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，其特征在于腹痛和肠道模式改变（例如，腹泻、便秘或两者），影响全世界10-15%的成人和儿童，美国每年的经济成本估计为60亿美元（仅成人IBS）。IBS对患者和临床医生具有挑战性，因为解释症状的机制尚未得到很好的理解，并且治疗并不总是有效的。在某些人中，饮食似乎发挥了作用。膳食碳水化合物（CHO）吸收不良可导致腹痛，胀气，腹胀和腹泻-症状非常接近IBS的症状。有证据表明，轻度形式的先天性蔗糖酶-异麦芽糖酶缺乏症或淀粉酶缺乏症可能存在于一些IBS患者中，导致蔗糖或淀粉消化不良。这些或其他CHO消化酶的缺乏可在其他健康个体中引起IBS样症状或加重现有IBS的症状。确定导致CHO吸收不良的酶缺乏的存在将通过为患者亚组中的GI症状提供可识别和可治疗的病因来显著改变先前诊断为IBS的患者的管理。因此，我们提出了以下具体目标：使用先前储存的来自IBS成人/儿童的仔细表型的DNA样本（n=805;以腹泻为主、以便秘为主、混合型和未分型）和无胃肠道疾病的健康成人/儿童对照组（n=560），所有人都完成了前瞻性疼痛和粪便日记：1）比较IBS患者与健康对照中蔗糖酶-异麦芽糖酶、麦芽糖酶-葡糖淀粉酶、乳糖酶-根皮苷水解酶和胰淀粉酶基因的变体频率。假设：肠CHO消化酶的编码和调节序列变异在IBS患者中更常见。2)确定遗传变异性与IBS临床表型（疼痛频率/严重程度、排便特征）之间的可能关系。假设：编码蔗糖酶-异麦芽糖酶、麦芽糖酶-葡糖淀粉酶、乳糖酶-根皮苷水解酶和胰淀粉酶的基因的变体与IBS患者中更高频率的腹痛症状和增加的排便频率相关。这项创新的探索性研究的结果可能会在确定成人和儿童IBS腹部和肠道症状的发病机制方面开辟新的天地。该提案的一个特别优势是现有的DNA样本集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临床研究中IBS患者的选择。该提案的多学科/多站点性质及其对成人和儿科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。这项建议 符合PA-12-139（R21）的目标，即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结局，其中IBS是一个特别关注的问题。