MDR1 gene: susceptibility in Spanish Crohn's disease and ulcerative colitis patients

BACKGROUND: The multidrug resistance MDR1 gene codes for a membrane transporter associated with inflammatory bowel disease. The polymorphism Ala893Ser/Thr (G2677T/A) previously showed significant association with Crohn's disease (CD) and the Ile1145Ile (C3435T) with ulcerative colitis (UC). We studied the association of both polymorphisms in an independent population to reveal the impact of the MDR1 gene on predisposition to inflammatory bowel disease. METHODS: Case-control study with 321 CD and 330 UC white Spanish patients recruited from the same center, and 352 healthy ethnically matched controls. RESULTS: A significant association of MDR1 C3435T with CD was observed (CC vs (CT + TT): P = 0.007; OR [95% CI] = 1.58 [1.12-2.23]). A CD susceptibility haplotype 2677T/C3435 was identified. No difference between UC patients as a whole and controls could be detected. CONCLUSIONS: New evidence supports the role of the MDR1 gene on CD susceptibility. Therefore, considering our results and those from others, the MDR1 gene behaves as a common risk factor for both CD and UC. We discovered that the C3435 allele conferring susceptibility to CD is different from the described 3435T UC risk allele.     

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.     

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.     

Evaluating the role of the genetic variations of PTPN22, NFKB1, and FcGRIIIA genes in inflammatory bowel disease: a meta-analysis

BACKGROUND: We tested several polymorphisms of genes involved in the mucosal immune system in a population of inflammatory bowel disease (IBD) patients to investigate their possible implication in disease predisposition. METHODS: Polymorphisms of 3 candidate genes (PTPN22, NFkB1, and FcGRIIIA) were investigated in 649 IBD patients (343 with Crohn's disease [CD] and 306 with ulcerative colitis [UC]), 176 unaffected relatives, and 256 healthy controls. Allele and genotype frequencies were correlated with clinical characteristics and major variants of the CARD15 gene. Our findings were pooled in a meta-analysis with the available studies in the literature. RESULTS: No significant difference for the PTPN22 and NFkB1 variants was found. In contrast, allele and genotype frequencies of the G559T allele of the FcGRIIIA gene were significantly different in CD patients compared to controls (allele T 12% versus 8%, odds ratio [OR] = 1.58, 95% confidence interval [CI] 1.06-2.35; GT genotype 23% versus 16%, OR = 1.64, 95% CI = 1.08-2.5). However, no significant overtransmission of the T allele was confirmed at the family-based analysis. For all genes, neither an interaction with CARD15 gene, nor a significant difference at genotype/phenotype analysis was demonstrated, included response to medical therapy. CONCLUSIONS: Although involved in autoimmune diseases, the PTPN22 and NFkB1 genes do not seem involved in the IBD predisposition, also according to meta-analysis results. The association with the G559T polymorphism of the FcGRIIIA gene in CD patients deserves further investigation.     

T300A polymorphism of ATG16L1 and susceptibility to inflammatory bowel diseases:A meta-analysis

AIM:To evaluate the association of the autophagy- related 16-like 1 (ATG16L1 ) T300A polymorphism (rs2241880) with predisposition to inflammatory bowel diseases (IBD) by means of meta-analysis.METHODS: Publications addressing the relationship between rs2241880/T300A polymorphism of ATG16L1 and Crohn‘s disease (CD) and ulcerative colitis (UC) were selected from the MEDLINE and EMBASE data-bases. To make direct comparisons between the data collected in these studies, the individual authors were contacted when...     

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.     

Toll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseases

BACKGROUND: Evidence that a deficient innate immune response toward the bacterial flora of the gut plays a role in the pathogenesis of inflammatory bowel disease (IBD) is growing. This is underscored by the finding of the association between CARD15 variants and Crohn's disease (CD) and D299G in Toll-like receptor (TLR) 4 and IBD. Our aims were to study nonsynonymous polymorphisms in other TLR genes in IBD. METHODS: Thirty-five single nucleotide polymorphisms (SNP) in TLR1-10 were identified from public databases. 284 IBD parent-child trios and a second independent cohort of 285 IBD patients and 191 healthy controls were genotyped with polymerase chain reaction-restriction fragment length polymorphisms. Patients were pooled for genotype-phenotype analyses. RESULTS: Although none of the SNPs was involved in disease susceptibility, a number of variants influenced the disease phenotype. A positive association between TLR1 R80T and pancolitis in UC (P = .045, OR [95% CI] 2.844 [1.026-7.844]) was found. The TLR2 R753G SNP was also associated with pancolitis (P = .027, OR [95% CI] 4.741 [1.197-18.773]). The relative risks for heterozygous patients to develop pancolitis were 5.8 and 3.3 for R80T and R753G, respectively. There was a negative association between TLR6 S249P and ulcerative colitis with proctitis only (P = .026, OR [95% CI] 0.223 [0.096-0.705]). In CD, we found a negative association between ileal disease involvement and TLR1 S602I (P = .03, OR [95% CI] 0.522 [0.286-0.950]). CONCLUSION: TLR2 and its cofactors TLR1 and TLR6 are involved in the initial immune response to bacteria by recognizing peptidoglycan. An association between nonsynonymous variants in the TLR1, -2, and -6 genes and extensive colonic disease in UC and CD was found. Our findings further highlight the role of an abnormal innate immune response in the pathogenesis of IBD.     

Associations between CD24 gene polymorphisms and inflammatory bowel disease:A meta-analysis

AIM: To evaluate the relationships between CD24 gene polymorphisms and the risk of inflammatory bowel disease(IBD), including ulcerative colitis(UC)and Crohn's disease(CD).METHODS: The PubMed, Web of Science and Cochrane Library databases were searched(up to May30, 2014). The search terms "CD24", "inflammatory bowel disease", "Crohn's disease", "Ulcerative colitis","IBD", "CD" or "UC"; and "polymorphism", "mutation"or "variant" were used. Association studies were limited to the English language, but no limitations in terms of race, ethnicity or geographic area were employed.Stata SE12 software was used to calculate the pooled odds ratios(ORs) with 95% confidence intervals(CIs).P 0.05 was considered statistically significant. The information was independently extracted from each eligible study by two investigators. Two common polymorphisms, C170T(rs8734) and TG1527del(rs3838646), in the CD24 gene were assessed.RESULTS: A total of three case-control studies including 2342 IBD patients and 1965 healthy controls were involved in this meta-analysis. The patients and controls were from Caucasian cohorts. The three articles included in this meta-analysis all conformed to Hardy-Weinberg equilibrium. This meta-analysis revealed that there were no significant associations between the two CD24 polymorphisms and the risk for IBD(all P 0.05). However, in a disease subgroup analysis, we found that the CD24 C170 T polymorphism was associated with an increased risk of UC in a dominant model(OR = 1.79, 95%CI: 1.15-2.77, P =0.009) and an additive model(OR = 1.87, 95%CI:1.19-2.93, P = 0.007), but this relationship was not present for CD. The CD24 TG1570 del polymorphism was significantly associated with CD in the additive model(OR = 1.24, 95%CI: 1.01-1.52, P = 0.037).CONCLUSION: Our findings provide evidence that the CD24 C170 T polymorphism might contribute to the susceptibility to UC, and the CD24 TG1527 del polymorphism might be associated with the risk of CD.     

Association of drug transporter gene ABCB1 (MDR1) 3435C to T polymorphism with colchicine response in familial Mediterranean fever

OBJECTIVE: Colchicine is a mainstay of treatment in familial Mediterranean fever (FMF); however, 5%-10% of patients do not respond to colchicine. Adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1 or MDR1) is a drug transporter that extrudes colchicine out of cells. ABCB1 gene 3435C to T polymorphism has been demonstrated to alter MDR1 expression in mononuclear cells. Thus, the amount of MDR1 in mononuclear cells may alter response to colchicine. We investigated the association between MDR1 3435C to T polymorphism and colchicine response in patients with FMF. METHODS: Patients (n = 120) were examined for colchicine responses. ABCB1 gene 3435C to T genotypes were determined to analyze associations with colchicine resistance. RESULTS: Ninety-eight patients were evaluated as responders and 22 as nonresponders. The distributions of ABCB1 CC, CT, and TT genotypes were significantly different between responsive and nonresponsive groups (chi-square = 6.86, p = 0.032). Colchicine resistance was significantly higher in patients harboring the C allele than in patients with TT genotype (odds ratio 9.71, 95% CI 1.58-58.76). Similarly, the mean colchicine dose to prevent remission was significantly lower in the TT group compared with subjects with the C allele (p = 0.014). CONCLUSION: Our study revealed an association between 3435C to T polymorphism and colchicine response in patients with FMF. Patients with the TT genotype for the ABCB1 3435C to T variant responded better to colchicine in terms of treatment efficacy and colchicine dose requirements.     

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.     

Effect of ABCB1 3435C>T transporter gene polymorphism on plasma efavirenz concentration in HIV-1 infected Thai adults

Objective:To investigate the influence of ABCB1 polymorphisms on the plasma level of efavirenz in Thai adult cases infected with HIV-1.Methods:A single nucleotide polymorphism of ABCB1 3435 CT(rs1045642) in the gene encoding ABCB1 was genotyped using real-time PCR-based alleles in 149 HIV-infected Thai adults receiving efavirenz treatment.Plasma concentrations of efavirenz were measured by high-performance liquid chromatography 12 hr after administration.The relationship between plasma efavirenz concentrations and ABCB1 3435 CT polymorphisms was analyzed.Results:Logistic regression analysis showed no significant predictors of high plasma efavirenz concentration in relation to age,gender,body weight,CD4 count and plasma HIV-1 RNA,blood biochemical parameters,antiretroviral duration or ABCB1 3435 CT polymorphisms,except for height(OR=0.902,95% CI:0.835-0.973)(P0.05).The minor allele frequency of ABCB1 3435 CT was0.446.The frequency of the heterozygous mutant ABCB1 3435 C/T was 53.02%(n=79),ABCB1 3435 T/T homozygous mutant was 18.12%(n=21) and the wild type ABCB1 3435 C/C genotype was 28.86%(n=43).The overall median plasma concentration of efavirenz in 149 HIV-infected Thai cases was 2.41 mg/L [IQR:(1.46-4.12) mg/L].The plasma concentration of efavirenz was higher in cases with ABCB1 3435 T/T homozygous mutant [2.73 mg/L,IQR:(2.02-4.19) mg/L] and ABCB1 3435 C/T heterozygous mutant [2.29 mg/L,IQR:(1.41-4.28) mg/L] genotypes compared to the wild type ABCB1 3435 C/C homozygous [2.1 mg/L,IQR:(1.37-3.53) mg/L].However,there was no statistically significant difference in the efavirenz concentration between the different genotypes(P0.05).Objective: To investigate the influence of ABCB1 polymorphisms on the plasma level of efavirenz in Thai adult cases infected with HIV-1.Methods: A single nucleotide polymorphism of ABCB1 3435 CT(rs1045642) in the gene encoding ABCB1 was genotyped using real-time PCR-based alleles in 149 HIV-infected Thai adults receiving efavirenz treatment. Plasma concentrations of efavirenz were measured by high-performance liquid chromatography 12 hr after administration. The relationship between plasma efavirenz concentrations and ABCB1 3435 CT polymorphisms was analyzed. Results: Logistic regression analysis showed no significant predictors of high plasma efavirenz concentration in relation to age, gender, body weight, CD4 count and plasma HIV-1 RNA, blood biochemical parameters, antiretroviral duration or ABCB1 3435 CT polymorphisms, except for height(OR=0.902, 95% CI: 0.835-0.973)(P0.05). The minor allele frequency of ABCB1 3435 CT was 0.446. The frequency of the heterozygous mutant ABCB1 3435 C/T was 53.02%(n=79), ABCB1 3435 T/T homozygous mutant was 18.12%(n=27) and the wild type ABCB1 3435 C/C genotype was 28.86%(n=43). The overall median plasma concentration of efavirenz in 149 HIV-infected Thai cases was 2.41 mg/L [IQR:(1.46-4.12) mg/L]. The plasma concentration of efavirenz was higher in cases with ABCB1 3435 T/T homozygous mutant [2.73 mg/L, IQR:(2.02-4.19) mg/L] and ABCB1 3435 C/T heterozygous mutant [2.29 mg/L, IQR:(1.41-4.28) mg/L] genotypes compared to the wild type ABCB1 3435 C/C homozygous [2.1 mg/L, IQR:(1.37-3.53) mg/L]. However, there was no statistically significant difference in the efavirenz concentration between the different genotypes(P0.05).Conclusions: There is no statistical significance for a tendency toward higher plasma efavirenz concentration in the ABCB1 3435 T/T and ABCB1 3435 C/T genotypes. No parameters of physiological characteristics in this study except for height were found to be predictors of high plasma efavirenz concentration in Thai HIV-1 infected cases.     

Replication of interleukin 23 receptor and autophagy-related 16-like 1 association in adult- and pediatric-onset inflammatory bowel disease in Italy

AIM： To investigate gene variants in a large Italian inflammatory bowel disease （IBD） cohort, and to analyze the correlation of sub-phenotypes （including age at diagnosis） and epistatic interaction with other IBD genes. METHODS： Total of 763 patients with Crohn＇s disease （CD, 189 diagnosed at age 〈 19 years）, 843 with ulcerative colitis （UC, 179 diagnosed 〈19 years）, 749 healthy controls, and 546 healthy parents （273 trios） were included in the study. The rs2241880 [autophagy-related 16-like 1 （ATG16L1）], rs11209026 and rs7517847 [interleukin 23 receptor （IL23R）], rs2066844, rs2066845, rs2066847 （CARD15）, rs1050152 （OCTN1）, and rs2631367 （OCTN2） gene variants were genotyped. RESULTS： The frequency of G allele of ATG16L1 SNP （Ala197Thr） was increased in patients with CD compared with controls （59% vs 54% respectively） （OR = 1.25, CI = 1.08-1.45, P = 0.003）, but not in UC （55%）. The frequency of A and G （minor） alleles of Arg381Gln, rs11209026 and rs7517847 variants of IL23R were reduced significantly in CD （4%, OR = 0.62, CI = 0.45-0.87, P = 0.005; 28%, OR = 0.64, CI = 0.55-0.75, P 〈 0.01）, compared with controls （6% and 38%, respectively）. The A allele （but not G） was also reduced signifi cantly in UC （4%, OR = 0.69, CI = 0.5-0.94, P = 0.019）. No association was demonstrated with sub-phenotypes and interaction with CARD15 , and OCTN1/2 genes, although both gene variants were associated with pediatric-onset disease. CONCLUSION： The present study confirms the association of IL23R polymorphisms with IBD, and ATG16L1 with CD, in both adult- and pediatric-onset subsets in our study population.     

IL-1 receptor antagonist (IL-1Ra) gene polymorphism in patients with inflammatory bowel disease in India

OBJECTIVE: An association between polymorphism in the gene coding for the anti-inflammatory cytokine interleukin-1-receptor antagonist (IL-1Ra) and ulcerative colitis (UC) has been reported. To date, there is no report from India confirming this association. In the present study the aim was to assess the allele frequencies and carriage rates of different alleles of 86 bp (base pair) variable number tandem repeat (VNTR) in intron 2 of the IL-1Ra gene in patients with inflammatory bowel disease (IBD) and healthy controls from northern India. MATERIAL AND METHODS: Eighty-two patients with UC, 21 with Crohn's disease (CD) and 141 ethnically matched controls were enrolled in this study. Genotyping was done using a polymerase chain reaction (PCR) amplification of the intron-2 fragment harboring a VNTR nucleotide sequence. The PCR products were separated on 2% agarose gel. Statistical analysis was performed using the chi-squared (chi(2)) test. RESULTS: The frequencies of allele 2 in UC, CD and healthy controls were 26%, 50% and 24%, respectively. The frequency of allele 2 in CD was higher than that in UC (p = 0.002; OR = 2.9) and healthy controls (p = 0.001; OR = 3.1; 95% CI = 1.5-6.3). Alleles 3 and 4 were absent in patients with CD, while allele 5 was absent in all three groups. CONCLUSIONS: The present study demonstrated an association between allele 2 and patients with CD but not with UC. Interestingly, the allele frequency and carriage rates of allele 2 were significantly higher in patients with CD than in patients with UC and in healthy subjects. Ethnic differences, genetic heterogeneity and sample size could be the reasons for such differences in comparison with studies from the West.     

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.     

Impact of ABCB1 Gene (C3435T/A2677G) Polymorphic Sequence Variations on the Outcome of Patients with Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia in Kashmiri Population: A Case–Control Study

Inherited polymorphic sequence variations in drug transport genes like ABCB1 impact a portion of patients with hematologic malignancies that show intrinsic or acquire resistance to treatment. Keeping in view inter-individual sensitivities for such drugs, we through this case–control study tested whether ABCB1 C3435T and G2677T polymorphisms have any influence on the risk and treatment response in patients with chronic myeloid leukemia (CML) and B-acute lymphoblastic leukemia (B-ALL). Genotyping for ABCB1 polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism in 100 CML and 80 B-ALL patients along with 100 age and gender matched healthy controls. ABCB1 C3435T and G2677T polymorphism showed no association with CML. Genotype distribution revealed significant higher frequency of TT genotype for both SNPs in B-ALL cases and associated with increased B-ALL risk (OR 2.5, p = 0.04 for 3435TT; OR 2.4, p = 0.04 for 2677TT). There was no significant difference in genotype frequency of 3435C > T and 2677G > T among resistant and responsive groups for the two leukemia types. Kaplan–Meier survival plots revealed significantly lower event free survival in CML and B-ALL patients that were carriers of 3435TT genotype (p < 0.05). Multivariate analysis considered 3435TT genotype as independent risk factor for imatinib resistance in CML cases (HR 6.24, p = 0.002) and increased relapse risk in B-ALL patients (HR 4.51, p = 0.03). The current study provides preliminary evidence of a significant association between variant TT genotype and increased B-ALL risk. Also, results suggest that ABCB1 3435TT genotype increases imatinib resistance in CML and influence therapeutic outcome in B-ALL.     

SLC11A1 polymorphisms in inflammatory bowel disease and Mycobacterium avium subspecies paratuberculosis status

AIM: To test for association of SLC11A1 with inflammatory bowel disease (IBD) and Mycobacterium avium subspecies paratuberculosis (MAP) status in a Caucasian cohort. METHODS: Five hundred and seven Crohn’s disease (CD) patients, 474 ulcerative colitis (UC) patients, and 569 healthy controls were genotyped for SLC11A1 1730G>A and SLC11A1 469+14G>C using pre-designed TaqMan  SNP assays. χ 2 tests were applied to test for association of single nucleotide polymorphisms (SNPs) with disease, and the presence of MAP DNA.RESULTS:SLC11A1 1730G>A and SLC11A 1469+14G>C were not associated with CD, UC, or IBD. The SLC11A1 1730A minor allele was over-represented in patients who did not require immunomodulator therapy (P = 0.002, OR: 0.29, 95% CI: 0.13-0.66). The frequency of the SLC11A1 469+14C allele was higher in the subset of study participants who tested positive for MAP DNA (P = 0.02, OR: 1.56, 95% CI: 1.06-2.29). No association of SLC11A1 1730G>A with MAP was observed.CONCLUSION: Although SLC11A1 was not associated with IBD, association with MAP suggests that SLC11A1 is important in determining susceptibility to bacteria implicated in the etiology of CD.     

MDR1 gene C3435T polymorphism and cancer risk: a meta-analysis of 34 case–control studies

Background

P-glycoprotein, the product of the MDR1 gene, is a transmembrane active efflux pump for a variety of environmental toxins and xenobiotics. Epidemiological studies have evaluated the association between MDR1 C3435T polymorphism and cancer susceptibility. However, published data are still inconclusive.

Methods

To derive a more precise assessment of this relevance, we performed a meta-analysis, up to September 2010, of 5,196 cases with different cancer types and 6,827 controls from 34 published case–control studies. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for MDR1 C3435T polymorphism and cancer were estimated using fixed- and random-effects models when appropriate.

Results

The overall results suggested that the variant was associated with a moderately increased cancer risk in all comparison models tested (OR?=?1.26, 95% CI: 1.06–1.50 for TT vs. CC; OR?=?1.19, 95% CI: 1.04–1.37 for CT vs. CC; OR?=?1.15, 95% CI: 1.01–1.32 for recessive model; OR?=?1.21, 95% CI: 1.06–1.38 for domain model, and OR?=?1.14, 95% CI: 1.04–1.26 for allele contrast). In the subgroup analysis by cancer types, significant associations were found in breast cancer (OR?=?1.66, 95% CI: 1.24–2.21 for TT vs. CC; OR?=?1.44, 95% CI: 1.14–1.82 for recessive model; OR?=?1.41, 95% CI: 1.10–1.81 for domain model; and OR?=?1.31, 95% CI: 1.13–1.52 for allele contrast) and renal cancer (OR?=?1.99, 95% CI: 1.37–2.90 for TT vs. CC; OR?=?1.74, 95% CI: 1.25–2.42 for domain model; OR?=?1.43, 95% CI: 1.09–1.88 for recessive model; and OR?=?1.40, 95% CI: 1.17–1.68 for allele contrast). However, no significant associations were found in colorectal cancer, gastric cancer, and acute lymphoblastic leukemia for all genetic models. In the ethnicity subgroup analysis, a significant association with cancer among Caucasians was found under the dominant model, homozygote comparison, CT versus CC comparison, and allele comparison.

Conclusions

In summary, this meta-analysis suggests that the MDR1 C3435T polymorphism is associated with cancer susceptibility, increasing the risk of breast and renal cancer.