Serotonin Transporter Gene Re-Sequencing in Patients with Irritable Bowel Sundrom

描述（由申请人提供）：肠易激综合征（IBS）是一种常见的慢性胃肠道（GI）疾病，以腹痛或不适与排便障碍相关的症状为特征。肠易激综合征患者患有高度的精神合并症，特别是抑郁、焦虑和创伤后应激障碍。我们假设肠易激综合征中常见的精神共病指向一个共同的病因，即影响肠道和大脑的血清素能信号的中断。血清素能神经传递的主要调节者是血清素转运体（SERT）。SERT通过再摄取5 -羟色胺进入突触来控制5 -羟色胺能信号的强度和持续时间，因此是肠易激综合征的候选基因。我们之前的研究表明，肠易激综合征患者中有一个亚组患有特别严重的肠易激综合征，他们更有可能患有精神疾病，尤其是抑郁症。因此，我们提出了一个假设，即存在一个具有SERT有害突变的成人亚组，其(a)在IBS中患有高GI症状负担，(b)具有高心理困扰率，以及(c)对所有形式的IBS治疗反应较差。在这项研究中，我们将使用ABI SOLiD平台对373名IBS患者和137名对照者的SERT基因编码区和非编码区进行测序。我们将使用生物信息学工具识别罕见的编码和非编码SERT序列变异（SERT突变）并表征其功能重要性。该研究的目的是：目的1：比较373名IBS患者和137名健康对照者中有害SERT突变的患病率。目的2：比较有和没有有害SERT突变的IBS患者在胃肠道症状和心理困扰症状方面的差异。目的3：比较具有和不具有有害SERT突变的IBS患者对认知行为治疗的反应。

DESCRIPTION (provided by applicant): Irritable Bowel Syndrome (IBS) is a common chronic gastrointestinal (GI) disorder characterized by symptoms of abdominal pain or discomfort associated with disturbed defecation. Patients with IBS suffer from a high degree of psychiatric comorbidity, in particular depression, anxiety, and posttraumatic stress disorder. We hypothesize that the frequent psychiatric comorbidity in IBS points to a common etiological factor, a disruption in serotonergic signaling affecting both the gut and the brain. The major regulator of serotonergic neurotransmission in the body is the serotonin transporter (SERT). SERT controls the intensity and duration of serotonergic signaling via re-uptake of serotonin into the synapse and is therefore a candidate gene for IBS. Our previous studies have shown that there is a subgroup of IBS patients with a particularly severe form of the disease who are more likely to suffer from psychiatric comorbidity, particularly depression. We therefore formulate the hypothesis that there is a subgroup of adults with deleterious mutations of SERT that (a) suffer from a high GI symptom burden in IBS, (b) have high rates of psychological distress, and (c) have a poor response to all forms of IBS treatment. In this study we will sequence the coding and non-coding regions of the SERT gene in 373 patients with IBS and 137 controls, using the ABI SOLiD platform. We will identify rare coding and non-coding SERT sequence variants (SERT mutations) and characterize their functional importance, using bioinformatics tools. The aims of the study are: Aim 1: Compare the prevalence of deleterious SERT mutations in 373 patients with IBS to 137 healthy controls. Aim 2: Compare IBS patients with and without deleterious SERT mutations with respect to GI symptoms and symptoms of psychological distress. Aim 3: Compare response to cognitive-behavioral treatment in IBS patients with and without deleterious SERT mutations. PUBLIC HEALTH RELEVANCE: Irritable bowel syndrome (IBS) is a common and painful gastrointestinal disease of unknown etiology, often accompanied by depression, anxiety, or posttraumatic stress disorder. Evidence points towards a global dysfunction of serotonin signaling as possible cause for this combination of gastrointestinal and psychiatric symptoms. The goal of this study is to test the hypothesis that harmful mutations of the serotonin transporter gene can cause IBS.