基因多态性与肠易激综合征的关系及其对药效的影响

目的探讨5-羟色胺转运体（SERT）基因启动子区域（5-HTTLPR）与第2内含子可变数目串联重复序列（VNTRs）多态性在正常人及肠易激综合征（IBS）患者的分布及对替加色罗治疗便秘型IBS（C-IBS）疗效的影响。方法用PCR检测87例IBS和96例对照者外周血2个基因的多态性;给予41例C-IBS患者4周替加色罗6mg,2次／d,治疗前后评估临床症状及便秘程度。结果IBS组5-HTTLPR基因型频率是S／S：52．9％,S／L：31．0％,L／L：16．1％;对照组分别为57．3％,35．4％及7．3％;IBS组VNTRs基因型频率是STin2．10／10：2．3％,STin2．12／10：17．2％,STin2．12／12：80．5％;对照组分别为2．1％,11．4％及86．5％;两组差异无统计学意义（P〉0．05）,但C-IBS组的I／L频率比对照组显著高（25.0％比7.3％,P〈0．05）。治疗后症状缓解率S／S型为85.0％,S／L型为70．0％,均显著优于L／L型的36．4％（P〈0．05）;主体症状评分和单个症状（排便次数、粪便性状、便后排空感等）改善在S／S和L／S型均优于L／L型（P〈0．05）。结论SERT基因多态性总体与IBS发病无关,但L／L型更易患C-IBS。替加色罗对C—IBS的疗效受基因型影响,L／L型疗效较差。     

肠易激综合征患者5-羟色胺转运体的基因多态性

目的 探讨5-羟色胺转运体(SERT)基因多态性在肠易激综合征(IBS)中的意义。方法 用PCR方法对48例健康对照和30例便秘型IBS(C-IBS)、32例腹泻型IBS(D-IBS)和19例交替型IBS(A-IBS)患者SERT基因的VNTRs和5-HTTLPR区多态性进行研究。结果 VNTRs区：IBS患者STin2．12／10基因型频率明显高于对照组,各亚型间基因型频率差异无显著性。5-HTTLPR区：C-IBS组L／L频率显著高于D-IBS、A-IBS和对照组;D-IBS、A-IBS组IMS频率显著高于C-IBS组。C-IBS组12／12-L／L基因型联合的频率显著高于A-IBS和D-IBS组。结论 SERT基因VNTRs区STin2．12／10基因型可能与IBS相关,具有L／L基因型以及12／12-L／L基因型联合的人群可能更易患C-IBS,IMS基因型的人群易患D-IBS和A-IBS。     

5-羟色胺转运体基因多态性与肠易激综合征的相关性

目的:探讨SERT基因启动子区5-HTTLPR和内含子2 VNTRs多态性在肠易激综合征(IBS) 中的意义．方法:采用PCR方法对51例腹泻型IBS(D- IBS)、58例便秘型IBS(C-IBS)、38例便秘腹泻交替型IBS(A-IBS)患者与48例健康对照者SERT基因启动子区5-HTTLPR和内含子2 VNTRs多态性进行比较分析．结果:C-IBS组L／L基因型及L等位基因频率显著高于对照组(31．0％vs 8．3％,X2=8．229, P<0．05;47．4％vs29．2％,X2=7．342,P<0．05), D-IBS组S／S基因型频率和S等位基因频率显著高于A-IBS和C-IBS组(S／S:56．9％vs 36．8％, 36．2％,P<0．05;S:71．6％vs 56．6％,52．6％, P<0．05),L／L基因频率显著低于A-IBS和C-IBS 组(9．8％vs 28．1％,P<0．05)．IBS各组与对照组之间内含子2 VNTRs多态性分布无显著性差异(P>0．05)．结论:具有L／L基因型和L等位基因的人更易患C-IBS,具有S／S基因型和S等位基因的人更易患D-IBS,L／L基因型可能是D-IBS的保护因素之一．     

替加色罗治疗肠易激综合征的系统评价

目的 评价替加色罗治疗肠易激综合征(irritable bowel syndrome,IBS)的有效性和安全性.方法 对替加色罗治疗便秘型或非腹泻型IBS的随机对照试验(RCTs)进行系统评价.结果 共纳入13项RCTs,7 189例患者.替加色罗12 mg/d和4 mg/d对总体IBS症状的改善均优于安慰剂;对腹痛/腹部不适症状的缓解与安慰剂比无显著差异;对腹胀的疗效,各研究结果不一致;腹泻发生率显著高于安慰剂,替加色罗组报道了2例缺血性心脏病,严重不良事件的发生率与安慰剂比无显著差异.结论 替加色罗能改善便秘型或非腹泻型IBS患者的总体症状;缓解腹痛/腹部不适和腹胀等症状的证据不足;腹泻是替加色罗的主要不良反应.     

替加色罗治疗便秘型肠易激综合征的多中心临床研究

采用多中心、随机、双盲、平行、安慰剂对照临床研究。510例符合罗马Ⅱ标准的C-IBS患者试验期8周,包括2周基线期,4周替加色罗6mg每日2次或安慰剂(替加色罗:安慰剂=1∶1)随机、双盲治疗期及2周停药随访期。评估标准:对患者全部IBS症状进行总体评估,对患者每个IBS参数(包括便秘严重程度)以及安全性进行评估。结果:替加色罗组患者总体IBS症状的主要疗效参数从第1周开始至整个治     

替加色罗治疗便秘型肠易激综合征的多中心临床研究

目的　通过患者对肠易激综合征 (IBS)症状的总体评估和对每个IBS症状的个别评估以及不良反应观察 ,评估替加色罗 6mg每日 2次治疗便秘型肠易激综合征 (C IBS)的疗效与安全性。方法　本研究是一项多中心、随机、双盲、平行、安慰剂对照临床研究。入选 51 0例符合罗马Ⅱ标准的C IBS患者 ,试验为期 8周 ,包括 2周基线期 ,4周替加色罗 6mg每日 2次或安慰剂 (替加色罗∶安慰剂=1∶1 )随机、双盲治疗期及 2周停药随访期。评估标准 :对患者全部IBS症状进行总体评估 ,对患者每个IBS参数 (包括便秘严重程度 )以及安全性进行评估。结果　替加色罗组患者总体IBS症状的主要疗效参数从第 1周开始至整个治疗期均有显著改善。替加色罗组其他IBS疗效参数 (如便秘、腹痛、腹部不适、腹胀 )评分从第 1周开始至整个治疗期仍均优于安慰剂组。说明替加色罗疗效更明显。在停药随访期 ,替加色罗组和安慰剂组各疗效参数评分虽有所降低 ,但相对于基线期仍均有所改善 ,但前者疗效明显优于后者 ,提示替加色罗的疗效至少可持续到停药后 2周。替加色罗组和安慰剂组发生不良事件的比例分别为 1 0 %和 6 %。替加色罗组最常见的不良事件为腹泻、腹痛和头晕 ,但发生率均较低 (<3 % )。实验室检查未发现异常。结论　替加色罗 6mg每日 2次能     

5-羟色胺4受体激动剂(替加色罗)临床应用进展

替加色罗（tegaserod）为一种5-羟色胺4（5-HT4）受体部分激动剂，自问世以来已广泛应用于治疗便秘型肠易激综合征（C-IBS），并在临床应用中取得良好疗效。随着对胃肠道5-HT4受体及其亚型的深入研究和认识以及替加色罗的临床应用观察，发现替加色罗对于多种胃肠道功能性疾病均有一定的治疗作用，本文将就替加色罗的临床应用进展作一综述。     

溃疡性结肠炎与5-羟色胺转运体基因多态性的关系

[目的]探讨溃疡性结肠炎(UC)与5-羟色胺转运体启动区(5-HTTLPR)基因多态性的关系。[方法]聚合酶链反应技术检测30例UC患者(病例组)与30例健康对照组5-HTTLPR多态性的分布频率。[结果]病例组5-HTTLPR的S/S基因频率为50.0%,健康对照组S/S基因频率为33.3%,2组之间比较差异有统计学意义(P<0.05)。病例组5-HTTLPR的L/S、L/L的基因频率分别为40.0%、10.0%,健康对照组L/S、L/L的基因频率分别为43.3%、23.3%,2组之间比较,差异无统计学意义(P>0.05)。[结论]5-HTTLPR的S/S基因型可能与UC的发病有关。     

不同HBV基因型感染慢性乙型肝炎患者对核苷(酸)类药物治疗的应答反应比较

目的研究与探讨HBV基因型与慢性乙型肝炎患者肝组织病理学变化及对核苷(酸)类抗病毒药物疗效的关系。方法随机将慢性HBV感染者541例分为4组:拉米夫定组136例、替比夫定组135例、恩替卡韦组135例和阿德福韦组135例,各治疗48周。治疗前应用聚合酶链反应法确定HBV基因型,并于治疗前和治疗48周时分别检测肝功能、HBV DNA和HBV M。其中109例行肝组织病理学检查。结果本组HBV B基因型94例(17.38%),C型410例(75.79%),B/C混合型37例(6.84%),未检出其他基因型;在B型感染者,肝组织G3占37.3%、S313.0%,C型感染者G3占8.7%、S3占22.7%,B基因型与C基因型之间比较,有统计学意义(P<0.05);在拉米夫定、恩替卡韦和替比夫定治疗患者,B型、C型和B/C混合型之间疗效的比较,有统计学差异(P<0.05),而在阿德福韦酯治疗患者,几种不同的基因型感染患者疗效无统计学差异(P>0.05)。结论 HBV基因型与患者肝组织病理学改变及对核苷类抗病毒治疗的疗效密切相关。     

枸橼酸莫沙比利分散片治疗便秘型肠易激综合征疗效机理的探讨

目的从5-羟色胺转运体基因型和肠道5-HT表达等方面探讨枸橼酸莫沙比利分散片治疗C—IBS疗效机制。方法应用PCR及免疫组化方法检测枸橼酸莫沙比利分散片治疗前后5一羟色胺转运体基因型和肠道5-HT的表达．并进行临床症状的临床评估。结果C—IBS组基因频率分别为：S／S：50．3％，S／L：24．9％，L／L：24．8％。与对照组相比，C-IBS组有较高的S／S基因频率。C—IBS组S／S、S／L、L几基因组治疗前5-HT表达率与治疗后各组及对照组比较均有统计学差异。S／S、S／L组组患者的每周排便次数均明显高于L几组：S／S组和S／L组患者每周大便性状平均分数均低于L几组：对于腹痛／腹部不适，3组基因型比较无差异；S／S组和S／L组患者腹胀症状缓解较L几组患者显著。治疗后，3组基因型患者总有效率分别地S／S：83．0％，S／L：71．0％，L／L：40．O％，差异有显著性。结论SIS型患者的SERT蛋白低表达。5-HT堆积，使5—HT4受体发生适应性下调或去敏感，可能与临床症状和药物疗效有关。     

Serotonin transporter gene polymorphism in irritable bowel syndrome

OBJECTIVES: Serotonin is a key mediator of intestinal peristalsis, and after it is secreted, it is effectively cleansed from the neuronal gap by means of a high affinity substance called serotonin transporter (SERT), which depends on the Na+ and Cl- ions localized in the presynaptic neuronal membranes. The aim of this study was to investigate SERT polymorphism in patients with irritable bowel syndrome (IBS). METHODS: SERT gene polymorphism was assessed by polymerase chain reaction on DNA chains obtained from leukocytes in serum samples from 54 patients diagnosed with IBS and 91 healthy subjects. The polymorphism of two regions (variable number tandem repeats and the SERT gene-linked polymorphic region [5-HTTLPR]) of SERT was assessed. RESULTS: SERT polymorphisms were found to be similar in healthy subjects and IBS patients (p > 0.05). IBS patients were divided into three groups: diarrhea predominant (n = 18), constipation predominant (n = 26), and alternating diarrhea and constipation (n = 10). These groups were compared with respect to gene polymorphism, and it was found that the 5-HTTLPR allele S/S genotype occurred with greater frequency in the constipation predominant group than in the other two subgroups (p < 0.05), and L/S genotype frequency in the diarrhea predominant group was higher than those in the constipation and control groups. CONCLUSIONS: No relationship was found between IBS and SERT gene polymorphism. It is conceivable that the presence of the S/S genotype in IBS patients carries an increased risk of the constipation predominant type of IBS, whereas the presence of the 5-HTTLPR allele L/S genotype carries an increased risk of the diarrhea predominant type.     

肝郁脾虚型肠易激综合征与5-羟色胺转运体基因多态性的关系

[目的]探讨肝郁脾虚型肠易激综合征（IBS）与5-羟色胺转运体（SERT）基因多态性的关系。[方法]用多聚酶链式反应技术（PCR）对50例肝郁脾虚型IBS患者与96例健康对照者SERT基因的启动子区（5-HTTLPER）和内含子2可变数目串联重复序列（VNTRs）多态性进行研究。[结果]肝郁脾虚型组5-HTTLPR基因频率分布是S／S 40．0％，L／S54．0％，L／L11．1％。健康对照组的分布频率是S／S57．3％，L／S35．4％，L／L7．3％。2组之间比较差异无统计学意义（P〉0．05），但肝郁脾虚型组的L／S基因频率比对照组明显升高（P〈0．05）。2组VNTRs区的多态性比较差异无统计学意义（P〉0．05）。[结论]拥有L／S基因型可能是肝郁脾虚型IBS的多个易患因素之一。     

The Association of Serotonin Transporter Genetic Polymorphisms and Irritable Bowel Syndrome and Its Influence on Tegaserod Treatment in Chinese Patients

The aims of this study were to investigate the relationship of genetic polymorphisms of the serotonin reuptake transporter and the clinical subtypes of irritable bowel syndrome and its influence on the efficacy of tegaserod in Chinese irritable bowel syndrome patients with constipation. Genetic polymorphisms were analyzed in 87 patients and 96 controls, then 41 irritable bowel syndrome patients with constipation received tegaserod for 4 weeks. The primary efficacy variable was the responder rate measured by Subject's Global Assessment of Relief. Secondary efficacy assessed the changes of individual symptoms weekly. There was no significant difference in genotype frequencies between the patients as a whole and the control group. The frequency of the L/L genotype in the serotonin transporter gene-linked polymorphic region was significantly higher in patients with constipation than in controls (25.0% vs. 7.3%). Responder rates to tegaserod were significantly higher in the S/S (85.0%) and L/S (70.0%) than in the L/L genotype (36.4%). All secondary variables also significantly improved in the S/S and L/S groups compared to the L/L group. This study suggests the hypothesis that individuals with the L/L genotype are vulnerable to development of irritable bowel syndrome with constipation, and patients with the L/L genotype respond poorly to treatment with a routine dose of tegaserod.     

皮质下缺血性抑郁症患者5-羟色胺转运体基因启动子区基因多态性和认知功能研究

目的 探讨皮质下缺血性抑郁症(SID)患者5-羟色胺转运体基因启动子区(5-HTTLPR)基因多态性分布特征和认知功能及其之间关系.方法 运用汉密尔顿抑郁量表(HAMD)、简易智能状态检查量表(MMSE)、蒙特利尔量表(MoCA)对所有被试者进行抑郁和认知功能评定.运用多聚酶链式反应-限制性片段长度多态性技术(PCR-RFLP)检测60例SID患者与60例健康老年对照者5-HTTLPR基因多态性的分布频率.结果 SID组与对照组比较,5-HTTLPR基因型频率及等位基因频率差异均有统计学意义(χ2=7.833及χ2=6.290,均P＜0.05),SID患者SS等位基因型频率(58.3%)显著高于对照组(23.3%);S等位基因频率(68.3%)也显著高于对照组(52.5%).SID组MoCA总分(23.63±1.59)分,低于对照组的(27.25±1.59)分,差异具有统计学意义(t=12.44,P＜0.01).结论 5-HTTLPR的SS基因型可能是SID的易感基因.SS纯合子可能是SID特别是女性发病的危险因子;等位基因L及其纯合子可能是SID抑郁症状的保护因子.SID患者存在一定的认知功能损害.

Abstract：

Objective To explore the polymorphisms of serotonin transporter gene-linked promoter region (5-HTTLPR) and cognitive function in patients with subcortical ischemic depression (SID). Methods A battery of neuropsychological tests including Hamilton Depression Scale (HAMD), Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to evaluate depression and cognitive function for all enrolled subjects. And the distribution frequency of 5-HTTLPR-promoter region polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in 60 SID patients and 60 health controls. Results There were significant differences in 5-HTTLPR genotypes and alleles between SID group and control group (χ2=7.833, χ2=6.290, both P＜0.05).The SID group showed higher genotype SS than did the control group (58.3% vs. 23.3%) and higher allele S (68.3% vs. 52.5%) but lower genotype LL (16.7% vs. 23.3%) and allele L (31.7% vs. 47.5%). SID group had lower MoCA score than did the control group [(23.63±1.59) scores vs. (27.25±1.59) scores, t=12.44, P＜0.01]. Conclusions The polymorphism of 5-HTTLPR gene may play an important role as a nosogenesis of SID. The frequency of SS genotype may be associated with SID especially in females, having more cognitive impairment. The genotype LL and allele L may be a protective factor for depression symptoms of SID.     

Candidate gene studies of fibromyalgia: a systematic review and meta-analysis

The aim of this study was to explore whether the candidate gene polymorphisms contribute to fibromyalgia susceptibility. The authors conducted a meta-analysis on associations between serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) S/L allele, catechol-O-methltransferase (COMT) val158Met, and serotonin 2A (5-HT2A) receptor 102T/C polymorphisms and fibromyalgia susceptibility as determined using the following: (1) allele contrast, (2) recessive, (3) dominant models, and (4) contrast of homozygotes. We also performed a systematic review with available data of the candidate genes. A total of 21 separate comparisons were considered in this systematic review and meta-analysis. Seventeen candidate genes and over 35 different polymorphisms were identified in studies on fibromyalgia susceptibility. Meta-analysis of the 5-HTTLPR S/L allele and COMT val158Met failed to reveal any association with fibromyalgia. However, meta-analysis of the C allele, CC + CT genotype, and CC versus TT genotype of the 5-HT2A receptor 102T/C polymorphism showed significant association with fibromyalgia. The overall OR of the association between the C allele and fibromyalgia was 1.333 (95% CI = 1.053–1.688, P = 0.017). The ORs for the CC + CT genotype, and CC versus TT genotype showed the same pattern as that observed for the C allele (OR = 1.541, 95% CI = 1.032–2.303, P = 0.035; OR = 1.838, 95% CI = 1.151–2.936, P = 0.011). This meta-analysis demonstrates that the 5-HT2A receptor 102T/C polymorphism confers susceptibility to fibromyalgia. In contrast, no association was found between the 5-HTTLPR S/L allele, COMT val158Met, and susceptibility to fibromyalgia.     

Neomycin Improves Constipation-Predominant Irritable Bowel Syndrome in a Fashion That Is Dependent on the Presence of Methane Gas: Subanalysis of a Double-Blind Randomized Controlled Study

Recent studies have shown that normalization of the lactulose breath test (LBT) with neomycin leads to a significant reduction in irritable bowel syndrome (IBS) symptoms. This subanalysis was done on the constipation-predominant IBS subgroup of patients (C-IBS) to test the ability of neomycin to improve constipation and its correlation with the elimination of methane on breath test. IBS subjects underwent LBT in a blinded fashion. They were then randomly allocated to neomycin or placebo groups. For the purpose of this analysis, only the C-IBS subjects were identified. They were then evaluated for global improvement, abdominal pain, and constipation severity. The ability of neomycin to eliminate methane and its associated improvement in constipation was also determined. One hundred eleven subjects meeting Rome I criteria for IBS were included in the study. Thirty-nine of these had C-IBS. Of these, 20 received placebo and 19 received neomycin. With neomycin, a global improvement of 36.7±7.9% was seen, compared to 5.0±3.2% for placebo (P < .001) in the intention-to-treat analysis. Constipation was improved by 32.6±9.9% with neomycin compared to 18.7±7.2% for placebo (P=.26). Of the original 111 subjects, 12 demonstrated methane on breath test. All 12 of these patients were constipation predominant. In the methane producers receiving neomycin or placebo, improvement in constipation was significantly greater in those receiving neomycin (44.0±12.3%) compared to placebo (5.0±5.1%) (P < .05). Treatment with neomycin improves constipation in C-IBS. This improvement depends on the presence and elimination of methane on breath test.