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）：肠易激综合症 (IBS) 是一种胃肠道 (GI) 疾病，其特征是腹痛和肠道模式改变（例如腹泻、便秘或两者兼而有之），影响整个世界 10-15% 的成人和儿童。美国每年的财务费用估计为 60 亿美元（仅成人 IBS）。 IBS 对患者和临床医生来说是一个挑战，因为人们对引起症状的机制尚不十分了解，并且治疗方法并不始终有效。对于某些人来说，饮食似乎起了一定作用。膳食碳水化合物 (CHO) 吸收不良会导致腹痛、肠胃胀气、腹胀和腹泻，这些症状与肠易激综合征 (IBS) 的症状非常相似。有证据表明，一些 IBS 患者可能存在较轻微的先天性蔗糖酶-异麦芽酶缺乏症或淀粉酶缺乏症，导致蔗糖或淀粉消化不良。这些或其他 CHO 消化酶的缺乏可能会导致健康个体出现类似 IBS 的症状，或加剧现有 IBS 的症状。识别导致 CHO 吸收不良的酶缺乏的存在，将为部分患者的胃肠道症状提供可识别和可治疗的病因，从而极大地改变先前诊断为 IBS 的患者的治疗。因此，我们提出以下具体目标： 使用先前储存的 DNA 样本，这些样本来自经过仔细表型分析的 IBS 成人/儿童（n=805；腹泻为主、便秘为主、混合型和未亚型）和健康成人/儿童对照（n=560）无胃肠道疾病，所有这些人都完成了前瞻性疼痛和粪便日记：1) 比较蔗糖酶-异麦芽糖酶、麦芽糖酶-葡糖淀粉酶、 IBS 患者与健康对照组的乳糖酶-根皮苷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异在 IBS 患者中更为常见。 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）之间可能的关系。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变异与 IBS 患者腹痛症状发生频率增加和排便频率增加相关。这项创新性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 IBS 患者进入临床研究的选择。该提案的多学科/多地点性质及其对成人和儿童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。这个提议 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的治疗结果，特别关注 IBS。