome; exome sequencing; genetic variant; genome wide association study; genome-wide; improved; inflammatory pain; insight; islet; lifestyle factors; novel; novel strategies; protein expression; public health relevance; rare variant; response; sex

Chronic pancreatitis (CP) is a progressive and destructive inflammatory disorder of the pancreas. One of the most distressing features is pain, which occurs in ~90% of patients, about half of whom have constant pain, which is associated with increased hospitalization and lower quality of life. Since there are multiple pain etiologies and since no standardized method exists to assess pain in patients with CP, novel approaches are needed to better understand the mechanisms of pain in CP and how it can be appropriately treated. The North American Pancreatitis Study 2 (NAPS2) recruited, phenotyped, and obtained biospecimens from the largest US cohort of pancreatitis, and we have completed a genome-wide association study (GWAS) that includes 1,171 NAPS2 CP cases for whom detailed phenotypic pain data are available. We propose to analyze the NAPS2 data set and biospecimens (DNA, serum, pancreas tissue) to define genetic risks and potential mechanisms of constant pain, identify markers of inflammatory pain, and characterize clinical pain complexes that can guide patient management. We have already identified through the full and a nested GWAS 8 candidate genes for "constant" pain. Aim 1 will determine whether these variants are associated with functional changes in genes associated with the constant pain phenotype. Targeted SNP genotyping and gene expression studies will be conducted, including mRNA studies and immunohistochemical staining in human samples. Aim 2 will determine whether c-reactive protein (CRP) or cytokine biomarkers correlate with constant pain. Pain is an indicator of active inflammation, with pro-inflammatory cytokines increasing pain, and anti-inflammatory cytokines diminishing pain. We will test 500 NAPS2 samples for elevated CRP and 10 Th1/Th2 cytokines as biomarkers of inflammation. For positive controls we will include blood samples from 40 acute pancreatitis patients who remain hospitalized for > 4 days for pain or inflammation. Aim 3 will apply machine-learning approaches to test for correlation of genotype, biomarkers, and morphology (obstruction) with quantitative measures of pain pattern, severity, and character as well as SF12 v2 quality of life scores (mental and physical) while controlling for sex, smoking, and alcohol. We anticipate that our machine learning approaches will provide decision rules for the proper classification of pain according to etiology worthy of formal testing in clinical trials. In addition, use of machine learning is anticipated to provide insight into pain mechanism by optimally linking the symptoms signatures, biomarkers, imaging studies, and genetics to complex mechanisms that are seen in patients with painful CP. The goal of this study is to use existing NAPS2 data and biospecimens to construct a framework for future clinical studies that test the effectiveness of personalized pain management based on our machine-learning-predicted etiology rather than symptoms alone.

慢性胰腺炎（CP）是一种进行性、破坏性的胰腺炎症性疾病。中的一个 最令人痛苦的特征是疼痛，约 90% 的患者会出现疼痛，其中约一半患者持续疼痛， 这与住院率增加和生活质量下降有关。因为有多种疼痛 由于没有标准化的方法来评估 CP 患者的疼痛，因此新的方法是 需要更好地了解脑瘫的疼痛机制以及如何适当治疗。北方 美国胰腺炎研究 2 (NAPS2) 从美国最大的胰腺炎研究中心招募、分析并获得生物样本 胰腺炎队列，我们​​已经完成了一项全基因组关联研究 (GWAS)，其中包括 1,171 NAPS2 CP 病例可获得详细的表型疼痛数据。我们建议分析 NAPS2 数据 组和生物样本（DNA、血清、胰腺组织）来定义遗传风险和潜在机制 持续疼痛，识别炎性疼痛标志物，并表征可以指导的临床疼痛复合体 患者管理。我们已经通过完整的和嵌套的 GWAS 确定了 8 个候选基因 “持续”的疼痛。目标 1 将确定这些变异是否与基因功能变化相关 与持续疼痛表型相关。有针对性的 SNP 基因分型和基因表达研究将 进行的研究，包括人类样本中的 mRNA 研究和免疫组织化学染色。目标2将 确定 C 反应蛋白 (CRP) 或细胞因子生物标志物是否与持续疼痛相关。疼痛是一种 活动性炎症的指标，促炎细胞因子会增加疼痛，并且具有抗炎作用 细胞因子减轻疼痛。我们将测试 500 个 NAPS2 样本的 CRP 升高和 10 个 Th1/Th2 细胞因子，如下所示 炎症的生物标志物。对于阳性对照，我们将包括 40 份急性胰腺炎的血液样本 因疼痛或炎症住院超过 4 天的患者。目标 3 将应用机器学习 测试基因型、生物标志物和形态（阻塞）与定量相关性的方法 疼痛模式、严重程度和特征的测量以及 SF12 v2 生活质量评分（精神和身体） 同时控制性、吸烟和饮酒。我们预计我们的机器学习方法将 为根据值得正式测试的病因学对疼痛进行正确分类提供决策规则 临床试验。此外，预计机器学习的使用将通过以下方式提供对疼痛机制的深入了解： 将症状特征、生物标志物、影像学研究和遗传学与复杂机制最佳地联系起来 常见于疼痛性 CP 患者。本研究的目标是利用现有的 NAPS2 数据和生物样本 为未来的临床研究构建一个框架，测试个性化疼痛管理的有效性 基于我们机​​器学习预测的病因学，而不仅仅是症状。