多药耐药基因多态性与炎症性肠病的临床研究
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摘要
目的探讨多药耐药基因(MDR1)多态性(C3435T和G2677T/A)与我国炎症性肠病的临床关联。
方法收集临床确诊的71例IBD患者(60例UC,11例CD)外周抗凝血,提取DNA,采用多聚酶链式反应-限制性内切酶片段长度多态性方法测定MDR1的多态性。同时记录IBD患者的病史和相关检查结果,记录UC患者使用激素的治疗反应,用于分组比较。对照组为性别匹配、年龄基本匹配的无消化道症状的健康体检者。调取60例确诊UC患者结肠镜检查的粘膜活检病理蜡块,同时留取门诊结肠镜检查正常的健康对照者的结肠粘膜,共20例。采用链霉菌抗生物素蛋白-过氧化酶(SP)法,了解结肠粘膜Pgp的表达变化。
结果⑴UC患者临床资料分析:60例UC患者男性多于女性,男女性别比例1.3:1,平均发病年龄38.7±13.0岁,20~40岁为发病高峰,平均病程3.7±4.3年。其中伴肠外表现者:胆结石4例(6.6%),口腔溃疡5例(8.3%),坏疽性脓皮病1例(1.6%)。使用口服激素或静脉激素治疗共30例(50%),其中激素耐药或依赖5例(16.6%),使用免疫抑制剂硫唑嘌呤治疗2例(6.7%)。临床类型以慢性复发型(41例,68.3%)和初发型(13例,21.7%)为主,慢性持续型5例(8.3%),暴发型1例(1.7%)。病变范围以全结肠型为主(25例,41.6%),直肠/直乙状结肠型21例(35%),广泛结肠型7例(11.7%),左半结肠型7例(11.7%)。活动期UC中全结肠炎患者及广泛结肠炎患者病变严重度以重度为主,而左半结肠炎患者及直肠/直乙状结肠炎患者病变严重度以轻度为主。病变范围与临床类型无关。⑵CD患者临床资料分析:11例CD患者平均发病年龄36.3±12.4岁,平均病程2.6±1.9年,男女性别比1.2:1。病变类型以非狭窄、非穿孔型(5例,45.5%)和狭窄型(5例,45.5%)为主,穿孔型1例(9.0%),伴肛周病变2例(18.2%)。病变部位以回肠型及回结肠型居多(分别为27.2%和36.4%)。行左半结肠切除术1例(9.1%)。使用激素治疗共6例(54.5%),其中强的松联合免疫抑制剂硫唑嘌呤治疗共4例(36.4%)。⑶MDR1基因型分析:病例组和对照组中MDR1 C3435T和G2677T/A基因分布符合Hardy-Weinberg平衡(P>0.05)。病例组中MDR1 C3435T基因型频率分别为CC型38.0%,CT型45.1%,TT型16.9%;MDR1 G2677/A基因型频率分别为GG型33.8%,GA型25.4%,GT型11.2%,TT型15.5%,TA型9.9%,AA型4.2%。MDR1 C3435T和G2677T/A各基因型在病例组和对照组中总体分布没有差别。C3435T TT基因型频率和T等位基因频率在IBD组和对照组中分布无显著差异,比较G2677T/A TT型基因频率和T等位基因频率在两组中的分布,也未发现统计学差异。C3435T各基因型与UC病变范围及病变严重度均无关。G2677T/A TT基因型在直肠/直乙状结肠炎中占有明显优势(P=0.048,OR 3.375(1.01~11.279)),但与UC病变严重度无关。观察记录全身应用糖皮质激素治疗的UC患者,按糖皮质激素治疗反应,分为激素有效组和激素依赖或耐药组。比较发现激素有效组与对照组相比MDR1基因型分布无统计学差异。C3435T TT基因型频率和T等位基因频率以及G2677T/A TT基因型频率和T等位基因频率在上述各组分布均无差异。⑷Pgp免疫组化结果:在UC病例组Pgp表达阳性率65%(39例),对照组Pgp表达阳性率55%(11例),两组Pgp阳性率无显著差异(χ2=0.640,P=0.424)。其中病例资料完整共37例,按照UC病变严重程度分组后比较,发现在UC轻度活动组Pgp表达阳性率最高(80%),但是与对照组及UC中度组、重度组相比,无统计学差别(P>0.05)。
结论(1)UC以青壮年发病居多,住院病例中累及全结肠多见。临床类型以慢性复发型为主。活动期UC中,病变范围与病变严重度有关。CD病变以非狭窄非穿孔型及狭窄型为主,病变部位以回肠及回结肠居多。(2)MDR1基因多态性在IBD组与对照组之间分布无差异。各基因型与UC病变严重度无关,但可能会影响UC病变范围,G2677T/A TT基因型与直肠/直乙状结肠炎明显相关。(3)未发现MDR1基因多态性与UC激素疗效相关,但由于样本量较少,进一步大样本研究仍有必要。(4)UC结肠粘膜Pgp表达与正常人相比无显著差异,UC病变严重度与Pgp表达无明显相关。
Purpose:To investigate the association between Multidrug resistance gene (MDR1) polymorphism (C3435T and G2677T / A) and inflammatory bowel disease(IBD) in China.
Methods:With collecting the clinical date of IBD patients, the genotype of C3435T and G2677T/A was detected using polymerase chain Reaction-restriction fragment length polymorphism(RFLP-PCR) in 71 patients with IBD(include 60 UC and 11 CD) and 71 healthy controls. The controls were gender and age-matched to cases. Then we investigate the association between Multidrug resistance gene polymorphism and the UC patients who use the glucocorticoid after stratified by the respond of the glucocorticoid. We collecte the mucosa biopsy wax block of 60 UC patients,and 20 cases of colonic mucosa biopsy specimens from healthy controls with normal colonoscopy.Then using streptavidin-biotin-peroxidase method(SP) to investigate the expression of Pgp in the colon mucosa
Results:(1) Clinical Analysis of UC: The ratio of male to female was 1.3:1 in 60 cases of UC. The mean age of onset was 38.7±13.0 years old and the mean duration of the disease was 3.7±4.3 years old. The peak of incidence was 20~40 years old.In the patients who had extra-intestinal manifestations, four of them(6.6%) have gall-stone,five of them(8.3%) had canker sore and one of them(1.6%) had pyoderma gangraenosum. A total of 30 cases used oral or intravenous glucocorticoid therapy, five of them (16.6%) were glucocorticoid-depedent or glucocorticoid-resistance, two of them used immunosuppressive agents azathioprine treatment. The cases of chronic relapsing(68.3%) and first onset(21.7%) were the most common,in all cases, 8.3% were chronic persistent,only 1.7% were acute fluminant type. The most of patients revealed pancolitis(41.6%),35% of patients had proctitis or proctosigmoiditis, 11.7% had extensive colitis,and 11.7% were diseased to the splenic flexure. In the active UC patients,most of the pancolitis and extensive colitis revealed severity disease, however, the left-side colitis and proctitis or proctosigmoiditis were mostly moderate severity. Disease extent is not correlated with disease clincical types. (2)Clinical Anaysis of CD: There were 11 cases of CD. The mean age of onset was 36.3±12.4 years old and the mean duration of the disease was 2.6±1.9 years old. The ratio of male to female was 1.2/1. In all the patients,one had left hemicolectomy (9.1%),two had perianal lesions(18.2%),six of them used glucocorticoid(54.5%), among the six patientsfour had used glucocorticoid and azathioprine. Disease behaviour was nonstricturing,nonpenetrating in 5 patients(45.5%),structuring in 5 patients(45.5%),and penetrating in 1 patient(9.0%). The location of most patients were terminal ileum and ileocolonic(27.2%,36.4%, respectively). (3) The genotype of MDR1 analysis: The MDR1 C3435T and G2677T/A gene distribution in line with the Hardy-Weinberg balance (P> 0.05) in the cases and controls. The genotype frequencies of CC,CT and TT of MDR1 C3435T were 38.0%,45.1% and 16.9%, respectively. The genotype frequencies of GG,GA,GT,TT,TA and AA of MDR1 G2677/A were 33.8%,25.4%,11.2%,15.5%,9.9%and 4.2%, respectively. No significant difference was observed for both MDR1 G2677T/A and C3435T polymorphisms on overall disease susceptibility for IBD patients compared to the control subjects. Both the T allele and TT genotype of the MDR1 3435 SNP were no significant difference in patients with IBD compared with healthy controls,the same as the T allele and TT genotype of the MDR1 2677 SNP.The C3435T SNP was not correlated with disease extent and disease severity of UC. The 2677TT genotype trend to be higher in the patients of sigmoiditis and proctitis(P=0.048,OR 3.375(1.01-11.279)),but there was no relationship between G2677T/A SNP and the disease severity of UC. The UC patients who received systemic glucocorticoid therapy were recruited and divided into steroid-effective colitis and steriod-dependent or steroid-refractory colitis according to the response to therapy. The genotype distribution was not statistically difference between the effective group and control group. There was no statistically difference of 3435T/2677T allele and 3435TT/2677TT genotype between steroid-effective group , steroid-dependent / steroid-refractory group and the controls.(4)The results of Pgp immunohistochemical: In the UC patients group, the positive rate of Pgp expression was 65%, while the positive rate in the control group was 55%. There was no difference between the two group(χ2=0.640,P=0.424). After stratified by the disease severity in the 37 patients with compelte case information, we found the positive rate of Pgp expression was highest in the mild severity group(80%), however it was no statistical difference(P>0.05). Conclusions:(1)In the hospitalized cases of UC, the onset is mostly middle-aged, pancolitis is the most common.The clinical type mostly is chronic relapsing.The disease extent is correlated with the disease severity in active UC. Disease behaviour of CD patients are mainly nonstricturing, nonpenetrating and structuring. While the location of most patients were terminal ileum and ileocolonic. (2) The distribution of MDR1 gene polymorphism in the IBD group and control group was found no significant difference. The genotypes of MDR1 are not associated with disease severity of UC,however,it may be effect the extent of disease, because the 2677TT genotype is correlated with sigmoiditis and proctitis. (3)We find there is no relationship between the MDR1 gene polymorphism and the respond of glucocorticoid therapy in UC patients. But as the sample is small, further study of larger sample is needed. (4) The expression of Pgp in the colon mucosa of UC patients is not different with controls. It is not associated with disease severity of UC.
方法收集临床确诊的71例IBD患者(60例UC,11例CD)外周抗凝血,提取DNA,采用多聚酶链式反应-限制性内切酶片段长度多态性方法测定MDR1的多态性。同时记录IBD患者的病史和相关检查结果,记录UC患者使用激素的治疗反应,用于分组比较。对照组为性别匹配、年龄基本匹配的无消化道症状的健康体检者。调取60例确诊UC患者结肠镜检查的粘膜活检病理蜡块,同时留取门诊结肠镜检查正常的健康对照者的结肠粘膜,共20例。采用链霉菌抗生物素蛋白-过氧化酶(SP)法,了解结肠粘膜Pgp的表达变化。
结果⑴UC患者临床资料分析:60例UC患者男性多于女性,男女性别比例1.3:1,平均发病年龄38.7±13.0岁,20~40岁为发病高峰,平均病程3.7±4.3年。其中伴肠外表现者:胆结石4例(6.6%),口腔溃疡5例(8.3%),坏疽性脓皮病1例(1.6%)。使用口服激素或静脉激素治疗共30例(50%),其中激素耐药或依赖5例(16.6%),使用免疫抑制剂硫唑嘌呤治疗2例(6.7%)。临床类型以慢性复发型(41例,68.3%)和初发型(13例,21.7%)为主,慢性持续型5例(8.3%),暴发型1例(1.7%)。病变范围以全结肠型为主(25例,41.6%),直肠/直乙状结肠型21例(35%),广泛结肠型7例(11.7%),左半结肠型7例(11.7%)。活动期UC中全结肠炎患者及广泛结肠炎患者病变严重度以重度为主,而左半结肠炎患者及直肠/直乙状结肠炎患者病变严重度以轻度为主。病变范围与临床类型无关。⑵CD患者临床资料分析:11例CD患者平均发病年龄36.3±12.4岁,平均病程2.6±1.9年,男女性别比1.2:1。病变类型以非狭窄、非穿孔型(5例,45.5%)和狭窄型(5例,45.5%)为主,穿孔型1例(9.0%),伴肛周病变2例(18.2%)。病变部位以回肠型及回结肠型居多(分别为27.2%和36.4%)。行左半结肠切除术1例(9.1%)。使用激素治疗共6例(54.5%),其中强的松联合免疫抑制剂硫唑嘌呤治疗共4例(36.4%)。⑶MDR1基因型分析:病例组和对照组中MDR1 C3435T和G2677T/A基因分布符合Hardy-Weinberg平衡(P>0.05)。病例组中MDR1 C3435T基因型频率分别为CC型38.0%,CT型45.1%,TT型16.9%;MDR1 G2677/A基因型频率分别为GG型33.8%,GA型25.4%,GT型11.2%,TT型15.5%,TA型9.9%,AA型4.2%。MDR1 C3435T和G2677T/A各基因型在病例组和对照组中总体分布没有差别。C3435T TT基因型频率和T等位基因频率在IBD组和对照组中分布无显著差异,比较G2677T/A TT型基因频率和T等位基因频率在两组中的分布,也未发现统计学差异。C3435T各基因型与UC病变范围及病变严重度均无关。G2677T/A TT基因型在直肠/直乙状结肠炎中占有明显优势(P=0.048,OR 3.375(1.01~11.279)),但与UC病变严重度无关。观察记录全身应用糖皮质激素治疗的UC患者,按糖皮质激素治疗反应,分为激素有效组和激素依赖或耐药组。比较发现激素有效组与对照组相比MDR1基因型分布无统计学差异。C3435T TT基因型频率和T等位基因频率以及G2677T/A TT基因型频率和T等位基因频率在上述各组分布均无差异。⑷Pgp免疫组化结果:在UC病例组Pgp表达阳性率65%(39例),对照组Pgp表达阳性率55%(11例),两组Pgp阳性率无显著差异(χ2=0.640,P=0.424)。其中病例资料完整共37例,按照UC病变严重程度分组后比较,发现在UC轻度活动组Pgp表达阳性率最高(80%),但是与对照组及UC中度组、重度组相比,无统计学差别(P>0.05)。
结论(1)UC以青壮年发病居多,住院病例中累及全结肠多见。临床类型以慢性复发型为主。活动期UC中,病变范围与病变严重度有关。CD病变以非狭窄非穿孔型及狭窄型为主,病变部位以回肠及回结肠居多。(2)MDR1基因多态性在IBD组与对照组之间分布无差异。各基因型与UC病变严重度无关,但可能会影响UC病变范围,G2677T/A TT基因型与直肠/直乙状结肠炎明显相关。(3)未发现MDR1基因多态性与UC激素疗效相关,但由于样本量较少,进一步大样本研究仍有必要。(4)UC结肠粘膜Pgp表达与正常人相比无显著差异,UC病变严重度与Pgp表达无明显相关。
Purpose:To investigate the association between Multidrug resistance gene (MDR1) polymorphism (C3435T and G2677T / A) and inflammatory bowel disease(IBD) in China.
Methods:With collecting the clinical date of IBD patients, the genotype of C3435T and G2677T/A was detected using polymerase chain Reaction-restriction fragment length polymorphism(RFLP-PCR) in 71 patients with IBD(include 60 UC and 11 CD) and 71 healthy controls. The controls were gender and age-matched to cases. Then we investigate the association between Multidrug resistance gene polymorphism and the UC patients who use the glucocorticoid after stratified by the respond of the glucocorticoid. We collecte the mucosa biopsy wax block of 60 UC patients,and 20 cases of colonic mucosa biopsy specimens from healthy controls with normal colonoscopy.Then using streptavidin-biotin-peroxidase method(SP) to investigate the expression of Pgp in the colon mucosa
Results:(1) Clinical Analysis of UC: The ratio of male to female was 1.3:1 in 60 cases of UC. The mean age of onset was 38.7±13.0 years old and the mean duration of the disease was 3.7±4.3 years old. The peak of incidence was 20~40 years old.In the patients who had extra-intestinal manifestations, four of them(6.6%) have gall-stone,five of them(8.3%) had canker sore and one of them(1.6%) had pyoderma gangraenosum. A total of 30 cases used oral or intravenous glucocorticoid therapy, five of them (16.6%) were glucocorticoid-depedent or glucocorticoid-resistance, two of them used immunosuppressive agents azathioprine treatment. The cases of chronic relapsing(68.3%) and first onset(21.7%) were the most common,in all cases, 8.3% were chronic persistent,only 1.7% were acute fluminant type. The most of patients revealed pancolitis(41.6%),35% of patients had proctitis or proctosigmoiditis, 11.7% had extensive colitis,and 11.7% were diseased to the splenic flexure. In the active UC patients,most of the pancolitis and extensive colitis revealed severity disease, however, the left-side colitis and proctitis or proctosigmoiditis were mostly moderate severity. Disease extent is not correlated with disease clincical types. (2)Clinical Anaysis of CD: There were 11 cases of CD. The mean age of onset was 36.3±12.4 years old and the mean duration of the disease was 2.6±1.9 years old. The ratio of male to female was 1.2/1. In all the patients,one had left hemicolectomy (9.1%),two had perianal lesions(18.2%),six of them used glucocorticoid(54.5%), among the six patientsfour had used glucocorticoid and azathioprine. Disease behaviour was nonstricturing,nonpenetrating in 5 patients(45.5%),structuring in 5 patients(45.5%),and penetrating in 1 patient(9.0%). The location of most patients were terminal ileum and ileocolonic(27.2%,36.4%, respectively). (3) The genotype of MDR1 analysis: The MDR1 C3435T and G2677T/A gene distribution in line with the Hardy-Weinberg balance (P> 0.05) in the cases and controls. The genotype frequencies of CC,CT and TT of MDR1 C3435T were 38.0%,45.1% and 16.9%, respectively. The genotype frequencies of GG,GA,GT,TT,TA and AA of MDR1 G2677/A were 33.8%,25.4%,11.2%,15.5%,9.9%and 4.2%, respectively. No significant difference was observed for both MDR1 G2677T/A and C3435T polymorphisms on overall disease susceptibility for IBD patients compared to the control subjects. Both the T allele and TT genotype of the MDR1 3435 SNP were no significant difference in patients with IBD compared with healthy controls,the same as the T allele and TT genotype of the MDR1 2677 SNP.The C3435T SNP was not correlated with disease extent and disease severity of UC. The 2677TT genotype trend to be higher in the patients of sigmoiditis and proctitis(P=0.048,OR 3.375(1.01-11.279)),but there was no relationship between G2677T/A SNP and the disease severity of UC. The UC patients who received systemic glucocorticoid therapy were recruited and divided into steroid-effective colitis and steriod-dependent or steroid-refractory colitis according to the response to therapy. The genotype distribution was not statistically difference between the effective group and control group. There was no statistically difference of 3435T/2677T allele and 3435TT/2677TT genotype between steroid-effective group , steroid-dependent / steroid-refractory group and the controls.(4)The results of Pgp immunohistochemical: In the UC patients group, the positive rate of Pgp expression was 65%, while the positive rate in the control group was 55%. There was no difference between the two group(χ2=0.640,P=0.424). After stratified by the disease severity in the 37 patients with compelte case information, we found the positive rate of Pgp expression was highest in the mild severity group(80%), however it was no statistical difference(P>0.05). Conclusions:(1)In the hospitalized cases of UC, the onset is mostly middle-aged, pancolitis is the most common.The clinical type mostly is chronic relapsing.The disease extent is correlated with the disease severity in active UC. Disease behaviour of CD patients are mainly nonstricturing, nonpenetrating and structuring. While the location of most patients were terminal ileum and ileocolonic. (2) The distribution of MDR1 gene polymorphism in the IBD group and control group was found no significant difference. The genotypes of MDR1 are not associated with disease severity of UC,however,it may be effect the extent of disease, because the 2677TT genotype is correlated with sigmoiditis and proctitis. (3)We find there is no relationship between the MDR1 gene polymorphism and the respond of glucocorticoid therapy in UC patients. But as the sample is small, further study of larger sample is needed. (4) The expression of Pgp in the colon mucosa of UC patients is not different with controls. It is not associated with disease severity of UC.
引文
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17 Sparreboom A, Danesi R, Ando Y,et al.Pharmacogenomics of ABC transporters and its role in cancer chemotherapy.Drug Resist Updat,2003,6:71-84 .
18 Schwab M,Schaeffeler E,Marx C,et al.Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis.Gastroenterology, 2003,124:26–33.
19 Brant SR,PanhuysenCI,Nicolae D,et al.MDR1 Ala893 polymorphism is associated with inflammatory bowel disease.Am J Hum Genet,2003, 73:1282–1292.
20梁惠琪,焦正,丁俊杰,等.多药耐药基因多态性和单倍体对环孢素A血药浓度的影响.中华检验医学杂志,2005,28(12):1235-1238.
21王玮,张小东,马麟麟,等.肾移植中他克莫司的血药浓度与多药耐药基因多态性的关系.中华医学杂志,2005,85(146):3277-3281.
22中华医学会消化病学分会炎症性肠病协作组.对我国炎症性肠病诊断治疗规范的共识意见.中华消化杂志,2007,27(8):545-550.
23 Best WR, Becktel JM, Singleton JW, et al.Development of a Crohn’s disease activity index.National Cooperative Crohn’s Disease Study.Gastroenterology, 1976,70:439-444.
24 Satsangi J, Silverberg MS, Vermeire S,et al.The Montreal classification of inflammatory bowel disease:controversies, consensus, and implications. Gut,2006, 55:749–753.
25 E.F. Stange,S.P.L.Travis,SVermeire,et al.European evidence-based Consensus on the diagnosis and management of ulcerative colitis.Journal of Crohn's and Colitis,2008,2: 1-23.
26 Turgut S,Turgut G,Atalay EO¨.Genotype and allele frequency of human multidrug resistance (MDR1) gene C3435T polymorphism in Denizli province of Turkey. Mol Biol Rep, 2006,33:295-300.
27 Masaki K, Tsuyoshi F, Alessandro S,et al.ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder.Progress in Neuro-Psychopharmacology & Biological Psychiatry,2008,32: 398–404.
28 Farrell RJ, Murphy A, Long A, et al.High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy. Gastroenterology, 2000,118:279–288.
29欧阳钦.炎症性肠病研究进展[M].成都:四川科学技术出版社,2000:120.
30 Cao Q, Si JM, Gao M, et al.Clinical presentation of inflammatory bowel disease: a hospital based retrospective study of 379 patients in eastern China.Chin Med J, 2005,118(9):747-752.
31 Rupert W.L.Leong, James Y.Lau, Joseph J.Y.Sung, et al.The Epidemiology and Phenotype of Crohn’s Disease in the Chinese Population. Inflamm Bowel Dis. 2004,10:646–651.
32 Soetikno RM, Lin OS,Heidenreich PA,et al.Increased risk of colorectal neoplasia inpatients with primarysclerosing cholangitis and ulcerative colitis: a meta-analysis.Gastrointest Endosc, 2002,56:48–54.
33 Nuako KW, Ahlquist DA, Mahoney DW, et al. Familial predisposition for colorectal cancer in chronic ulcerative colitis: a case-control study. Gastroenterology, 1998, 115: 1079–1083.
34 Jess T, Loftus EV, Velayos FS, et al.Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested casecontrol study from Copenhagen county, Denmark and Olmsted county, Minnesota.AmJ Gastroenterol,2007,102:829–836.
35 Velayos FS, Loftus Jr EV, Jess T,et al. Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study. Gastroenterology, 2006, 130:1941–1949.
36 Itzkowitz SH, Present DH.Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease.Inflamm Bowel Dis,2005,11: 314–321.
37 Jolles S,Niclasse S,Benson E.Combination oral and topical tacrolimus in therapy-resistant pyoderma gangrenosum.Br J Dermatol,1999,140:564–565.
38 Brooklyn TN, Dunnill GS, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, doubleblind placebo-controlled trial. Gut, 2006, 55:505–509.
39 Ho GT, Nimmo ER, Tenesa A,et al.Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis. Gastroenterology, 2005,128:288-296.
40 Fiedler T,Büning C,Reuter W,et al.Possible role of MDR1 two-locus genotypes for young-age onset ulcerative colitis but not Crohn's disease.Eur J Clin Pharmacol,2007,63(10):917-925.
41 Palmieri O,Latiano A,Valvano R,et al.Multidrug resistance 1 gene polymorphisms are not associated with inflammatory bowel disease and response to therapy in Italian patients.Aliment Pharmacol Ther,2005,22:1129-1138.
42 Urcelay E, Mendoza JL, Martin MC, et al.MDR1 gene: susceptibility in SpanishCrohn’s disease and ulcerative colitis patients.Inflamm Bowel Dis,2006,12: 33-37.
43 Potocnik U, Ferkolj I, Glavac D, et al.Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis. Genes Immun, 2004,5:530-539.
44 Oostenbrug LE,Di jkstra G,Nolte IM, et al.Absence of association between the multidrug resistance (MDR1) gene and inflammatory bowel disease.Scand J Gastroenterol,2006,41(10):1174-1182.
45 Fischer S, Lakatos PL, Hungarian IBD Study Group, et al.ATP-binding cassette transporter ABCG2 (BCRP) and ABCB1 (MDR1) variants are not associated with disease susceptibility, disease phenotype response to medical therapy or need for surgeryin Hungarian patients with inflammatory bowel diseases.Scand J Gastroenterol, 2007,42(6):726-733.
46 Annese V,Valvano MR,Palmieri O, et al.multidrug resistance 1 gene in inflammatory bowel disease:A meta-analysis.World J Gastroenterol,2006,12(23): 3636-3644.
47 Ameyaw M, Regateiro F, Li T, et al.MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics, 2001, 11(3):217-221.
48 Teh LK, Lee WL, Amir J, et al.Single step PCR for detection of allelic variation of MDR1 gene (P-glycoprotein) among three ethnic groups in Malaysia.J Clin Pharm Ther, 2007,32(3):313-319.
49 Farnood A,Naderi N,Moghaddam SJ, et al.The frequency of C3435T MDR1 gene polymorphism in Iranian patients with ulcerative colitis.Int J Colorectal Dis, 2007,22(9):999-1003.
50 Lee BI, Choi KY, Lee KM, et al. Is C3435T polymorphism of MDR1 related to inflammatory bowel disease or colorectal cancer in Korean? Korean J Gastroenterol, 2006,47(1):22-29.
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52 Lilianna B, Mateusz K, Agnieszka D, et al.Effect of ABCB1 (MDR1) 3435C >T and 2677G >A,T polymorphisms and P-glycoprotein inhibitors on salivary digoxin secretion in congestive heart failure patients. Pharmacological Reports, 2007,59:333-339.
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54 Farrell RJ,Menconi MJ,Keates AC, et al.P-Glycoprotein-170 inhibition significantly reduces cortisol and ciclosporin efflux from human intestinal epithelial cells and T lymphocytes.Aliment Pharmacol Ther,2002,16:1021–1031.
55 Hirano T, Onda K, Toma T, et al.MDR1 mRNA expressions in peripheral blood mononuclear cells of patients with ulcerative colitis in relation to glucocorticoid administration.Clin Pharmacol,2004 44(5):481-486.
56 Daniel F, Loriot MA, Seksik P, et al.Multidrug resistance gene-1 polymorphisms and resistance to cyclosporine A in patients with steroid resistant ulcerative colitis. Inflamm Bowel Dis, 2007,13(1):19-23.
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60 Moritra Y, Sakaeda T, Horinouchi M, et al. MDR1 genotype-related duodenal absorption rate of digoxin in healthy Japanese subjects.Pharm Res,2003,20: 552–556.
61 Verstuyft C, Schwab M, Schaeffeler E, et al. Digoxin pharmacokinetics and MDR1 genetic polymorphisms.Eur J Clin Pharmacol,2003,58: 809–812.
62 Andrew Owen, Chris Goldring, Paul Morgan, et al. Relationship between the C3435T and G2677T(A) polymorphisms in the ABCB1 gene and P-glycoprotein expression in human liver.Br J Clin Pharmacol,2005,59:365-370.
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65 Langmann T, Moehle C, Mauerer R, et al. Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes. Gastroenterology, 2004,127:26–40.
66 Englund G, Jacobson A, Rorsman F, et al.Efflux transporters in ulcerative colitis: decreased expression of BCRP (ABCG2) and Pgp (ABCB1).Inflamm Bowel Dis, 2007,13(3):291-297.
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2 Judge T,Lichtenstein GR.The NOD2 gene and Crohn's disease:another triumph for molecular genetics.Gastroenterology,2002,122:826-828.
3 Subhani J,Montgomery SM,Ounder RE,et al.Concordance rates of twins and siblings in inflammatory bowel disease.Gut,1998,42:40-42.
4 Truelove S, Witts L.Cortisone in ulcerative colitis.BMJ,1995,ii: 1041–1048.
5 Faubion W, Loftus E, Harmsen W, et al. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology, 2001,121: 255–260.
6 Munkholm P,Langholz E,Davidsen M,et al.Frequency of glucocorticoid resistance and dependency in Crohn’s disease.Gut,1994,35: 360–362.
7 Lindgren SC, Flood LM,Kilander AF,et al. Early predictors of glucocorticosteroid treatment failure in severe and moderately severe attacks of ulcerative colitis.European Journal of Gastroenterology and Hepatology,1998, 10: 831–835.
8 Hearing SD, Norman M,Probert CSJ,et al.Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes.Gut,1999,45: 382– 388.
9 Hearing SD,Norman M,Smyth C,et al.Wide variation in lymphocyte steroid sensitivity among healthy human volunteers.J Clin Endocrinol Metab,1999,84: 4149–4154.
10 Farrell RJ, Kelleher D.Glucocorticoid resistance in inflammatory bowel disease.J Endocrinol, 2003,178(3):339-346.
11 Ueda K,Okamura N,Hirai M,et al. Human P-glycoprotein transports cortisol, aldosterone and dexamethasone, but not progesterone. Biol Chem, 1992, 267: 24248–24252.
12 Karin D,Matthias S,Martin F.Identification of Budesonide and Prednisone as Substrates of the Intestinal Drug Efflux Pump P-glycoprotein.Inflamm Bowel Dis,2004,10:578-583.
13 Panwala CM, Jones JC, Viney JL. A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis.J Immunol, 1998,161:5733–5744.
14 Wilk JN, Bilsborough J, Viney JL. The mdr1a-/- mouse model of spontaneous colitis: a relevant and appropriate animal model to study inflammatory bowel disease.Immunol Res, 2005, 31:151-159.
15 Hoffmeyer S, Burk O, von Richter O, et al.Functional polymorphisms of the human multidrug-resistance gene:multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.Proc Natl Acad Sci USA,2000,97:3473–3478.
16 Cascorbi I,Gerloff T,Johne A,et al.Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects.Clin Pharmacol Ther,2001,69:169–174.
17 Sparreboom A, Danesi R, Ando Y,et al.Pharmacogenomics of ABC transporters and its role in cancer chemotherapy.Drug Resist Updat,2003,6:71-84 .
18 Schwab M,Schaeffeler E,Marx C,et al.Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis.Gastroenterology, 2003,124:26–33.
19 Brant SR,PanhuysenCI,Nicolae D,et al.MDR1 Ala893 polymorphism is associated with inflammatory bowel disease.Am J Hum Genet,2003, 73:1282–1292.
20梁惠琪,焦正,丁俊杰,等.多药耐药基因多态性和单倍体对环孢素A血药浓度的影响.中华检验医学杂志,2005,28(12):1235-1238.
21王玮,张小东,马麟麟,等.肾移植中他克莫司的血药浓度与多药耐药基因多态性的关系.中华医学杂志,2005,85(146):3277-3281.
22中华医学会消化病学分会炎症性肠病协作组.对我国炎症性肠病诊断治疗规范的共识意见.中华消化杂志,2007,27(8):545-550.
23 Best WR, Becktel JM, Singleton JW, et al.Development of a Crohn’s disease activity index.National Cooperative Crohn’s Disease Study.Gastroenterology, 1976,70:439-444.
24 Satsangi J, Silverberg MS, Vermeire S,et al.The Montreal classification of inflammatory bowel disease:controversies, consensus, and implications. Gut,2006, 55:749–753.
25 E.F. Stange,S.P.L.Travis,SVermeire,et al.European evidence-based Consensus on the diagnosis and management of ulcerative colitis.Journal of Crohn's and Colitis,2008,2: 1-23.
26 Turgut S,Turgut G,Atalay EO¨.Genotype and allele frequency of human multidrug resistance (MDR1) gene C3435T polymorphism in Denizli province of Turkey. Mol Biol Rep, 2006,33:295-300.
27 Masaki K, Tsuyoshi F, Alessandro S,et al.ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder.Progress in Neuro-Psychopharmacology & Biological Psychiatry,2008,32: 398–404.
28 Farrell RJ, Murphy A, Long A, et al.High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy. Gastroenterology, 2000,118:279–288.
29欧阳钦.炎症性肠病研究进展[M].成都:四川科学技术出版社,2000:120.
30 Cao Q, Si JM, Gao M, et al.Clinical presentation of inflammatory bowel disease: a hospital based retrospective study of 379 patients in eastern China.Chin Med J, 2005,118(9):747-752.
31 Rupert W.L.Leong, James Y.Lau, Joseph J.Y.Sung, et al.The Epidemiology and Phenotype of Crohn’s Disease in the Chinese Population. Inflamm Bowel Dis. 2004,10:646–651.
32 Soetikno RM, Lin OS,Heidenreich PA,et al.Increased risk of colorectal neoplasia inpatients with primarysclerosing cholangitis and ulcerative colitis: a meta-analysis.Gastrointest Endosc, 2002,56:48–54.
33 Nuako KW, Ahlquist DA, Mahoney DW, et al. Familial predisposition for colorectal cancer in chronic ulcerative colitis: a case-control study. Gastroenterology, 1998, 115: 1079–1083.
34 Jess T, Loftus EV, Velayos FS, et al.Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested casecontrol study from Copenhagen county, Denmark and Olmsted county, Minnesota.AmJ Gastroenterol,2007,102:829–836.
35 Velayos FS, Loftus Jr EV, Jess T,et al. Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study. Gastroenterology, 2006, 130:1941–1949.
36 Itzkowitz SH, Present DH.Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease.Inflamm Bowel Dis,2005,11: 314–321.
37 Jolles S,Niclasse S,Benson E.Combination oral and topical tacrolimus in therapy-resistant pyoderma gangrenosum.Br J Dermatol,1999,140:564–565.
38 Brooklyn TN, Dunnill GS, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, doubleblind placebo-controlled trial. Gut, 2006, 55:505–509.
39 Ho GT, Nimmo ER, Tenesa A,et al.Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis. Gastroenterology, 2005,128:288-296.
40 Fiedler T,Büning C,Reuter W,et al.Possible role of MDR1 two-locus genotypes for young-age onset ulcerative colitis but not Crohn's disease.Eur J Clin Pharmacol,2007,63(10):917-925.
41 Palmieri O,Latiano A,Valvano R,et al.Multidrug resistance 1 gene polymorphisms are not associated with inflammatory bowel disease and response to therapy in Italian patients.Aliment Pharmacol Ther,2005,22:1129-1138.
42 Urcelay E, Mendoza JL, Martin MC, et al.MDR1 gene: susceptibility in SpanishCrohn’s disease and ulcerative colitis patients.Inflamm Bowel Dis,2006,12: 33-37.
43 Potocnik U, Ferkolj I, Glavac D, et al.Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis. Genes Immun, 2004,5:530-539.
44 Oostenbrug LE,Di jkstra G,Nolte IM, et al.Absence of association between the multidrug resistance (MDR1) gene and inflammatory bowel disease.Scand J Gastroenterol,2006,41(10):1174-1182.
45 Fischer S, Lakatos PL, Hungarian IBD Study Group, et al.ATP-binding cassette transporter ABCG2 (BCRP) and ABCB1 (MDR1) variants are not associated with disease susceptibility, disease phenotype response to medical therapy or need for surgeryin Hungarian patients with inflammatory bowel diseases.Scand J Gastroenterol, 2007,42(6):726-733.
46 Annese V,Valvano MR,Palmieri O, et al.multidrug resistance 1 gene in inflammatory bowel disease:A meta-analysis.World J Gastroenterol,2006,12(23): 3636-3644.
47 Ameyaw M, Regateiro F, Li T, et al.MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics, 2001, 11(3):217-221.
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