Associations of allelic variants of the multidrug resistance gene (ABCB1 or MDR1) and inflammatory bowel disease and their effects on disease behavior: a case-control and meta-analysis study

BACKGROUND: Allelic variants of the ATP-binding cassette, subfamily B member 1 (ABCB1), also known as the multidrug resistance gene (MDR1) that encodes the membrane-bound efflux transporter P-glycoprotein 170 (PGP-170), have been associated with inflammatory bowel disease but with conflicting results. METHODS: The present study examined the association of ABCB1 C3435T and G2677T/A in a large British case-control cohort of 828 Crohn's disease, 580 ulcerative colitis (UC) cases, and 285 healthy controls. The effect of these variants was further examined with respect to phenotypic and epidemiological characteristics. A meta-analysis was carried out of our results and those from 8 previously published association studies of the C3435T variant in inflammatory bowel disease. RESULTS: The 2677T allele was significantly increased in British UC cases compared with controls (45.2% vs. 39.6%; P = 0.034). In particular, the TT genotype was significantly associated with severe UC (odds ratio [OR] 1.90; 95% CI 1.01-3.55) and the use of steroids in UC (OR 1.77; 95% CI 1.08-2.88). No significant association was seen with C3435T and UC, Crohn's disease, or any clinical subgroup. A meta-analysis of 9 association studies of C3435T showed a significant association of the 3435T allele with UC (OR 1.12; 95% CI 1.02-1.23; P = 0.013) but not with CD. CONCLUSIONS: These results indicate that ABCB1 sequence variants are associated with a small increase in the risk of developing UC and may influence disease behavior.     

Multidrug resistance 1 gene polymorphism and susceptibility to inflammatory bowel disease

BACKGROUND: Several studies have evaluated the role of the multidrug resistance 1 gene (MDR1) polymorphism, which encodes the membrane-bound efflux transporter P-glycoprotein 170, in determining susceptibility to and disease behavior in inflammatory bowel disease (IBD), but with conflicting results. METHODS: A total of 211 patients with Crohn's disease (CD), 97 patients with ulcerative colitis (UC), and 212 control subjects were investigated for the presence of MDR1 G2677T/A and C3435T polymorphisms. Genotype frequencies of CD and UC patients were compared to those observed in a control population. Genotype-phenotype correlations with major clinical features were also established and estimated risks (odds ratio [OR] with 95% confidence interval [CI]) for the mutations were calculated by a logistic regression analysis and multiple correspondent analysis. RESULTS: No significant difference was observed for genotype frequencies for both MDR1 G2677T/A and C3435T polymorphisms on overall disease susceptibility for either CD or UC patients compared with control subjects. A significant association was found between the MDR1 C3435T polymorphism and patients with ileo-colonic CD (OR = 3.34; 95% CI: 1.34-8.27). Interestingly, a negative association was found between MDR1 C3435T polymorphism in patients with a positive family history for IBD (OR = 0.44; 95% CI: 0.20-0.95) and articular manifestations (OR = 0.29; 95% CI: 0.13-0.68). Both susceptible and protective effects were identified. No significant association between G2677T/A polymorphism and any specific subphenotypes was found, nor was there any association with subphenotypic categories of UC and both single nucleotide polymorphisms. CONCLUSIONS: The results of our study suggest that MDR1 gene polymorphism could have a role in determining susceptibility to IBD. The variability of this possible effect in the several studies reported so far may be the indirect expression of the complex role played by the MDR1 gene and its product, P-glycoprotein 170, in the regulation of host-bacteria interactions and in the pathogenesis of IBD.     

Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis

BACKGROUND AND AIMS: The MDR1 gene encodes P-glycoprotein 170, an efflux transporter that is highly expressed in intestinal epithelial cells. The MDR1 exonic single nucleotide polymorphisms (SNPs) C3435T and G2677T have been shown to correlate with activity/expression of P-glycoprotein 170. METHODS: This was a case-control analysis of MDR1 C3435T and G2677T SNPs in a large well-characterized Scottish white cohort (335 with ulcerative colitis [UC], 268 with Crohn's disease [CD], and 370 healthy controls). We conducted 2-locus haplotype and detailed univariate and multivariate genotypic-phenotypic analyses. RESULTS: The MDR1 3435 TT genotype (34.6% vs 26.5%; P = .04; odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.04-2.44) and T-allelic frequencies (58.2% vs 52.8%; P = .02; OR, 1.28; 95% CI, 1.03-1.58) were significantly higher in patients with UC compared with controls. No association was seen with CD. The association was strongest with extensive UC (TT genotype: 42.4% vs 26.5%; P = .003; OR, 2.64; 95% CI, 1.34-4.99; and T allele: 63.9% vs 52.8%; P = .009; OR, 1.70; 95% CI, 1.24-2.29), and this was also confirmed on multivariate analysis ( P = .007). The G2677T SNP was not associated with UC or CD. These 2 SNPs lie in linkage disequilibrium in our population (D', .8-.9; r 2 , .7-.8). Two-locus haplotypes showed both positive (3435T/G2677 haplotype: P = .03; OR, 1.44) and negative (C3435/2677T haplotype: P = .002; OR, .35) associations with UC. Homozygotes for the haplotype 3435T/G2677 were significantly increased in UC ( P = .017; OR, 8.88; 95% CI, 1.10-71.45). CONCLUSIONS: Allelic variations of the MDR1 gene determine disease extent as well as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the need for further detailed haplotypic studies.     

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

OBJECTIVE: MDR1 (ABCB1), a member of the ATP-binding cassette (ABC) transporters, is an attractive candidate gene for the pathogenesis of inflammatory bowel diseases (IBD) and perhaps for response to therapy. Since limited data are available on MDR1 and ABCG2 polymorphisms in East European IBD patients, the aim of this study was to investigate ABCG2 and MDR1 variants and responses to medical therapy and/or disease phenotype in Hungarian patients. MATERIAL AND METHODS: A total of 414 unrelated IBD patients (Crohn's disease (CD): 265, age: 35.2+/-12.1 years, duration: 8.7+/-7.6 years and ulcerative colitis (UC): 149, age: 44.4+/-15.4 years, duration: 10.7+/-8.9 years) and 149 healthy subjects were investigated. ABCG2 G34A, C421A and MDR1 C3435T, G2677T/A single nucleotide polymorphisms (SNPs) were detected using real-time polymerase chain reaction (PCR). Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: The frequency of the ABCG2 and MDR1 SNPs was not significantly different among IBD, CD, UC patients and controls. There was no difference in risk for steroid resistance in CD patients carrying variant ABCG2 (19.6% versus non-carriers 18.4%, p=NS) or MDR1 3435T (CC: 22.2% versus CT/TT: 17.6%) alleles. In addition, carriage of the variant allele was not associated with disease phenotype, presence of extra-intestinal manifestations, smoking, response to infliximab therapy or the need for surgery. In UC, the carriage of variant ABCG2 alleles seemed to be preventive for arthritis (15.5% versus 31.7%, OR: 0.39, 95% CI: 0.16-0.98). CONCLUSIONS: MDR1 and ABCG2 SNPs were not associated with disease susceptibility or disease phenotype in Hungarian patients, and variant alleles did not predict the response to medical therapy or the need for surgery. Further studies are needed to clarify the association between the presence of ABCG2 variants and arthritis in UC.     

Is C3435T polymorphism of MDR1 related to inflammatory bowel disease or colorectal cancer in Korean?]

BACKGROUND/AIMS: Multidrug resistance 1 (MDR1) gene encodes P-glycoprotein in intestinal epithelium, which serves as a transmembrane efflux pump of various toxins. mdr1 knockout mice develop spontaneous colitis under specific pathogen free conditions. However, it is unclear that C3435T polymorphism of MDR1 is related to ulcerative colitis. Other studies suggest MDR1 may have an important role in colorectal carcinogenesis. Thus, we evaluated whether MDR1 C3435T polymorphism is present in Korean and it is associated with inflammatory bowel disease or colorectal cancer. METHODS: The genotype distributions of the C3435T polymorphism were investigated by PCR-RFLP method in 94 patients with ulcerative colitis, 24 patients with Crohn's disease, 64 patients with colorectal cancer and each of gender-matched controls with equal numbers. RESULTS: There was no significant difference in frequencies of 3435T allele and 3435TT genotype between patients with ulcerative colitis and controls (p=0.443, p=0.194). No significant difference was present in frequencies of 3435T allele and 3435TT genotype between patients with Crohn's disease and controls (p=0.378, p=1.000). There was neither significant difference in frequencies nor 3435T allele or 3435TT genotype between patients with colorectal cancer and controls (p=0.250, p=0.211). C3435T genotype was not associated with the age of onset or other clinical characteristics in patients with ulcerative colitis, Crohn's disease or colorectal cancer. CONCLUSIONS: MDR1 C3435T polymorphism is also present in Korean and the dominant allele is C. However, there is no evidence that C3435T polymorphism of MDRI is associated to inflammatory bowel disease or colorectal cancer in Korean.     

Absence of association between the multidrug resistance (MDR1) gene and inflammatory bowel disease

OBJECTIVE: The multidrug resistance (MDR1) gene encodes for P-glycoprotein, a drug efflux pump. Mice deficient for the MDR1a gene spontaneously develop colitis. In humans, a polymorphism in exon 26 (C3435T) is associated with reduced expression levels and function of MDR1. Currently there are controversial data on the association between MDR1 and inflammatory bowel disease (IBD). The purpose of this study was to examine the involvement of this gene in IBD in a large population of Dutch patients with IBD and family-based controls. MATERIAL AND METHODS: A total of 781 IBD cases and 315 controls were investigated. CD phenotypes were determined according to the Vienna Classification. Individuals were genotyped for six single nucleotide polymorphisms (SNPs) close to and in the MDR1 locus. This included the C3435T variant and six microsatellite markers close to and in the MDR1 locus. Single locus association analysis, haplotype association analysis and haplotype sharing statistic (HSS) were used to search for differences between patients and controls. RESULTS: No association was observed for any of the SNPs with IBD as a group, or for ulcerative colitis, Crohn's disease and Crohn's disease phenotypes, either by single locus or haplotype association analysis or by HSS. CONCLUSIONS: No association was observed between the MDR1 gene and IBD. This suggests that it is unlikely that MDR1 plays a role in IBD susceptibility.     

Role of the PXR gene locus in inflammatory bowel diseases

BACKGROUND: The pregnane X receptor gene (PXR/NR1I2) has been recently associated with an increased risk for inflammatory bowel disease (IBD), although a subsequent case-control study failed to replicate the original association in an independent population. This nuclear receptor regulates genes involved in the detoxification process in the liver and intestine, like ABCB1/MDR1. PXR expression was significantly reduced in the colon of patients with ulcerative colitis (UC), but remained unaffected in Crohn's disease (CD) patients. Considering previous results, we aimed at investigating the impact of this locus on IBD predisposition in the Spanish population.METHODS: Three PXR polymorphisms, including the 1 more strongly correlated with IBD risk in the initial study at -25385C/T (rs3814055) and the 6 haplotypes conformed by them, were analyzed in 365 UC and 331 CD patients and compared with 550 ethnically matched controls.RESULTS: The overall haplotypic distribution showed a significant difference between UC and CD patients (P = 0.05; chi(2) = 10.84). Among UC patients a significant difference was seen between those with extensive colitis and controls (P = 0.004; chi(2) = 17.04), mainly due to the presence of a risk haplotype (rs3814055*T//rs6784598*C//rs2276707*C: P = 0.001; odds ratio [OR] = 1.66, 95% confidence interval [CI] 1.20-2.30). Patients with extensive UC carrying the -25385T allele showed increased susceptibility compared with left-sided colitis patients and with healthy subjects. In patients with extensive UC a significantly different distribution of genotypes of the MDR1 G/A change located in intron 3 (rs3789243) was observed between carriers/noncarriers of the -25385T risk allele (P = 0.005).CONCLUSIONS: Our data seem to support the association of the PXR locus with extensive UC and the interaction between PXR and MDR1 genes.     

Cyclooxygenase-2, multidrug resistance 1, and breast cancer resistance protein gene polymorphisms and inflammatory bowel disease in the Danish population

Objective. Crohn's disease (CD) and ulcerative colitis (UC) are characterized by an impaired mucosal defence to normal constituents of the intestinal flora and a dysregulated inflammatory response. The purpose of the study was to investigate whether single nucleotide polymorphisms (SNPs) in genes involved in these processes were associated with CD and UC. Material and methods. Allele frequencies of the cyclooxygenase 2 (COX-2/PTGS2/PGHS2) G-765C and breast cancer resistance protein (BCRP/ABCG2) C421A as well as allele and haplotype frequencies of multidrug resistance 1 (MDR1, ABCB1) SNPs G2677T/A, C3435T and G-rs3789243-A (intron 3) were assessed in a Danish case-control study comprising 373 CD and 541 UC patients and 796 healthy controls. Results. Carriers of the homozygous COX-2 and MDR1 intron 3 variant had a relatively high risk of CD, odds ratio (95% CI) (OR (95% CI))=2.86 ((1.34–5.88) p=0.006) and 1.39 ((0.99–1.92) p=0.054), respectively, and for UC of 2.63 ((1.33–5.26) p=0.005) and 1.28 ((0.96–1.51) p=0.093), respectively, assuming complete dominance. No association was found for BCRP or other MDR1 SNPs, or for selected MDR1 haplotypes. No effect-modification of smoking habit at the time of diagnosis was found. Conclusions. An effect of the COX-2 polymorphism on both CD and UC was shown which is compatible with the presence of a recessive allele in linkage equilibrium with the SNP marker in the COX-2 gene. The polymorphism located in intron 3 of the MDR1 gene showed a weak association with CD, and a marginally suggestive association with UC.     

MDR1 polymorphisms and response to azathioprine therapy in patients with Crohn's disease

BACKGROUND: To investigate the contribution of multidrug resistance 1 (MDR1) gene pharmacogenetics (G2677T/A and C3435T) to the efficacy of azathioprine in inducing remission in patients with Crohn's disease (CD). METHODS: A cohort of 327 unrelated Spanish patients with CD recruited from a single center was studied. All patients were rigorously followed up for at least 2 years (mean time, 11.5 years). A case-control analysis of MDR1 G2677T/A and C3435T SNPs and 2 loci haplotypes in 112 steroid-dependent CD patients treated with azathioprine was performed. Patients were classified on the basis of response to azathioprine. RESULTS: A total 76 patients treated with azathioprine for longer than 3 months were included. Remission was achieved in 42 CD patients (55.3%). A higher frequency of the 2677TT genotype was found in nonresponders than in responders (17.65% versus 7.14%; OR = 2.8; 95% CI; 0.6-12.1; P = 0.11). Nonresponders to azathioprine were found to have a higher frequency of the 3435TT genotype than did CD patients who had achieved clinical remission (17.64% versus 4.76%; OR = 4.3; 95% CI, 0.8-22.8; P = 0.06). The 2677T/3435T haplotype was also more abundant in nonresponders (29.4% versus 20.2%), whereas the 2677G/3435C haplotype was more frequent in responders (58.3% versus 47.1%). Lack of response to azathioprine therapy in CD patients was 1.8-fold greater in carriers of the 2677T/3435T haplotype than in carriers of the 2677G/3435C haplotype (OR = 1.8; 95% CI, 0.82-3.9; P = 0.14). CONCLUSIONS: The results of our study indicate higher frequencies of the 2677TT and 3435TT genotypes and the 2677T/3435T haplotype in CD patients who did not respond to azathioprine. Additional replications in independent populations would confirm the real impact of these polymorphisms in response to azathioprine therapy.     

The frequency of C3435T MDR1 gene polymorphism in Iranian patients with ulcerative colitis

Back ground and Aims The MDR1 (multidrug resistance) gene, located on chromosome 7, is in one of the inflammatory bowel disease susceptibility loci. It produces P-glycoprotein, a transmembrane efflux pump, transferring drugs and toxins from intracellular to extracellular domains. In the human gastrointestinal (GI) tract, P-glycoprotein is found in high concentrations on the epithelial cells of the colon and small intestine. MDR1 gene polymorphisms such as C3435T are associated with lower P-glycoprotein expression, and thus it is suggested to have an association with ulcerative colitis. We tried to determine the frequency of C3435T polymorphism of the MDR1 gene in Iranian patients with ulcerative colitis and to compare it with a healthy control population. Materials and methods In this case–control-designed study, 300 unrelated ulcerative colitis patients and 300 sex-and-age-matched healthy controls were enrolled. They were visited at a tertiary center during a 2-year period (2003–2005). DNA of patients and controls was amplified by polymerase chain reaction with specific primers, and C3435T polymorphism was detected by the restriction fragment length polymorphism method. Results The frequency of the 3435T allele was significantly higher in ulcerative colitis patients compared to the controls (p < 0.001). The frequency of homozygote T/T and heterozygote C/T genotypes were also significantly higher in Iranian patients with ulcerative colitis (p = 0.044 and 0.041, respectively). Conclusion This study suggests that C3435T polymorphism of the MDR1 gene has an association with ulcerative colitis in Iranian population as previously reported in western countries.     

Multidrug resistance gene-1 polymorphisms and resistance to cyclosporine A in patients with steroid resistant ulcerative colitis

BACKGROUND: Cyclosporine A (CsA) is inconstantly effective in inducing remission in acute attacks of ulcerative colitis (UC) not responding to steroids. This study aimed to establish whether multidrug resistance gene (MDR)1 polymorphisms would be associated with CsA failure. PATIENTS AND METHODS: The distribution of the different genotypes of single nucleotide polymorphisms (SNP) G2677T/A and C3435T of MDR1 exons 21 and 26, respectively, was studied in 154 patients (mean age, 44 yr) who had received CsA to treat severe attacks of steroid resistant UC in 11 centers in France and Belgium. Patients were classified as CsA failure (n = 50) when they needed colectomy within 30 days after CsA initiation. The SNPs were detected by use of a 5' nuclease allelic discrimination assay. RESULTS: There was a significant association between the G2677T/A polymorphism distribution (exon 21) and the risk for CsA failure (P = 0.0001). The TT genotype of exon 21 was significantly associated with the risk compared with the two other genotypes (odds ratio, 3.77; 95% confidence interval, 1.42-9.97, P = 0.007). There was no significant association between the genotype C3435T distribution (exon 26) and the risk of CsA failure (P = 0.23). CONCLUSION: The TT genotype of exon 21 MDR1 polymorphisms is associated with a higher risk of CsA failure in patients with steroid resistant UC. Further studies should be performed to establish whether other treatments could be more efficient to avoid surgery in this subset of patients.     

IL-17基因多态性与中国汉族人群炎症性肠病的关系

目的:研究IL-17A和IL-17F的5个多态性位点与中国汉族人炎症性肠病之间的关系.方法:采用病例-对照研究方法,收集确诊的溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn’s disease,CD)患者共350例(UC270例;CD80例),健康对照组268例,收集外周血标本2mL,提取DNA,运用LDR(ligasedetection reaction allelic)技术进行多态性检测.采用SPSS17.0软件进行数据分析.结果:CD患者中IL-17F(rs763780,7488T/C)突变等位基因C的频率明显高于对照组(13.8%vs8.4%,P=0.044,OR=1.74,95%CI1.01-2.99).在亚型分析中,rs763780基因多态性与CD病变范围有关,突变等位基因C在CD回结肠型患者中的频率明显高于对照组(P=0.02).IL-17A(rs2275913,G-197A)与UC患者疾病的严重程度有弱相关性,含有突变基因A的患者倾向于临床轻型.IL-17F(rs763780,7488T/C)多态性与U C患者发病年龄之间有弱相关性,T/C基因型患者趋向于年轻型(P=0.046).结论:IL-17F rs763780基因多态性与CD易感性之间有弱相关性,在亚组分析中发现rs763780与CD的病变范围和UC的发病年龄有关.IL-17A rs2275913基因多态性与UC疾病严重程度呈负相关.     

Association between IL-18 gene promoter polymorphisms and inflammatory bowel disease in a Japanese population

BACKGROUND: Interleukin-18 (IL-18) is a pleiotropic cytokine that induces the production of interferon (IFN)-gamma and also to regulate Th2 cytokines. Recently, association studies between IL-18 gene promoter polymorphisms and several Th1- or Th2-mediated inflammatory diseases were reported. In inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), recent evidence suggests that IL-18 is involved in the pathogenesis. METHODS: Using DNA direct sequencing, we investigated IL-18 gene promoter polymorphisms at -607C/A and -137G/C. Allele, genotype, and haplotype frequencies were determined in 210 Japanese patients with UC, 205 patients with CD, and 212 controls. RESULTS: In UC, the -137C allele frequency was significantly higher in the proctitis-type patients than in controls (Pc = 0.0068). The -137 genotype frequency was also significantly different in the proctitis-type patients than in controls (Pc = 0.032). No other allele and genotype frequencies were significantly associated with UC after Bonferroni correction. Furthermore, the frequency of haplotype 2 (-607A, -137C), which had a lower promoter activity and IFN-gamma mRNA level than the other haplotypes as previously reported, was significantly higher in the proctitis-type patients than in controls (Pc = 0.01). In CD, we could not find any significant differences. CONCLUSIONS: IL-18 gene promoter polymorphisms may not be associated with disease susceptibility but related to the extent of disease in UC.     

HLA-Cw基因多态性与炎症性肠病的关系

目的 探讨人类白细胞抗原(HLA) -Cw等位基因与炎症性肠病(IBD)的相关性,以期发现IBD的易感基因。方法 采用序列特异性引物聚合酶链反应(PCR-SSP)方法,对100例溃疡性结肠炎(UC)、73例克罗恩病(CD)和106例健康对照进行HLA-Cw基因分型。结果 UC患者组HLA-Cw* 07基因表型频率为0.430,明显高于健康对照组(0.226),P=0.002;CD患者组HLA-Cw* 12基因表型频率为0.356,明显高于健康对照组(0.123),P=0.000。结论 HLA-Cw* 07基因可能与UC易感性密切相关;HLA-Cw*12基因可能与CD易感性密切相关。     

Absence of association between the multidrug resistance (MDR1) gene and inflammatory bowel disease

Objective. The multidrug resistance (MDR1) gene encodes for P-glycoprotein, a drug efflux pump. Mice deficient for the MDR1a gene spontaneously develop colitis. In humans, a polymorphism in exon 26 (C3435T) is associated with reduced expression levels and function of MDR1. Currently there are controversial data on the association between MDR1 and inflammatory bowel disease (IBD). The purpose of this study was to examine the involvement of this gene in IBD in a large population of Dutch patients with IBD and family-based controls. Material and methods. A total of 781 IBD cases and 315 controls were investigated. CD phenotypes were determined according to the Vienna Classification. Individuals were genotyped for six single nucleotide polymorphisms (SNPs) close to and in the MDR1 locus. This included the C3435T variant and six microsatellite markers close to and in the MDR1 locus. Single locus association analysis, haplotype association analysis and haplotype sharing statistic (HSS) were used to search for differences between patients and controls. Results. No association was observed for any of the SNPs with IBD as a group, or for ulcerative colitis, Crohn's disease and Crohn's disease phenotypes, either by single locus or haplotype association analysis or by HSS. Conclusions. No association was observed between the MDR1 gene and IBD. This suggests that it is unlikely that MDR1 plays a role in IBD susceptibility.     

Association between polymorphisms in the Toll-like receptor 4, CD14, and CARD15／NOD2 and inflammatory bowel disease in the Greek population

AIM: Crohn's disease (CD) and ulcerative colitis (DC) are multifactorial diseases with a significant genetic background. Apart from CARD15/NOD2 gene, evidence is accumulating that molecules related to the innate immune response such as CD14 or Toll-like receptor 4 (TLR4), are involved in their pathogenesis. In further exploring the genetic background of these diseases, we investigated the variations in the CARD15/NOD2 gene (Arg702Trp, Gly908Arg and Leu1007fsinsC), and polymorphisms in the TLR4 gene (Asp299Gly and Thr399Ile) as well as in the promoter of the CD14 gene (T/C at position -159) in Greek patients with CD and UC. METHODS: DNA was obtained from 120 patients with CD, 85 with UC and 100 healthy individuals. Genotyping was performed by allele specific PCR or by PCR-RFLP analysis. RESULTS: The 299Gly allele frequency of the TLR4 gene and the T allele and TT genotype frequencies of the CD14 promoter were significantly higher in CD patients only compared to healthy individuals (P= 0.026<0.05; P= 0.0048<0.01 and P= 0.047<0.05 respectively). Concerning the NOD2/CARD15 mutations the overall presence in CD patients was significantly higher than that: in UC patients or in controls. Additionally, 51.67% of the CD patients were carriers of a TLR4 and/or CD14 polymorphic allele and at least one variant of the NOD2/CARD15, compared to 27% of the UC patients. It should be pointed out that both frequencies significantly increased as compared with the 10% frequency of multiple carriers found in healthy controls. A possible interaction of the NOD2/CARD15 with TLR4 and especially CD14, increased the risk of developing inflammatory bowel disease (IBD). CONCLUSION: Our results indicate that co-existence of a mutation in either the TLR4 or CD14 gene, and in NOD2/CARD15 is associated with an increased susceptibility to developing CD compared to UC, and to developing either CD or UC compared to healthy individuals.     

Lymphoid tyrosine phosphatase R620W variant and inflammatory bowel disease in Tunisia

AIM:To assess the possible association between PTPN22(R620W) gene polymorphism and inflammatory bowel disease(IBD).METHODS:One hundred and sixty-four patients with IBD 105 Crohn‘s disease(CD) and 59 ulcerative colitis(UC) and 100 healthy controls were recruited.Genotyping of the PTPN22 gene 1858C→T polymorphism was performed by restriction fragment length polymorphism-polymerase chain reaction with Rsa Ⅰ digestion.RESULTS:The genotypic and allelic frequencies of(R620W) PTPN22 gene polymorphism reveal a sign...     

Association between Toll-like receptor 4 and inflammatory bowel disease

BACKGROUND: The human Toll-like receptor 4 (TLR4) participates in the innate response. Recently, the TLR4 variant Asp299Gly has been described to affect the response of this receptor to lipopolysaccharide. As such, there is a potentially important role of TLR4 in the pathogenesis of inflammatory bowel disease (IBD). We studied the involvement of TLR4 in IBD in a large population of Dutch patients with IBD and in family-based controls. METHODS: In 781 IBD cases and 315 controls, genotyping was performed forAsp299Gly and Thr399Ile variants and for 4 microsatellite markers flanking TLR4. Association analysis and the were applied. In addition, interaction of TLR4 with the caspase recruitment domain containing protein 15 gene (CARD15) was studied in patients with Crohn's disease (CD). RESULTS: The haplotype sharing statistic showed association at microsatellite marker D9S1864 with IBD (P = 0.0019), and in particular with CD (P = 0.0025) and at TLR406 with ulcerative colitis (UC; P = 0.027). No association was found for Asp299Gly and Thr399Ile. However, the frequencies of both variant allele carriers were higher among CD cases with a disease onset > or = 40 years than among controls. No evidence for interaction between TLR4 and CARD15 was found. CONCLUSIONS: Haplotype analysis shows that TLR4 is associated with both CD and UC. The Asp299Gly and Thr399Ile variants do not show an association with CD, UC, or IBD as a group, indicating that these polymorphisms are likely not the causal ones. We propose that the 2 polymorphisms are in linkage with (the) disease susceptibility variant(s) located elsewhere on TLR4.     

TNFalpha and IL-10 gene polymorphisms in inflammatory bowel disease. Association of -1082 AA low producer IL-10 genotype with steroid dependency

OBJECTIVES: An altered production of cytokines underlies inflammatory bowel disease (IBD) susceptibility. Various polymorphisms at the IL-10 and TNFalpha gene promoters control cytokine production levels. The influence of these polymorphisms on susceptibility to ulcerative colitis (UC) and Crohn's disease (CD) and their association with clinical features were analyzed. SUBJECTS AND METHODS: Genetic polymorphisms of TNFalpha (-308 G/A) and IL-10 (-1082 G/A, -812 C/T, and -592 C/A) were determined using the LightCycler system with hybridization probes matched with one sequence variant. The study population included 99 UC patients, 146 CD patients, and 343 matched controls. RESULTS: We did not find association between TNFalpha or IL-10 gene polymorphisms and UC or CD susceptibility, though a slight influence of -1082*G allele in UC appearance was observed. In a stratified analysis, a highly significant association between the -1082 AA IL-10 genotype and the steroid dependency was observed in IBD (p < 0.0001), contributing both UC (p = 0.004) and CD (p = 0.003) to this association. In contrast, TNFalpha genotypes did not influence steroid dependency in IBD. Further, the contribution of cytokine genotypes and of clinical features to the appearance of steroid-dependent status (dependent variable) was studied by multivariate analysis. The steroid-dependent phenotype correlated in UC with extensive disease (p = 0.010) and with the low producer -1082 AA IL-10 genotype (p = 0.002) and in CD with penetrating disease (p = 0.010), arthritis (p = 0.011), and the -1082 AA IL-10 genotype (p = 0.006). CONCLUSIONS: The main conclusion is that carriage of the -1082 AA IL-10 genotype (low producer) is a relevant risk factor for developing steroid-dependent IBD.