Psychophysiology of Irritable Bowel Syndrome

肠易激综合症的心理生理学

• 批准号: 7901982
• 负责人: WILLIAM E WHITEHEAD
• 金额: $ 9.13万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901982
• 关键词: Accounting; Address; Adult; Affect; Attention; Bacteria; Bacterial Gastroenteritis; Biological; Biopsy; Boxing; Childhood; Classification; Clinical; Cluster Analysis; Collaborations; Collection; Consensus; Constipation; Data; Databases; Development; Diagnosis; Diarrhea; Diet; Differential Diagnosis; Dimensions; Disease; Distress; Effectiveness; Environment; Environmental Exposure; Equation; Etiology; Failure; Feces; Fiber; Functional disorder; Future; Gastroenterologist; Gastrointestinal Motility; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Research; Genotype; Glean; Goals; Grant; Health; Health Care Costs; Heterogeneity; Impairment; Inflammation; Inflammatory; Interdisciplinary Study; Irritable Bowel Syndrome; Label; Learning; Life; Literature; Logistic Regressions; MAP2K1 gene; Measures; Methodology; Modeling; Outcome; Pain; Parents; Patients; Perception; Phenotype; Physiological; Pilot Projects; Population; Principal Component Analysis; Probiotics; Prospective Studies; Protocols documentation; Psychological reinforcement; Psychologist; Psychophysiology; Quality of life; Recording of previous events; Recruitment Activity; Regression Analysis; Reporting; Research; Research Personnel; Review Literature; Risk Factors; Rome; Serum; Sick Role; Single Nucleotide Polymorphism; Small Intestines; Specimen; Subgroup; Surveys; Symptoms; Temporomandibular Joint Disorders; Testing; Theoretical model; Woman; Work; base; case control; cell motility; chronic pain; cohort; drug development; effective therapy; experience; gene environment interaction; gene interaction; genetic association; genetic risk factor; improved; psychologic; psychological distress; psychosocial; public health relevance; social; stability testing; systematic review; three-dimensional modeling; translational study

DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) affects 10% of US adults and is associated with significant impairment in quality of life. Despite decades of research, there is no consensus on its pathophysiology and no consistently effective treatment. Genetic studies have yielded inconsistent findings. Our hypothesis is that this has occurred because IBS is not a unitary disorder but a group of different disorders with distinct etiologies, which require different treatments. Our previous grant supported this heterogeneity hypothesis: we tested more than 50 physiological and psychological variables in 267 IBS patients and identified 4 independent clusters: constipation- predominant (IBS-C), diarrhea-predominant (IBS-D), pain-hypersensitive (IBS-Pn), and psychologically distressed (IBS-Psy). The aims of this proposal are to (1) identify genetic polymorphisms associated with these 4 IBS phenotypes; (2) develop, for each phenotype, an etiologic model that includes gene-environment and gene-gene interactions; and (3) test and refine these models using structural equation modeling. Associations between each IBS phenotype and genetic polymorphisms will be assessed using a Pain Panel consisting of 350 selected genes (3200 SNPs) gleaned from a systematic literature review. Associations will be considered significant only if confirmed in two independent cohorts of 225-300 IBS patients and 200-225 healthy controls. As an example of the types of models we will construct, we hypothesize for the IBS-Pn phenotype, genes regulating inflammation (e.g. MAP2K1) and genes regulating pain sensitivity more directly (e.g., GABRG2) interact to influence vulnerability to IBS-Pn, and we hypothesize that inflammatory genes may require the environmental trigger of bacterial gastroenteritis for expression while genes related to pain sensitivity may be modulated by childhood social learning through modeling and reinforcement of illness behavior. We will also test the stability of IBS phenotypes by (1) retesting 50 IBS patients with the full phenotyping protocol 6 months after initial testing and (2) surveying all subjects annually to discover changes in symptoms and diagnoses. Data acquired in this study will augment our database of IBS patients and healthy controls, which contains biological specimens (DNA, serum, some biopsies) as well as clinical and physiological data stored for future studies. This translational study entails multidisciplinary collaboration between experienced teams of pain geneticists, gastroenterologists, and psychologists. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE The irritable bowel syndrome (IBS) affects 10% of the population and results in $8 billion dollars in annual health care costs, but there is no consensus on its pathophysiology or treatment. The hypothesis of our research is that IBS is not one disorder but a group of disorders with different etiologies, for which different treatments will be appropriate. Identifying these different phenotypes of IBS and the genetic markers associated with them may help to identify new targets for drug development and may help us to individualize treatment and thereby make it more successful.

描述（由申请人提供）：肠易激综合症 (IBS) 影响 10% 的美国成年人，并与生活质量的严重损害相关。尽管进行了数十年的研究，但对其病理生理学尚未达成共识，也没有一致有效的治疗方法。遗传学研究得出了不一致的结果。我们的假设是，发生这种情况是因为 IBS 不是一种单一的疾病，而是一组具有不同病因的不同疾病，需要不同的治疗。我们之前的资助支持了这种异质性假设：我们测试了 267 名 IBS 患者的 50 多个生理和心理变量，并确定了 4 个独立的集群：便秘为主 (IBS-C)、腹泻为主 (IBS-D)、疼痛过敏 (IBS) -Pn) 和心理困扰 (IBS-Psy)。该提案的目的是 (1) 鉴定与这 4 种 IBS 表型相关的遗传多态性； (2) 针对每种表型开发一个病因学模型，其中包括基因-环境和基因-基因相互作用； (3) 使用结构方程模型测试和完善这些模型。将使用由从系统文献综述中收集的 350 个选定基因（3200 个 SNP）组成的疼痛面板来评估每种 IBS 表型和遗传多态性之间的关联。仅当在由 225-300 名 IBS 患者和 200-225 名健康对照组成的两个独立队列中得到证实时，关联才被视为显着。作为我们将构建的模型类型的一个例子，我们假设 IBS-Pn 表型、调节炎症的基因（例如 MAP2K1）和更直接调节疼痛敏感性的基因（例如，GABRG2）相互作用以影响 IBS-Pn 的脆弱性，并且我们假设炎症基因可能需要细菌性胃肠炎的环境触发因素才能表达，而与疼痛敏感性相关的基因可能通过儿童社会学习通过建模和强化疾病行为来调节。我们还将通过以下方式测试 IBS 表型的稳定性：(1) 在初次测试后 6 个月，使用完整的表型分析方案重新测试 50 名 IBS 患者；(2) 每年对所有受试者进行调查，以发现症状和诊断的变化。这项研究中获得的数据将扩充我们的 IBS 患者和健康对照数据库，其中包含生物样本（DNA、血清、一些活组织检查）以及为未来研究而存储的临床和生理数据。这项转化研究需要经验丰富的疼痛遗传学家、胃肠病学家和心理学家团队之间的多学科合作。公众健康相关性：项目叙述肠易激综合症 (IBS) 影响着 10% 的人口，每年造成 80 亿美元的医疗保健费用，但对其病理生理学或治疗方法尚未达成共识。我们研究的假设是，IBS 不是一种疾病，而是一组具有不同病因的疾病，针对这些疾病需要采取不同的治疗方法。识别 IBS 的这些不同表型以及与之相关的遗传标记可能有助于确定药物开发的新靶标，并可能帮助我们进行个体化治疗，从而使其更加成功。