Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis

BACKGROUND & AIMS: The human multidrug resistance 1 (MDR1) gene product P-glycoprotein is highly expressed in intestinal epithelial cells, where it constitutes a barrier against xenobiotics. The finding that mdr1a knockout mice develop a form of colitis that is similar to ulcerative colitis, which can be prevented by antibiotics, indicates a barrier function for P-glycoprotein against the invasion of bacteria or toxins. Because the MDR1 single nucleotide polymorphism C3435T is associated with lower intestinal P-glycoprotein expression, we tested whether this polymorphism predisposes to development of ulcerative colitis. METHODS: Allele frequencies and genotype distributions of the C3435T single nucleotide polymorphism were investigated in 149 patients with ulcerative colitis, 126 patients with Crohn's disease, and sex-matched healthy controls. RESULTS: Significantly increased frequencies of the 3435T allele and the 3435TT genotype were observed in patients with ulcerative colitis compared with controls (3435T: P = 0.049; odds ratio, 1.4; 95% confidence interval, 1.02-1.94; 3435TT: P = 0.045; odds ratio, 2.03; 95% confidence interval, 1.04-3.95). In contrast, frequencies of the T allele and the TT genotype were the same in patients with Crohn's disease as in controls (P = 0.66 and P = 0.59, respectively). In comparison to 998 non-sex-matched controls, the effect for the TT genotype in ulcerative colitis patients was more pronounced (P = 0.0055; odds ratio, 2.1). CONCLUSIONS: The higher frequency of the 3435TT genotype in patients with ulcerative colitis corroborates the findings from the mdr1a knockout mice. The results support the notion that P-glycoprotein plays a major role in the defense against intestinal bacteria or toxins. Impairment of barrier function in 3435TT subjects could render this genotype more susceptible to the development of ulcerative colitis.     

Multi-drug resistance 1 polymorphism is associated with reduced risk of gastric cancer in the Japanese population

BACKGROUND AND AIMS: Host genetic factors play a key role in gastric carcinogenesis, but the mechanism has not been clarified. The multi-drug resistance 1 (MDR1) gene mediates the expression of P-glycoprotein, which has a role in active transport of various substrates, including xenobiotics, and thus has a protective function in various tissues and organs like gastrointestinal epithelial cells. C3435T polymorphism in exon 26 of the MDR1 gene influences P-glycoprotein expression and activity in the gastrointestinal tract. We investigated the influences of MDR1 gene polymorphism on the risk of gastric cancer. METHOD: The study was performed on 157 patients with gastric cancer (GC) and 104 patients without GC as the control group. C3435T polymorphism of MDR1 was investigated by PCR-RFLP in all of the patients. RESULTS: The MDR1 3435 TT genotype showed a significantly higher frequency in controls than in GC patients (OR = 0.43; 95% CI = 0.23-0.79). There were no significant differences of the CT and CC genotype frequencies between GC patients and controls. We also found that the 3435TT genotype of MDR1 was associated with a lower risk of non-cardiac cancer (OR = 0.42; 95% CI = 0.23-0.79), middle-third cancer (OR = 0.36; 95% CI = 0.17-0.77), advanced cancer (OR = 0.31; 95% CI = 0.13-0.73), venous invasion (OR = 0.30; 95% CI = 0.10-0.91), and lymph node metastasis (OR = 0.28; 95% CI = 0.13-0.65). CONCLUSION: Our data suggest that 3435T/T polymorphism of MDR1 is associated with a reduced risk of gastric cancer in the Japanese population.     

Analysis of whole genomic expression profiles of Helicobacter pylori related chronic atrophic gastritis with IL‐1B‐31CC/‐511TT genotypes

OBJECTIVE:   Many studies have linked cytokine interleukin‐1B gene polymorphisms to H. pylori‐related gastric cancer development. The current study evaluated the characterization of whole genomic expression profiles of the premalignant condition: H. pylori‐related chronic atrophic gastritis (CAG) with IL‐1B‐31CC/‐511TT genotypes. METHODS: IL‐1B‐31/‐511 gene polymorphisms were determined by DNA sequences. RNA was extracted and expression profiles were performed using Agilent human whole genomic oligonucleotide microarrays (G4112F). The expression of three samples with H. pylori infection was compared to that of three samples without H. pylori infection from samples of six CAG patients, all with IL‐1B‐31CC/‐511TT genotypes. Differentially expressed genes related to H. pylori‐induced CAG with IL‐1B‐31CC/‐511TT genotypes were screened and analyzed further by Gene Ontology (GO) and pathway. Validation of the microarray data was performed using qRT‐PCR. RESULTS: A total of 124 differentially expressed genes and 32 GO term annotations were identified between H. pylori positive and negative groups in the six CAG samples with IL‐1B‐31CC/‐511TT genotypes. The signaling pathways identified were oxidative phosphorylation and epithelial cell signaling in H. pylori infection. Five overlapping genes were contained in identified GO terms and pathways: ATP6V0B, NDUFS5, NDUFV2, ATP6V1F and ATP6V1G1. Comparisons of qRT‐PCR data and the previously reported data with the results of gene chips support the validity of our microarray data. CONCLUSION: The H. pylori‐related CAG with IL‐1B‐31CC/‐511TT genotypes has shown to be the more malignant phenotype than H. pylori negative CAG with IL‐1B‐31CC/‐511TT genotypes. Mitochondrial energy metabolism probably plays a crucial role as it is the molecular mechanism of host–bacterial interactions.     

Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia

The significance of genetic background in childhood acute lymphoblastic leukemia (ALL) is not well understood. Polymorphisms of genes encoding for xenobiotics and drug transporters are potential factors, which can influence the risk of developing ALL and its clinical outcome. P-glycoprotein (P-gp) is an adenosine triphosphate-binding cassette (ABC)-family transporter involved in protection against xenobiotics and multi-drug resistance. Recently, the single-nucleotide polymorphism C3435T of MDR1 gene has been found to be associated with altered tissue expression and function of P-gp. To evaluate whether C3435T MDR1 polymorphism is associated with the occurrence and outcome of ALL, 113 children with ALL (median age 5.1 yr) and 175 healthy individuals of Polish Caucasian origin were studied by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) assay. The mutant homozygous TT genotype was found to be associated with occurrence of ALL (OR, 95% CI; 1.8, 1.1-3.1; P = 0.037). Besides, the analysis of factors influencing clinical outcome of our ALL patient cohort showed that CC genotype carriers had significantly lower event-free survival probability (pEFS) (0.62 vs. 0.87; P = 0.007) and overall survival probability (pOS) (0.72 vs. 0.91; P = 0.006). The Cox proportional hazards model-based analysis revealed that the hazard ratios for lower pEFS and lower pOS among CC homozygous subjects were 3.9 (P = 0.008) and 3.3 (P = 0.02), respectively. In conclusion, the results of the present study provide evidence that C3435T MDR1 polymorphism may involve both the susceptibility to and the clinical outcome of childhood ALL. Carriers of the TT genotype are more at risk of developing ALL than other individuals, whereas CC genotype carriers are supposed to have worse prognosis.     

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.     

Homozygous 825T Allele of the GNB3 Protein Influences the Susceptibility of Japanese to Dyspepsia

The role of genetics in the susceptibility to functional dyspepsia (FD) is not well established. Recently, two different associations were reported between FD and G-protein beta3 (GNB3) subunit gene polymorphism. We aim to clarify the association between GNB3 protein C825T polymorphism and dyspepsia in the Japanese population. Eight-nine dyspeptics and 94 nondyspeptic subjects enrolled in this study. All subjects underwent gastroscopy and patients with significant upper gastrointestinal findings were excluded. Other diseases were also excluded by face-to-face history and physical examination. GNB3 protein C825T polymorphisms were determined by polymerase chain reaction-restriction fragment-length polymorphism. H. pylori infection status was examined by histology or antibody against H. pylori. Nonsignificant correlation was found between GNB3 protein homozygous 825T and unexplained dyspepsia (OR = 1.65, 95% CI: 0.87–3.13). However, among H. pylori-negative subjects, homozygous GNB3 protein 825T significantly increased the risk of dyspepsia (16.7% versus 40.5%; CC versus TT; OR = 5.10, 95% CI: 1.21–21.43, CC versus others; OR = 3.40, 95% CI: 1.16–9.93, respectively). This significant association remained after logistic regression analysis with adjustment for sex and age (CC versus TT; OR = 5.73, 95% CI: 1.27–25.82, CC versus others; OR = 3.08, 95% CI: 1.02–9.25). No significant correlation was found between GNB3 polymorphism and any dyspeptic symptoms. Our data suggest that the homozygous 825T allele of GNB3 protein is associated with dyspepsia in the H. pylori-negative Japanese population. The role of genetics in the development of dyspepsia needs further evaluation.     

多药耐药基因MDR1 C3435T基因多态性对根除幽门螺杆菌疗效的影响

目的研究多药耐药基因MDR1 C3435T基因多态性对质子泵抑制剂联合阿莫西林与克拉霉素三联1周疗法根除幽门螺杆菌（砀,）治疗的影响。方法选取101例却阳性的慢性胃炎或消化性溃疡患者,分成2组,分别进入埃索美拉唑联合阿莫西林与克拉霉素方案（EAC）或奥美拉唑联合阿莫西林与克拉霉素方案（OAC）进行1周根除治疗。采用聚合酶链反应-限制性内切片段长度多态性（polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP）的方法检测MDR1 C3435T基因型,比较不同基因型患者之间埤,根除率的差异。结果MDR1 CC3435、C3435T和3435TT的却根除率分别为72．4％、88．2％和81．0％。MDR1 C3435T各基因型组间却根除率比较均元显著性差异。结论MDR1 C3435T基因多态性与却根除疗效无显著相关性。     

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.     

Helicobacter pylori Infection Enhances Gastric Mucosal Inflammation in Individuals Carrying the 260-T Allele of the CD14 Gene

Background/Aims

We aim to evaluate the association between promoter polymorphism of the clusters of differentiation 14 (CD14) gene and Helicobacter pylori-induced gastric mucosal inflammation in a healthy Korean population.

Methods

The study population consisted of 267 healthy subjects who visited our hospital for free nationwide gastric cancer screening. Promoter polymorphism at -260 C/T of the CD14 gene was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. The severity of gastric mucosal inflammation was estimated by a gastritis score based on the sum of the values of the grade and activity of the gastritis. Expression of soluble CD14 (sCD14) was assessed by quantitative sandwich ELISA.

Results

CD14 polymorphism was not associated with H. pylori infection. There were no significant differences in gastritis scores among the genotype subgroups, but subjects carrying the CD14 -260 CT/TT genotype had significantly higher sCD14 levels than those carrying the CC genotype. Subjects with the 260-T allele of the CD14 gene and H. pylori infection had significantly higher sCD14 levels than those with the same genotype but without infection.

Conclusions

In individuals with the T allele at the -260 site of the promoter region of the CD14 gene, H. pylori infection accentuates gastric mucosal inflammation.     

IL‐1 RN 2/2 genotype and simultaneous carriage of genotypes IL‐1 RN 2/2 and IL‐1β‐511 T/T associated with oesophagitis in Helicobacter pylori‐negative patients

Background: Interleukin‐1 receptor antagonist genotype 2/2 is associated with a prolonged and enhanced inflammatory response. It is suspected of being a risk factor for atrophic gastritis and gastric cancer and for some autoimmune diseases. No specific genetic risk factors for oesophagitis have been identified so far and there are no reports of IL‐1 polymorphism in relation to oesophageal disease. Methods: We studied the IL‐1RN, IL‐1β‐511 and IL‐1β?+?3953 polymorphisms in an unselected series of 142 adult patients scheduled for gastrointestinal endoscopy because of dyspepsia. The control group consisted of university staff and students (n?=?179). Helicobacter pylori status was determined by antibody testing and bacterial detection. Results: Endoscopic oesophagitis was noted in 40 patients. The IL‐1RN 2/2 genotype was significantly more prevalent in the patients with H. pylori‐negative oesophagitis than in the control subjects (27% versus 9%; OR 3.574, CI 1.23–10.35, P?=?0.034) or in the dyspeptic patients (27% versus 7%; OR 5.089, CI 1.51–17.11, P?=?0.009). IL‐1β‐511 T/T genotype tended to be more frequent in the H. pylori‐negative patients with oesophagitis than in the control subjects (P?=?0.071). The strongest association was between the simultaneous carriage of genotypes IL‐1RN 2/2 and IL‐1β ‐511 T/T and H. pylori‐negative oesophagitis, where the combined genotype was more prevalent than in the control subjects (23% versus 6%; OR 4.492, CI 1.40–14.46, P?=?0.012) or the dyspeptic patients without oesophagitis (23% versus 3%; OR 9.706, CI 2.12–44.42, P?=?0.003). Conclusion: The results indicate that the IL‐1RN 2/2 genotype and the carriage of combined genotypes IL‐1RN 2/2?+?IL‐1β‐511 T/T are associated with H. pylori‐negative oesophagitis. This is the first report on the association between IL‐1 gene polymorphism and oesophagitis.     

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.     

Effect of the C3435T Polymorphism of the Multidrug Resistance 1 Gene on the Severity of Inflammatory Bowel Disease in Iranian Azeri Turks

Background/Aim:

Multidrug resistance 1 (MDR1) gene encodes for P-glycoprotein (P-gp), a transmembrane efflux pump transferring both exogenous and endogenous substrate from the cells. In the human gastrointestinal tract, P-gp is found in high concentrations on the epithelial cells of the colon and small intestine. It is hypothesized that the expression level of MDR1 gene is related to susceptibility of both forms of inflammatory bowel disease (IBD). The aim of this study was to investigate the association of C3435T Single Nucleotide Polymorphism in IBD patients with/without clinical symptoms in Iranian Azeri Turks.

Settings and Design:

A total of 116 patients with IBD and 92 healthy subjects were analyzed.

Materials and Methods:

We investigated the distribution of MDR1 C3435T polymorphism via polymerase chain reaction – Restriction Fragment Length Polymorphism technique.

Statistical Analysis Used:

All statistical analyses were calculated with the SPSS for Windows 16.0. The Fisher exact test was used to test for departure from Hardy-Weinberg equilibrium of the genotype frequencies (P > 0.05).

Results:

The data showed that IBD patient with homozygous variant carrying MDR1 3435 T/T genotype has elevated risk for development of routine IBD clinical symptoms like Abdominal pain (P = 0.005) and chronic Diarrhea (P = 0.013) compared with MDR1 3435 C/C homozygotes who has reduced risk for development of IBD symptoms.

Conclusions:

Our data showed that patients with MDR1 3435 T/T are more susceptible to the development of some routine IBD clinical symptoms (P < 0.05). This study suggests a protective role for the MDR1 3435 C/C versus MDR1 3435 T/Tgenotype and C versus T allele for the progression of IBD in this cohort.     

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.     

Effects of CYP2C19 and MDR1 genotype on the eradication rate of Helicobacter pylori infection by triple therapy with pantoprazole, amoxycillin and clarithromycin

Backgrounds:  CYP2C19 polymorphism plays an important role in the metabolism of proton pump inhibitors. The multidrug resistance (MDR)1 genotype is associated with the successful eradication of Helicobacter pylori . The aim of the present study was to investigate the effects of CYP2C19 and MDR1 genotypes on the eradication rate of H. pylori using a pantoprazole-based triple therapy.
Methods:  A total of 210 patients infected with H. pylori were treated with 40 mg pantoprazole, 500 mg clarithromycin and 1000 mg amoxicillin twice daily for 7 days. The CYP2C19 genotype was determined with polymerase chain reaction (PCR)–restriction fragment length polymorphism analysis. The MDR1 C3435T polymorphism was identified by PCR-based allele-specific amplification (PCR-ASA).
Results:  Of the 210 patients who completed the study, 174 (82.9%, 95.0% confidence interval [CI], 77.8–88.0%) achieved successful eradication after the first cycle of therapy. The eradication rates for H. pylori were 86.7%, 81.1% and 82.1% in the homozygous extensive, heterozygous extensive and poor metabolizer groups, respectively ( P  = 0.65). Moreover, the cure rates in the CC, CT, and TT groups were 82.7%, 84.4% and 76.9%, respectively ( P  = 0.66). Multiple logistic regression analysis revealed that endoscopic diagnosis was a significant independent risk factor for treatment failure.
Conclusion:  The eradication rates of H. pylori by pantoprazole, amoxicillin and clarithromycin were not significantly different among the CYP2C19 and MDR1 genotypes. Hence, the cure rate of H. pylori in the Korean population was no different for the CYP2C19 and MDR1 genotypes.     

心房颤动患者ABCB1基因多态性与达比加群酯临床疗效的关系

目的 探索维吾尔族(维族)心房颤动患者ABCA1基因C3435T位点多态性与达比加群酯治疗效果的关系.方法 选取2015年1月至2016年12月在新疆医科大学第五附属医院住院或门诊就诊的维族、汉族心房颤动患者166例作为研究对象.检测入选患者的ABCA1基因C3435T位点多态性,再分别检测并比较不同基因型患者达比加群...     

Association of a functional polymorphism (C59038T) in GTP cyclohydrolase 1 gene and Type 2 diabetic macrovascular disease in the Chinese population

Nitric oxide (NO) unavailability plays an important role in the progression of macrovascular diseases in Type 2 diabetes (T2DM). C59038T polymorphism in GTP cyclohydrolase 1 (GCH1) gene is a functional mutation involved in NO metabolism and cardiovascular risk in a multiethnic population. To clarify the relationship between C59038T polymorphism and macrovascular disease in T2DM, an association study was performed among 611 unrelated T2DM patients. C59038T polymorphism was detected by polymerase chain reaction (PCR) restriction fragment length polymorphism. The PCR products after digestion displayed three genotypes, including CC, CT, and TT. The prevalence of cardiovascular disease, cerebrovascular disease, and peripheral vascular disease was significantly higher in T2DM patients with TT genotype than those with CC or CT genotype (P<.001). Compared with CC or CC+CT genotype, T2DM patients with TT genotype had a significantly increased risk of macrovascular disease (P<.001, P=.001), with odds ratio for 4.717 [95% confidnce interval: 3.056–7.370] and 4.082 (2.716–5.868), respectively. Subjects with TT genotype showed lower levels of plasma NOx (nitrite and nitrate), flow-mediated artery dilatation and activities of superoxide dismutase but higher levels of plasma malonaldehyde and intima-media thickness of carotid artery than those with CC or CT genotype (P<.05). This study demonstrated that in Chinese T2DM population, C59038T polymorphism was associated with an increased risk of macrovascular disease, which was likely due to its effects on NO metabolism, oxidative stress, and subsequently vascular dysfunction.     

Associations of methylenetetrahydrofolate reductase C677T genotype with blood pressure levels in Chinese population with essential hypertension

Objective: To confirm the association between baseline blood pressure (BP) levels and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in patients with essential hypertension. Methods: A total of 347 patients were enrolled from the Dongzhi community in Anhui Province, China. The C677T polymorphism of the MTHFR gene was detected using high-throughput TaqMan allelic discrimination assay. Baseline BP was measured using a standardized mercury-gravity monometer. Results: In the whole sample, the frequency of the MTHFR C677T genotypes CC, CT, and TT were 38.6%, 48.1%, and 13.3%, respectively. In a recessive model (CC+CT versus TT genotypes), baseline diastolic blood pressure (DBP) was significantly higher in patients with the TT genotype compared to those with the CT or CC genotypes (P= 0.013). We also divided all patients into three groups based on the tertiles of the baseline BP distribution. Compared to subjects in the lowest tertile of DBP, the adjusted odds of having the TT genotype among subjects in the highest tertile was 2.6 (95% CI: 1.1 to 6.2). However, no significant associations were observed between baseline systolic blood pressure (SBP) and the MTHFR C677T polymorphism. Conclusions: The MTHFR gene polymorphism could be an important genetic determinant of baseline DBP levels in Chinese essential hypertensive patients.     

Hepatitis C virus infection alters lipid metabolism depending on IL28B polymorphism and viral genotype and modulates gene expression in vivo and in vitro

Hepatitis C virus (HCV) interacts with lipid receptors to enter the cell, circulates as lipoviroparticle and is secreted as VLDL. We aimed to investigate the role of the rs12979860 polymorphism in the IL28B gene in 143 with chronic hepatitis C genotype 1, 144 infected with genotype 3, 90 genotype 4 and 413 noninfected individuals on lipid profile and to test the impact of HCV infection in an in vitro model on VLDL biosynthesis‐related gene expression rs12979860 polymorphism was analysed using real‐time PCR coupled to Fluorescence Resonance Energy Transfer (FRET). Huh7.5 (rs12979860 CT) and Huh7 (genotype CC) cells were infected with JFH‐1 particles and serum from patients infected with genotypes 1 and 3. Gene expression of apolipoprotein B (apoB), microsomal triglyceride transfer protein (MTP), acetyl CoA carboxylase (ACC), diacylglycerol acyltransferase 2 (DGAT2), diacylglycerol acyltransferase 1 (DGAT1) and low‐density lipoprotein receptor (LDLr) genes were determined by semiquantitative RT‐PCR in vivo and in vitro. Genotype CC rs12979860 polymorphism was associated with significantly higher serum LDL and total cholesterol levels in patients with hepatitis C genotype 1 but not in patients with hepatitis C genotype 3, genotype 4 and control (noninfected) population. Genotype CC was more often seen in genotype 3 and healthy people in comparison with genotype 1; P = 0.001. In vitro results showed that HCV infection promotes lipid metabolism gene expression induction depending on viral genotype, but to a lesser extent in cells with CT genotype. These results demonstrate that IL28B genotype influences lipid metabolism in patients with hepatitis C but not in noninfected and it seems to be viral genotype‐mediated. HCV infection modifies lipid‐related genes expression (DGAT1 and DGAT2) in cultured cells based on viral genotype and IL28 polymorphism.     

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.     

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.