与IBS有关的突变 可运用于治疗


  【24drs.com】根据在线发表于3月10日胃肠病学期刊的基因组分析,大肠激躁症(IBS)患者约2%有SCN5A基因突变,干扰了钠离子通道功能;研究结果提供了原本未知的IBS病理机转,以及可能的治疗选项。
  
  资深作者、明尼苏达州梅约诊所个人化医学中心主任、胃肠科医师Gianrico Farrugia在诊所新闻稿中表示,这让我们对这个目前只能治疗症状的疾病带来希望,可望发展出疾病修饰制剂,希望可以影响IBS的长期治疗。
  
  IBS在西半球的盛行率估计为15%-20%,目前大多只能针对IBS症状如痉挛、腹痛、腹胀、胀气、腹泻、便秘等进行治疗。
  
  之前有关IBS病因的理论认为是饮食、曾受的创伤、焦虑和/或遗传影响,而这是首次有报告定义引起IBS的基因突变-SCN5A基因-影响了Nav1.5通道,这是胃肠道平滑肌和心脏起搏器上面的钠离子通道,因此会影响肠道功能。
  
  特别的是,SCN5A控管钠通道Nav1.5电位门的α亚单位,因为SCN5A突变影响心脏起博器引起心律不整的病患有许多人也有IBS症状,研究者试图确认是否有部分的IBS病患有SCN5A突变而影响Nav1.5功能。
  
  对584名IBS病患以及1,380名对照组进行的钠离子通道基因组分析显示,IBS病患有2.2%出现SCN5A基因缺损,对照组则无;SCN5A的突变类型表现在HEK-293细胞,用电压箝位分析评估钠离子通道功能。
  
  作者们写道,约2%的IBS病患有SCN5A突变,其中大多是干扰钠离子通道丧失功能的突变,研究结果提供IBS的新病理机转及可能的新治疗选项。
  
  全基因组关联研究辨识了IBS与SCN5A 基因的讯息关联,该基因在4组独立的IBS病患和对照组出现复制(总共1,745名研究对象)。
  
  虽然大部分IBS是腹泻型,约占整体研究对象的25%,便秘型IBS(IBS-C)者比较多属于SCN5A突变,IBS-C类型占SCN5A突变的31%,而腹泻型IBS仅10%有此突变(P < .05)。
  
  电压箝位实验的电生理分析显示,SCN5A突变的13人中有10名和Nav1.5功能异常有关,包括9个丧失钠离子通道功能、1个钠离子通道功能增强。
  
  降低NaV1.5功能影响最大的是发生在 p.A997T-NaV1.5突变,用mexiletine这个药物培养这个突变细胞时,钠电流恢复。
  
  将mexiletine给予IBS-C型且有SCN5A突变的患者,不只重建钠离子通道功能,也消除了病患的便秘与腹痛。
  
  作者们结论表示,在这个人化医疗的时代,我们发现,具有基因复杂性的疾病,如IBS,可能有一些病患可以确认是基因异常,离子通道和内脏痛与[胃肠]蠕动机转有直接关连,因此,离子通道可能和IBS病理有关,有某些IBS病患的SCN5A突变显著影响功能,我们对此首度提供了直接的分子性与功能性证据。
  
  资料来源:http://www.24drs.com/professional/list/content.asp?x_idno=7065&x_classno=0&x_chkdelpoint=Y
  

Mutations Linked to IBS, May Lead to Treatment

By Laurie Barclay, MD
Medscape Medical News

Approximately 2% of patients with irritable bowel syndrome (IBS) have a mutation of the SCN5A gene that disrupts sodium channel function, according to a genotype analysis published online March 10 in Gastroenterology. This finding offers clues to a previously unknown pathogenic mechanism underlying IBS and possible treatment options.

"This gives us hope that from only treating symptoms of the disease, we can now work to find disease-modifying agents, which is where we really want to be to affect long-term treatment of IBS," senior author Gianrico Farrugia, MD, gastroenterologist and director of the Mayo Clinic Center for Individualized Medicine in Rochester, Minnesota, said in a clinic news release.

In the Western Hemisphere, estimated prevalence of IBS is about 15% to 20%. Most currently available treatments for IBS target the symptoms, which may include cramping, abdominal pain, bloating, gas, diarrhea, and constipation.

Previous theories concerning the etiology of IBS have suggested a role for diet, previous trauma, anxiety, and/or genetics, but this is the first report of a defined genetic mutation causing a subset of IBS. The culprit is a mutation of the SCN5A gene that affects the Nav1.5 channel, a sodium channel in the gastrointestinal smooth muscle and pacemaker cells, and thereby disrupts bowel function.

Specifically, SCN5A encodes the α subunit of the voltage-gated Na+channel Nav1.5. Because many patients with cardiac arrhythmias caused by mutations in SCN5A affecting pacemaker cells also have IBS symptoms, the investigators sought to determine whether some patients with IBS have SCN5A variants affecting Nav1.5 function.

Genotype analysis of the sodium channel in 584 patients with IBS and 1380 control subjects showed a defect in the SCN5A gene in 2.2% of the IBS patients compared with none of the control subjects. Mutant forms of SCN5A were expressed in HEK-293 cells, and voltage clamp analysis allowed evaluation of sodium channel function.

"About 2% of IBS patients carry mutations in SCN5A," the authors write. "Most of these are loss-of-function mutations that disrupt Na+ channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options."

Mutations Linked to Sodium Channel Function, IBS Symptoms

A genome-wide association study identified an IBS association signal for the SCN5A gene, which was replicated in 4 independent cohorts of patients with IBS and control patients (total, 1745 participants).

Although diarrhea-predominant IBS was the most prevalent form of IBS, occurring in 25% of the overall study population, constipation-predominant IBS (IBS-C) was significantly more prevalent among individuals with SCN5A mutations. IBS-C occurred in 31% of persons with SCN5A mutations, whereas diarrhea-predominant IBS occurred in only 10% (P < .05).

Electrophysiologic analysis of voltage-clamp experiments showed that 10 of 13 detected SCN5A mutations were associated with abnormal Nav1.5 function, including 9 with loss of sodium channel function and 1 with gain of sodium channel function.

The greatest effect in reducing NaV1.5 function occurred with the p.A997T-NaV1.5 mutation. When cells with this mutation were incubated with the drug mexiletine, sodium current was restored.

Giving mexiletine to a patient with IBS-C and this variant of the SCN5A mutation not only restored the function of the sodium channel but also abolished the patient's constipation and abdominal pain.

"In the dawn of the personalized medicine era we are discovering that for genetically complex diseases such as IBS there may be cohorts of patients with well-defined genetic abnormalities," the authors conclude. "Ion channels are directly involved in the mechanisms of visceral pain and [gastrointestinal] motility, therefore ion channelopathies may be involved in pathogenesis of IBS. For the first time we provide the direct molecular and functional evidence for functionally significant SCN5A mutations in a subset of IBS patients."

The National Institutes of Health, the Mayo Clinic Center for Cell Signaling in Gastroenterology, the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program, and the Swedish Research Council supported this study. One coauthor has reported serving as a consultant for Boston Scientific, Medtronic, and St. Jude Medical and receiving royalties or other funds from Transgenomic. Dr. Farrugia and the other authors have disclosed no relevant financial relationships.

Gastroenterology. Published online March 10, 2014.

    
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