基因多态性与肠易激综合征的关系及其对药效的影响

Serotonin transporter gene polymorphisms in irritable bowel syndrome and their impact on tegaserod treatment

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6 mg,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L／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。

Objective To investigate the serotonin reuptake transporter （SERT） genetic polymorphisms in the 5-hydroxytryptamine （5-HT） transporter gene-linked polymorphic region （5-HTTLPR） and the variable number tandem repeats （VNTRs） in intron 2 among Chinese people, and their relationship to the pathogenesis of irritable bowel syndrome （IBS） ; and to investigate the impact of SERT geno .types on the efficacy of 5-HT4 receptor agonist tegaserod in constipation predominant type（C-IBS） patients. Methods PCR was used to detect the genetic polymorphisms in 87 patients with IBS confirmed with Rome Ⅱ criteria and 96 healthy subjects, then 41 C-IBS patients received tegaserod 6 mg twice daily for 4 weeks. Each patient recorded his or her symptoms in a diary. Efficacy was assessed by patient＇s experience of overall symptoms and severity of constipation before and after the treatment. Results The 5-HTTLPR genotypes frequencies were： S/S 52. 9% ,S/L 31.0%, L/L 16. 1% in IBS patients; and S/S 57. 3%, S/L 35.4%, L/L 7. 3% in control. VNTRs genotypes were STin2. 10/10：2. 3%, STin2. 12/10：17. 2%, STin2. 12/12： 80. 5% in IBS patients; and STin2. 10/10：2. 1%, STin2. 12/10：11.4%, STin2. 12/12：86. 5% in control. There was no significant difference in the two genotypes frequencies between IBS and control groups （ P 〉 0.05 ）. However, the allele frequency of the L/L genotype was significantly higher in the C-IBS group than in control （25.0% vs 7. 3% , P 〈0. 05）. The clinical responder rates of tegaserod in S/S （85.0%） and S/L （ 70. 0% ） genotypes differed significantly from that （ 36. 4% ） in L/L genotype （ P 〈 0.05 ）. The scores of Subject＇s Global Assessment of relief after treatment were： S/S 1.35 ±0. 81, S/L 1.70±0. 95 vs L/L 2.27 ± 0.45 （ P 〈 0. 05 ）. All other variables for assessment of efficacy including stool frequency, stool consistency and sensation of bowel complete evacuation in L/L genotype were also significantly poorer than those in S/S and S/L （P 〈 0. 05）. Conclusions 5-HTTLPR and VNTRs genetic polymorphisms existed in Chinese people. In general, the genotypes were not involved in the pathogenesis of IBS. However people with L/L genotype were vulnerable for development of C-IBS. The 5-HTTLPR genetic polymorphisms influenced the efficacy of tegaserod treatment in C-IBS patients with L/L being poorer than S/S and S/L genotypes.