Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer

This study was designed to investigate, in the Turkish population, an association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of gastric and colorectal cancer. Our study was carried out in 35 patients with gastric cancer (20 men, 15 women) and 144 controls (75 men, 69 women) and 52 colorectal cancer (31 men, 21 women). MTHFR C677T genotypes were determined by polymerase chain reaction, restriction fragment length polymorphism techniques. No differences were observed in the distribution of MTHFR genotypes or allele frequencies in cases versus controls. The homozygous mutation (T/T) in the MTHFR gene was identified in 14.3% of gastric cancer versus 10.4% of controls. MTHFR C677T frequencies of the CC, CT and TT genotypes among colorectal cancer patients were 34.6%, 51.9% and 13.5%, respectively. MTHFR C677T polymorphism may not be important in an individual's susceptibility to gastric and colorectal cancer in Turkey and may not be a useful marker for identifying patients at high risk of developing gastric and colorectal cancer.     

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and susceptibility to gastric adenocarcinoma in an Italian population

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the metabolism of folate, which provides a methyl donor for DNA methylation and deoxynucleoside synthesis. We performed a case-control study to explore the relationship between two common MTHFR polymorphisms (C677T and A1298C), their combination and interaction with environmental exposures, on gastric adenocarcinoma susceptibility and progression in an Italian population. One hundred and two cases and 254 hospital controls, matched by age and gender, were enrolled. Individuals carrying the MTHFR 677T allele showed an increased risk of gastric cancer (odds ratio (OR) 1.62, 95% confidence interval (CI) 0.98-2.67), particularly among ever smokers (OR 2.10, 95% CI 1.07-5.33) and, among 677 TT individuals, those with a low intake of fruit and vegetables (OR 2.18, 95% CI 1.05-4.54). The strongest effect, however, was noted for the MTHFR 677 TT genotype among the diffuse gastric cancer histotype (OR 2.92, 95% CI 1.12-7.60). No association was detected for the effect of MTHFR A1298C polymorphism. Survival analysis did not show any association between each polymorphism on the overall survival, although when the analysis was restricted to the first year of follow-up after the surgical intervention an improved survival was noted among MTHFR 677 CC subjects compared with the T allele carriers (p value for log-rank test 0.02). In conclusion, MTHFR 677 (any T genotype) appears to modulate an individual's susceptibility to gastric cancer, particularly when combined with cigarette smoking and among those with a low intake of fruit and vegetables. Our results also suggest that an aberrant DNA methylation pattern, through impaired folate metabolism, might play a key role in gastric carcinogenesis. A possible survival effect of the MTHFR C677T genotype in gastric cancer patients deserves further investigations with larger sample sizes.     

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and susceptibility to gastric adenocarcinoma in an Italian population

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the metabolism of folate, which provides a methyl donor for DNA methylation and deoxynucleoside synthesis. We performed a case–control study to explore the relationship between two common MTHFR polymorphisms (C677T and A1298C), their combination and interaction with environmental exposures, on gastric adenocarcinoma susceptibility and progression in an Italian population. One hundred and two cases and 254 hospital controls, matched by age and gender, were enrolled. Individuals carrying the MTHFR 677T allele showed an increased risk of gastric cancer (odds ratio (OR) 1.62, 95% confidence interval (CI) 0.98–2.67), particularly among ever smokers (OR 2.10, 95% CI 1.07–5.33) and, among 677 TT individuals, those with a low intake of fruit and vegetables (OR 2.18, 95% CI 1.05–4.54). The strongest effect, however, was noted for the MTHFR 677 TT genotype among the diffuse gastric cancer histotype (OR 2.92, 95% CI 1.12–7.60). No association was detected for the effect of MTHFR A1298C polymorphism. Survival analysis did not show any association between each polymorphism on the overall survival, although when the analysis was restricted to the first year of follow-up after the surgical intervention an improved survival was noted among MTHFR 677 CC subjects compared with the T allele carriers (p value for log-rank test 0.02). In conclusion, MTHFR 677 (any T genotype) appears to modulate an individual's susceptibility to gastric cancer, particularly when combined with cigarette smoking and among those with a low intake of fruit and vegetables. Our results also suggest that an aberrant DNA methylation pattern, through impaired folate metabolism, might play a key role in gastric carcinogenesis. A possible survival effect of the MTHFR C677T genotype in gastric cancer patients deserves further investigations with larger sample sizes.     

Common ABCB1 polymorphisms associated with susceptibility to infantile spasms in the Chinese Han population

Infantile spasms are a severe epileptic encephalopathy with a variety of etiologies that occur in infancy and early childhood. Subjects with infantile spasms are at a higher risk for evolving into intractable epileptic spasms, tending to be refractory to conventional antiepileptic drugs. Genetic polymorphisms of the P-glycoprotein-encoding gene ABCB1 are suspected to be associated with pharmacoresistance phenotypes in epilepsy patients. Conflicting findings have been reported in different populations; few studies have explored whether this apparent association is affected by other host factors, such as specific epilepsy syndrome. We performed a case-control study to determine whether the risk of infantile spasms is influenced by common ABCB1 polymorphisms in a Han Chinese children's population consisting of 91 patients and 368 healthy individuals. DNA was isolated from whole blood, and three genetic polymorphisms (C1236T, G2677T/A, and C3435T) were assayed by PCR-RFLP. There were significant differences in the distributions of 3435TT [P = 0.001; odds ratio = 2.47; 95% confidence interval (CI) = 1.44-4.27] and 3435CT [P < 0.001; odds ratio = 0.28; 95% CI = 0.15-0.54] genotypes between infantile spasm cases and controls. No significant differences were observed in allelic and haplotypic frequencies of ABCB1 polymorphisms between the two groups. This study demonstrated that variations in the C3435T gene play an important role in the pathogenesis of infantile spasms in the Han Chinese population; 3435TT is associated with increased risk of having this epilepsy syndrome.     

Genetic variants in MARCO are associated with the susceptibility to pulmonary tuberculosis in Chinese Han population

Background

Susceptibility to tuberculosis is not only determined by Mycobacterium tuberculosis infection, but also by the genetic component of the host. Macrophage receptor with a collagenous structure (MARCO) is essential components required for toll like receptor-signaling in macrophage response to Mycobacterium tuberculosis, which may contribute to tuberculosis risk.

Principal Findings

To specifically investigated whether single nucleotide polymorphisms (SNPs) in MARCO gene are associated with pulmonary tuberculosis in Chinese Han population. By selecting tagging SNPs in MARCO gene, 17 tag SNPs were identified and genotyped in 923 pulmonary tuberculosis patients and 1033 healthy control subjects using a hospital based case-control association study. Single-point and haplotype analysis revealed an association in intron and exon region of MARCO gene. One SNP (rs17009726) was associated with susceptibility to pulmonary tuberculosis, where the carriers of the G allele had a 1.65 fold (95% CI = 1.32–2.05, p _corrected = 9.27E–5) increased risk of pulmonary tuberculosis. Haplotype analysis revealed that haplotype GC containing G allele of 17009726 and haplotype TGCC (rs17795618T/A, rs1371562G/T, rs6761637T/C, rs2011839C/T) were also associated with susceptibility to pulmonary tuberculosis (p _corrected = 0.0001 and 0.029, respectively).

Conclusions

Our study suggested that genetic variants in MARCO gene were associated with pulmonary tuberculosis susceptibility in Chinese Han population, and the findings emphasize the importance of MARCO mediated immune responses in the pathogenesis of tuberculosis.     

MMP-9 polymorphisms are related to serum lipids levels but not associated with colorectal cancer susceptibility in Chinese population

Matrix metalloproteinases (MMPs) play an important role in cancer development and aggression. MMP-9 polymorphisms may affect MMPs expression and contribute to interindividual differences in susceptibility to a wide spectrum of cancers. The purpose of this study was to investigate the association of MMP-9 P574R and R668Q polymorphisms with colorectal cancer (CRC); and to explore the relationship among the polymorphisms and clinicopathologic parameters, serum tumor markers and lipids. The genotypes were determined by polymerase chain reaction-restriction fragment lengthy polymorphism (PCR-RFLP). Tumor markers were measured with the Electro ChemiL uminescence method. Lipids levels were analyzed using an automatic biochemistry analyzer. The both polymorphisms were not associated with the risk of CRC risk. The clinicopathologic parameters, tumor markers were not associated with MMP-9 polymorphisms. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly higher in patients with P574R PP genotype compared with patients with P574R PR combined RR genotypes (P?=?0.043 and P?=?0.038 respectively). Our data suggested that MMP-9 P574R and R668Q were not associated with CRC risk, but P574R affected serum LDL-C and TC levels in CRC patients.     

Methylenetetrahydrofolate reductase 677TT genotype might be associated with an increased lung cancer risk in Asians

Background

The association between methylenetetrahydrofolate reductase (MTHFR) 677C > T polymorphism and lung cancer risk has been studied in various populations with conflicting results. The aim of this study was to assess the association strength by a meta-analysis of published studies.

Methods

We searched PubMed and Chinese Biomedical (CBM) databases for relevant literatures published by July 18, 2012. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to assess the strength of the association.

Results

A total of 20 studies comprising 11,653 cases and 12,032 controls were included in the final meta-analysis. Using the random effect model, we found that MTHFR 677TT variant genotype was associated with an increased lung cancer risk (OR = 1.26, 95% CI = 1.05–1.50, P = 0.011 for TT vs. CC; OR = 1.19, 95% CI = 1.03–1.37, P < 0.001 for TT vs. CC + CT; OR = 1.11, 95% CI = 1.02–1.22, P = 0.017 for T allele vs. C allele). In the further stratified analyses, the increased lung cancer risk was found in Asian subjects (OR = 1.31, 95% CI = 1.01–1.71, P = 0.045 for TT vs. CC; OR = 1.17, 95% CI = 1.00–1.38, P = 0.048 for TT vs. CC + CT). There were no evidences for obvious publication bias in the overall meta-analysis and Asian subjects.

Conclusions

MTHFR 677TT genotype might increase the susceptibility of lung cancer, especially in Asians.     

Genetic polymorphisms of XRCC1 gene and susceptibility to gastric cancer in Chinese Han population

Abstract

This study aims to evaluate whether the c.1471G?>?A and c.1686C?>?G genetic polymorphisms of XRCC1 gene influencing gastric cancer susceptibility. A total of 813 subjects with Chinese Han ethnicity were enrolled. Our data suggest that the allele and genotype frequencies are significantly different from gastric cancer patients with cancer-free controls. We find that c.1471G?>?A and c.1686C?>?G genetic polymorphisms statistically increase the risk of gastric cancer. Our findings indicate these two genetic polymorphisms are related with the susceptibility to gastric cancer, and could be used as molecular markers for detecting gastric cancer in Chinese Han ethnicity.     

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and nonsyndromic orofacial clefts susceptibility in a southern Chinese population

Nonsyndromic orofacial clefts (NSOC) are one of the most common congenital anomalies in humans. Great efforts have been taken to unravel its genetic background. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism and two of its functional polymorphisms, MTHFR C677T and MTHFR A1298C, might be associated with NSOC susceptibility. The aim of the present study was to investigate their associations with risks of NSOC in a southern Chinese population. We found that MTHFR 677 TT and 677 CT/TT were associated with increased risk of cleft lip with or without cleft palate; meanwhile, MTHFR 1298 AC and 1298 AC/CC had protective effects against cleft lip with or without cleft palate. In further stratified analysis, we found that MTHFR 677 CT contributed to elevated risk of cleft lip only, as did MTHFR 677 CT/TT. On the contrary, MTHFR 1298 AC and 1298 AC/CC appeared to be protective against cleft lip with cleft palate. These results suggested that these two polymorphisms were involved in the development of NSOC in a southern Han Chinese population.     

Association of PTEN polymorphisms with susceptibility to hepatocellular carcinoma in a Han Chinese population

The phosphate and tension homolog (PTEN) is a tumor suppressor gene that controls a variety of biological processes including cell proliferation, migration, and death. The association of PTEN polymorphisms with risk for many cancers has been reported, but hepatocellular carcinoma (HCC) has not yet been studied. The present study is the first attempt to assess the association of PTEN polymorphisms with HCC susceptibility. We genotyped one insertion/deletion polymorphism (rs34421660) by polymerase chain reaction (PCR) method and three tag single-nucleotide polymorphisms (rs10490920, rs532678, and rs701848) by polymerase chain reaction-restriction fragment length polymorphism in 134 HCC patients and 215 healthy controls. We found that the four polymorphisms were not associated with HCC, at both the allele and genotype levels. However, after reconstructing PTEN haplotypes according to genotyping data and linkage disequilibrium status of four polymorphisms, we found that the T-C-C-del haplotype was associated with decreased HCC risk (odds ratio?=?0.19, 95% confidence interval?=?0.06-0.56) and the T-T-T-ins haplotype was associated with increased HCC risk (odds ratio?=?1.63, 95% confidence interval?=?1.14-2.33). Thus, our results prove that PTEN haplotypes may be associated with HCC susceptibility in a Chinese Han population.     

No association of Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in susceptibility to gallbladder cancer

Gallbladder carcinoma (GBC) is a leading cause of cancer deaths in north India. Evidence has highlighted the role of abnormal DNA methylation patterns on inappropriate gene expression in development and progression of various cancers. 5,10-Methylenetetrahydrofolate reductase (MTHFR) plays a major role in provision of methyl groups for DNA methylation. A C/T substitution in MTHFR at nucleotide 677 results in replacement of ala222-to-val in the N-terminal catalytic domain of protein, and causes considerable decrease in enzymatic activity. Thus, MTHFR C677T polymorphism may influence genetic susceptibility to GBC. The present study aimed to examine the role of C677T MTHFR polymorphism in conferring genetic susceptibility to GBC. The present study included 146 proven GBC patients and 210 healthy controls. Genotyping was done by PCR-RFLP method. The MTHFR C677T genotypes in control population were in Hardy-Weinberg equilibrium (p = ns). No statistically significant difference was observed in frequency of variant TT genotype in GBC patients in comparison to healthy controls (4.1% and 2.9%). Stratification of GBC patients on the basis of presence or absence of gallstones showed no significant association with the disease. Further, gender and age of onset of the disease did not show any significant association. In conclusion, the present study indicates that the genetic risk for GBC is not modulated by MTHFR C677T polymorphism.     

Methylenetetrahydrofolate reductase (MTHFR-677 and MTHFR-1298) genotypes and haplotypes and plasma homocysteine levels in patients with occlusive artery disease and deep venous thrombosis

The aim was to investigate different genotypes and haplotypes of methylenetetrahydrofolate reductase (MTHFR-677, -1298) and plasma concentration of total homocysteine (tHcy) in Macedonian patients with occlusive artery disease (OAD) and deep venous thrombosis (DVT). Investigated groups consists of 80 healthy, 74 patients with OAD, and 63 patients with DVT. Plasma tHcy was measured with Microplate Enzyme Immunoassay. Identification of MTHFR genotypes and haplotypes was done with CVD StripAssay. The probability level (P-value) was evaluated by the Student's t-test. Plasma concentration of tHcy in CC and CT genotypes of MTHFR C677T was significantly increased in patients with OAD and in patients with DVT. Plasma concentration of tHcy in AC genotype of MTHFR A1298C was increased in patients with OAD and in patients with DVT. Plasma concentration of tHcy was significantly increased in AA genotype of patients with OAD, but not in patients with DVT. We found a significant increase of plasma tHcy in patients with OAD in comparison with healthy respondents for normal:heterozygote (CC:AC), heterozygote:normal (CT:AA), and heterozygote:heterozygote (CT:AC) haplotypes. Plasma concentration of tHcy in patients with DVT in comparison with healthy respondents was significantly increased for normal:normal (CC:AA), normal heterozygote (CC:AC), and heterozygote:heterozygote (CT:AC) haplotypes. We conclude that MTHFR C677T and MTHFR A1289C genotypes and haplotypes are connected with tHcy plasma levels in Macedonian patients with OAD and DVT.     

Replication of putative susceptibility loci from genome-wide association studies associated with coronary atherosclerosis in Chinese Han population

Background

Coronary atherosclerosis, the main cause of cardiovascular disease, is a progressive disease. Recent Genome Wide Association Studies (GWASs) discovered several novel loci associated with coronary artery disease (CAD) or its main complication myocardial infarction (MI). In this study, we investigated the associations between previously reported CAD- and MI-associated variants and coronary atherosclerosis in Chinese Han population.

Methodology/Principal Findings

We performed a case-control association study with 2,335 coronary atherosclerosis patients and 1,078 controls undergoing coronary angiography of Chinese Han from China. Fourteen single nucleotide polymorphisms (SNPs), located at 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21.3, 10q11.21 and 15q22.33, were genotyped in our sample collection. Six SNPs at 9p21 were associated with coronary atherosclerosis susceptibility (P_trend<0.05) and rs10757274 showed the most significant association (P = 2.38×10⁻⁰⁸, OR = 1.34). These associations remained significant after adjustment for multiple comparisons. Rs17465637 at 1q41 (P_trend = 6.83×10⁻⁰³, OR = 0.86) also showed significant association with coronary atherosclerosis, but the association was not significant after multiple comparisons. Additionally, rs501120 (P = 8.36×10⁻⁰³, OR = 0.80) at 10q11.21 was associated with coronary atherosclerosis in females, but did not show association in males and all participants. Variants at 1p13.3, 2q36.3, 6q25.1 and 15q22.33 showed no associations with coronary atherosclerosis and main cardiovascular risk factors in our data.

Conclusions/Significance

Our findings indicated variants at 9p21 were significantly associated with coronary atherosclerosis in Han Chinese. Variants at 1q41 showed suggestive evidence of association and variants at 10q11.21 showed suggestive evidence of association in females, which warrant further study in a larger sample.     

CRP Gene polymorphism contributes genetic susceptibility to dyslipidemia in Han Chinese population

C-reactive protein (CRP), an inflammatory marker that statistically predicts future cardiovascular risk, has been reported to be associated with plasma lipid level changes. Whether CRP genetic variants affect lipid metabolism is of importance to investigate. A community-based study population including 2,731 adult subjects aged 18–62 years was used to evaluate the association of CRP gene with dyslipidemia and five tagging SNPs (tagSNPs) were genotyped. Multiple logistic regression was applied to further evaluate relationships between the SNPs and lipid metabolism abnormality and general linear model was applied to compare plasma lipid levels between genotypes. Association analyses indicated that recessive model of SNPs rs876537 and rs4285692 had significant association with elevated HDL after adjustment for covariates. Odds ratio (OR) of rs876537 were 0.60 for HDL > 1.54 versus 1.04–1.54 mmol/L (P = 0.011), as well as, ORs were 0.617 for HDL > 1.83 versus ≤1.35 mmol/L (P = 0.002) and 0.724 for HDL = 1.59–1.83 versus ≤1.35 mmol/L (P = 0.028) respectively. OR of rs4285692 was 0.634 for HDL > 1.83 versus ≤1.35 mmol/L (P = 0.027). Further stratification analysis found significant associations of rs10737175 with elevated HDL (>1.54 vs. 1.04–1.54 mmol/L, OR 0.629 and P = 0.027) and elevated TG (≥1.70 vs. <1.70 mmol/L, ORs of additive and dominant models were 0.628, 0.545 and P values were 0.006, 0.003 respectively) in female. rs4285692 was significantly associated with elevated LDL (≥3.37 vs. <3.37 mmol/L), ORs equaled to 1.532, 2.281 for additive model and recessive model and P values were 0.028, 0.024 respectively in male. Furthermore, quantitative trait analysis indicated the variation T to C of rs876537 significantly affect decreased plasma HDL level (P = 0.014). Our findings suggest that CRP genetic polymorphisms independently had positive association with the risk of HDL, LDL and TG elevating and further replication in other large population and biological function research would be warranted.     

Lysyl oxidase 473 G>A polymorphism and breast cancer susceptibility in Chinese Han population

Lysyl oxidase (LOX) is an extracellular enzyme critical for the cross-linking of collagens and elastin. The LOX gene has also been shown to inhibit the transforming activity of Ras oncogene signaling. Recently, a single-nucleotide polymorphism (SNP) of LOX G473A (rs1800449) has been demonstrated to be associated with increased risk of breast cancer in African American women. In this hospital-based case-control study, the association of LOX polymorphism with breast cancer susceptibility in Chinese Han population was investigated. In total, 238 female patients with breast cancer and 234 age-matched healthy controls recruited were genotyped. We found a significant difference in the frequency of the LOX G473A genotype between the breast cancer and control groups. Individuals with GA genotype showed a 2.79-fold (95% confidence interval?=?1.87-4.16) increased risk of breast cancer compared with subjects carrying GG genotype (p?相似文献   

Genetic polymorphisms in translesion synthesis genes are associated with colorectal cancer risk and metastasis in Han Chinese

Translesion synthesis (TLS) polymerases have low processivity and fidelity compared with replicative polymerases. Defective function of TLS polymerases result in chromosome instability. The aim of this study was to evaluate the effects of TLS genes on susceptibility and metastasis in colorectal cancer (CRC). Four single nucleotide polymorphisms (SNPs) (rs462779, rs11153292, rs373572 and rs2233004) of TLS genes were genotyped in the pilot cohort consisted of 516 patients with CRC and 503 controls, and then replicated in the replication cohort of 421 cases and 446 controls. The genotype frequencies of rs462779 and rs373572 were significantly different between CRC patients and controls in both two cohorts, even after it was adjusted by age, gender and smoking status. Stratified analysis showed that rs462779 and rs373572 were significantly associated with both colon and rectum cancer. In patients with metastatic CRC, the frequency of AA genotype of rs373572 was significantly increased as compared with those without metastasis CRC (P=0.001). Furthermore, rs462779 and rs373572 exhibited remarkably cumulative effect on the risk of CRC (trend P value=0.001). No significant difference was observed between other SNPs and CRC. These results suggest that polymorphisms in TLS genes are associated with susceptibility to CRC in Chinese and might be a novel biomarker for the predication of metastasis risk of CRC.     

Screening for an inherited susceptibility to colorectal cancer

The principal Mendelian disorders predisposing to colorectal cancer are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). FAP is caused by mutations in the adenomatous polyposis coli (APC) gene. HNPCC is caused by a mutation in one of at least five mismatch repair genes. It is important to identify individuals with these conditions because colon cancer will occur in at least 80% and onset is earlier than in the general population. Potential benefits of identification include improved compliance with recommended surveillance, early detection of polyps, reduction in cancer mortality, and reassurance for relatives found to be negative with attendant savings in the time and expense of surveillance. For classic FAP, the large number of polyps readily identifies affected persons. For HNPCC, identification of individuals meriting DNA sequencing requires either recognition of a suspect family history or finding high microsatellite instability in a tumor. Individuals accepting the offer of genetic counseling and DNA testing often have more cancers in their family, are motivated to inform relatives, have a larger social network, and have more confidence in their coping ability. Individuals who decline are often concerned about their own or their family's emotional reaction or fear discrimination.