Psychophysiology of Irritable Bowel Syndrome

描述（由申请人提供）：肠易激综合征（IBS）影响10%的美国成年人，并与生活质量的显著损害有关。尽管有几十年的研究，但对其病理生理学没有共识，也没有持续有效的治疗方法。遗传学研究得出了不一致的结果。我们的假设是，这是因为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，需要不同的治疗方法。我们之前的资助支持这种异质性假设：我们在267名IBS患者中测试了50多个生理和心理变量，并确定了4个独立的聚类：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）。本提案的目的是（1）确定与这4种IBS表型相关的遗传多态性;（2）为每种表型开发一个病因学模型，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。每种IBS表型和遗传多态性之间的关联将使用由从系统性文献综述中收集的350个选定基因（3200个SNP）组成的Pain Panel进行评估。只有在225-300例IBS患者和200-225例健康对照的两个独立队列中证实时，相关性才被认为是显著的。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MAP 2K 1）和更直接调节疼痛敏感性的基因（例如，GABRG 2）相互作用，影响IBS-Pn的脆弱性，我们假设，炎症基因可能需要细菌性胃肠炎的环境触发表达，而与疼痛敏感性相关的基因可能通过儿童社会学习，通过建模和疾病行为的强化来调节。我们还将通过以下方式测试IBS表型的稳定性：（1）在初始测试后6个月使用完整的表型方案重新测试50名IBS患者，以及（2）每年调查所有受试者以发现症状和诊断的变化。在这项研究中获得的数据将增加我们的IBS患者和健康对照数据库，其中包含生物标本（DNA，血清，一些活检）以及为未来研究存储的临床和生理数据。这项转化研究需要疼痛遗传学家，胃肠病学家和心理学家经验丰富的团队之间的多学科合作。公共卫生相关性：肠易激综合征（IBS）影响10%的人口，每年造成80亿美元的医疗费用，但对其病理生理学或治疗尚无共识。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，不同的治疗方法将是适当的。识别这些不同的IBS表型和与它们相关的遗传标记可能有助于确定药物开发的新靶点，并可能有助于我们个性化治疗，从而使其更加成功。

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.