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

描述(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，其特征是腹痛或与排便障碍相关的不适症状。IBS患者患有高度的精神共病，特别是抑郁、焦虑和创伤后应激障碍。我们假设IBS中频繁的精神疾病共病指向一个共同的病因，即影响肠道和大脑的5-羟色胺能信号的中断。体内5-羟色胺能神经传递的主要调节因子是5-羟色胺转运体(SERT)。SERT通过重新摄取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IBS的候选基因。我们之前的研究表明，有一组IBS患者患有特别严重的疾病，他们更有可能患有精神共病，特别是抑郁症。因此，我们提出假设，有一组具有SERT有害突变的成年人(A)在IBS中遭受高GI症状负担，(B)有高比例的心理苦恼，(C)对所有形式的IBS治疗反应差。在这项研究中，我们将使用ABI Solid平台对373例IBS患者和137名对照的SERT基因的编码区和非编码区进行测序。我们将识别罕见的编码和非编码SERT序列变体(SERT突变)，并利用生物信息学工具表征它们的功能重要性。本研究的目的是：目的1：比较373例IBS患者和137例健康对照的SERT有害突变的发生率。目的：比较具有和不存在有害SERT突变的IBS患者的胃肠道症状和心理苦恼症状。目的3：比较伴有和不伴有有害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.