Genetic Analysis of Carbohydrate Maldigestion in Irritable Bowel Syndrome

肠易激综合征碳水化合物消化不良的遗传分析

• 批准号: 8701693
• 负责人: Robert J Shulman
• 金额: $ 22.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701693
• 关键词: Abdomen; Abdominal Pain; Accounting; Adult; Affect; Alpha-glucosidase; Amylases; Carbohydrates; Caring; Celiac Disease; Characteristics; Child; Childhood; Clinical; Clinical Research; Code; Communities; Constipation; DNA; DNA Library; Data; Diagnosis; Diarrhea; Diet; Dietary Carbohydrates; Direct Costs; Eating; Economic Burden; Effectiveness; Emotional; Enrollment; Enzymes; Etiology; Facilities and Administrative Costs; Feces; Financial cost; Flatulence; Food; Frequencies; Fructose; Functional Gastrointestinal Disorders; Gastrointestinal Diseases; Gene Mutation; Genes; Genetic; Goals; Individual; Intestines; Irritable Bowel Syndrome; Lactase Phlorizin Hydrolase; Lactose; Link; Malabsorption Syndromes; Mutation; Nature; Nutrient; Oligo-1,6-Glucosidase; Outcome; Pain; Pancreas; Pathogenesis; Patient Care; Patients; Pattern; Phenotype; Play; Public Health; Quality of life; Recurrence; Reducing diet; Role; Sampling; Severities; Starch; Subgroup; Sucrase; Sucrose; Symptoms; Translations; Variant; clinical phenotype; clinical practice; congenital sucrose isomaltose malabsorption; diaries; enzyme deficiency; gastrointestinal symptom; genetic analysis; improved; infancy; innovation; multidisciplinary; novel; prospective; public health relevance; sucrase-isomaltase-maltase

DESCRIPTION (provided by applicant): Irritable Bowel Syndrome (IBS) is a gastrointestinal (GI) disorder characterized by abdominal pain and alterations in bowel pattern (e.g., diarrhea, constipation, or both) affecting 10-15% of adults and children throughout the world with annual US financial costs estimated at $6 billion dollars (adult IBS alone). IBS is challenging to patient and clinicians in that the mechanism(s) accounting for symptoms are not well understood and treatments are not consistently effective. In some individuals diet seems to play a role. Malabsorption of dietary carbohydrates (CHOs) can cause abdominal pain, flatulence, bloating, and diarrhea - symptoms which very closely mimic those of IBS. There is evidence that milder forms of congenital sucrase- isomaltase deficiency or amylase deficiency may exist in some patients with IBS resulting in sucrose or starch maldigestion. Deficiency of these or other CHO digesting enzymes could cause IBS-like symptoms in an otherwise healthy individual or exacerbate symptoms in existent IBS. Identifying the presence of enzyme deficiencies leading to CHO malabsorption would dramatically change the management of patients previously diagnosed with IBS by providing an identifiable and treatable etiology for GI symptoms in a subset of patients. Therefore, we propose the following Specific Aims: Using previously banked DNA samples from carefully phenotyped adults/children with IBS (n=805; diarrhea predominant, constipation predominant, mixed type, and unsubtyped) and healthy adult/child Controls (n=560) without GI disease all of whom completed prospective pain and stool diaries: 1) Compare the frequency of variants in the sucrase-isomaltase, maltase-glucoamylase, lactase-phlorizin hydrolase, and pancreatic amylase genes in patients with IBS versus healthy Controls. Hypothesis: Coding and regulatory sequence variants of intestinal CHO digestive enzymes are more frequent in those with IBS. 2) Determine the possible relationship between genetic variability and IBS clinical phenotype (pain frequency/severity, stooling characteristics). Hypothesis: Variants in the genes encoding sucrase- isomaltase, maltase-glucoamylase, lactase-phlorizin hydrolase, and pancreatic amylase are associated with a greater frequency of abdominal pain symptoms and increased stooling frequency in those with IBS. Results from this innovative exploratory study are likely to break new ground in identifying the pathogenesis of abdominal and bowel symptoms in adults and children with IBS. A particular strength of the proposal is the existing set of DNA samples and prospectively collected symptom data. The novel finding of patients with CHO digesting enzyme deficiency would alter dramatically the approach to diagnosis, management, and treatment as well as selection of IBS patients into clinical studies. The multidisciplinary/multisite nature of this proposal and its use of adult and pediatric patients further enhance its applicability and potential biomedical impact. This proposal fits with the goals of PA-12-139 (R21) to undertake short term preliminary clinical studies to facilitate translation into clinical practice and improve patient outcomes with IBS being a particular focus.

描述（由申请人提供）：肠易激综合征（IBS）是一种胃肠道（GI）疾病，其特征是腹痛和肠模式的改变（例如，腹泻，便秘或两者兼而有之），全世界的成人和儿童的年度为10-15％，每年的美国财务成本估计为60亿美元的成年人（成人IBS IBS）。 IBS对患者和临床医生具有挑战性，因为对症状的解释机制尚不清楚，并且治疗尚未始终有效。在某些人中，饮食似乎起着作用。饮食中碳水化合物（CHOS）的吸收不良会导致腹痛，肠胃气胀，腹胀和腹泻 - 非常紧密地模仿IBS的症状。有证据表明，一些IBS患者可能存在较轻的先天性舒适酶 - 异藻酶缺乏或淀粉酶缺乏症，导致蔗糖或淀粉麦芽糖浆。这些或其他CHO消化酶的缺乏可能会导致现有IBS中本来健康的个体或加剧症状的IBS样症状。通过确定导致CHO吸收不良的酶缺乏症的存在将大大改变先前诊断为IBS的患者的治疗，通过在一部分患者中为GI症状提供可识别且可治疗的病因。因此，我们提出以下具体目的：使用先前库存的IBS/儿童（n = 805；腹泻；腹泻，便秘，主要，混合类型和未灌注的腹泻）和健康的成人/儿童控制（n = 560）（n = 560），没有GI疾病的所有疾病，他们的前瞻性疼痛和脚步疾病的频率是：1） IBS与健康对照组的患者中，舒张酶 - 异构酶，麦芽酶 - 葡萄糖酶，乳酸磷酸酶水解酶和胰淀粉酶基因。假设：肠道CHO消化酶的编码和调节序列变体在IBS患者中更为频繁。 2）确定遗传变异性与IBS临床表型（疼痛频率/严重程度，僵化特征）之间的可能关系。假设：编码舒适酶异构酶，麦芽糖酶 - 葡萄糖酶，乳酸磷酸二氯化物酶水解酶和胰淀粉酶的变异与腹痛症状的频率更高，与IBS患者的粪便频率更高有关。这项创新的探索性研究的结果可能会破坏新的基础，以确定成人和IBS儿童腹部和肠症状的发病机理。该提案的一个特殊优势是现有的DNA样本和前瞻性收集的症状数据。 CHO消化酶缺乏症患者的新发现将极大地改变诊断，管理和治疗的方法，以及在临床研究中选择IBS患者。该提案的多学科/多物质性质及其对成人和小儿患者的使用进一步增强了其适用性和潜在的生物医学影响。这个建议 符合PA-12-139（R21）的目标，以进行短期初步临床研究，以促进转化为临床实践并改善患者的预后，而IBS是特别重点。