Methylenetetrahydrofolate reductase tagging polymorphisms are associated with risk of esophagogastric junction adenocarcinoma: a case-control study involving 2,740 Chinese Han subjects.
ABSTRACT: In this study, we aimed to determine the potential association of MTHFR tagging single nucleotide polymorphisms (SNPs) with risk of developing esophagogastric junction adenocarcinoma (EGJA). MTHFR rs1801133 G>A, rs3753584 T>C, rs4845882 G>A, rs4846048 A>G and rs9651118 T>C polymorphisms were genotyped in 1,677 healthy individuals and 1,063 patients with EGJA. We found that MTHFR rs1801133 G>A polymorphism was significantly associated with the risk of developing EGJA (AA vs. GG: adjusted P = 0.001; GA/AA vs. GG: adjusted P = 0.007 and AA vs. GA/GG: adjusted P = 0.001). However, for MTHFR rs4845882 G>A polymorphism, the decreased risk of EGJA was found in two genetic models (AA vs. GG: adjusted P = 0.002 and AA vs. GA/GG: adjusted P = 0.005). In addition, for MTHFR rs3753584 T>C and rs9651118 T>C polymorphisms, a tendency to decreased risk of EGJA was noted. In a subgroup analysis, a significantly decreased risk of EGJA in <64 years subgroup was identified. We found that MTHFR Grs1801133Trs3753584Grs4845882Ars4846048Crs9651118, Grs1801133Crs3753584Ars4845882Ars4846048Trs9651118 and Grs1801133Trs3753584Ars4845882Grs4846048Trs9651118 haplotypes significantly decreased the risk of EGJA (P = 0.002, P < 0.001 and P = 0.038, respectively). In conclusion, our study demonstrates that MTHFR rs1801133 G>A may be associated with the increased risk of EGJA. Meanwhile, MTHFR rs3753584 T>C, rs4845882 G>A and rs9651118 T>C polymorphisms and haplotypes may decrease the risk of EGJA in Eastern Chinese Han population. Further studies with large sample size and detailed gene-environmental data are needed to validate our conclusion.
Project description:Polymorphisms in one-carbon metabolism genes may influence the susceptibility to hepatocellular carcinoma (HCC). In the present study, we studied methylenetetrahydrofolate reductase (MTHFR) tagging polymorphisms in 584 HCC cases and 923 controls. Polymerase chain reaction was harnessed to detect MTHFR genotype. Overall, our results showed that genotype distribution of MTHFR rs4846048 and rs4845882 polymorphisms was not different between HCC patients and controls. MTHFR rs9651118 and rs1801133 loci were protective factors for HCC (rs9651118: CT vs. TT: adjusted odds ratio (OR) = 0.67, 95% confidence interval (CI): 0.49-0.90, P=0.008 and TC/CC vs. TT: adjusted OR = 0.70, 95% CI: 0.53-0.93, P=0.015; rs1801133: GA vs. GG: adjusted OR = 0.72, 95% CI: 0.54-0.97, P=0.031, AA/GA vs. GG: adjusted OR = 0.76, 95% CI: 0.57-0.99, P=0.045). However, MTHFR rs3753584 locus was a candidate for susceptibility to HCC (CT vs. TT: adjusted OR = 1.67, 95% CI: 1.20-2.32, P=0.003 and TC/CC vs. TT: adjusted OR = 1.59, 95% CI: 1.15-2.20, P=0.005). Results of haplotype analysis suggested that MTHFR Grs1801133Trs3753584Grs4845882Ars4846048Trs9651118 was associated with the risk of HCC (OR = 1.55, 95% CI: 1.16-2.07, P=0.003). The power of our study also confirmed these associations (the value of power >0.80). In summary, our findings suggested that MTHFR rs3753584, rs9651118 and rs1801133 polymorphisms may affect the risk of HCC in Chinese Han population. In future, our findings should be further validated in additional case-control studies.
Project description:Esophagogastric junction adenocarcinoma (EGJA) may be associated with obesity and overweight. Thus, any variant in energy metabolism-related gene may influence the development of EGJA. In this study, we recruited 720 EGJA cases and 1541 noncancer controls. We selected IGF2BP2 rs4402960 G?>?T, rs1470579 A?>?C, IGF1 rs5742612 A?>?G and IGFBP3 rs3110697 G?>?A, rs2270628 C?>?T and rs6953668 G?>?A loci and assessed the relationship of these polymorphisms with lymph node status and susceptibility of EGJA. We found that IGF2BP2 rs1470579 A?>?C and IGFBP3 rs6953668 G?>?A polymorphisms were associated with the decreased risk of EGJA ( IGF2BP2 rs1470579: CC vs AA: adjusted odds ratio [OR]?=?0.65, 95% confidence interval [CI]?=?0.43-0.98, P?=?0.041 and CC vs AA/AC: adjusted OR?=?0.62, 95% CI?=?0.41-0.93, P?=?0.021 and IGFBP3 rs6953668: GA vs GG: adjusted OR?=?0.66, 95% CI?=?0.47-0.93, P?=?0.019 and GA/AA vs GG: adjusted OR?=?0.68, 95% CI?=?0.48-0.95, P?=?0.026). However, we also found that IGF1 rs5742612 A?>?G polymorphism increased the risk of LNM among patients with EGJA (GG vs AA: adjusted OR?=?1.88, 95% CI?=?1.02-3.46, P?=?0.042 and GG vs AA/AG: adjusted OR?=?1.92, 95% CI?=?1.06-3.47, P?=?0.032). This study suggests that IGF2BP2 rs1470579 A?>?C and IGFBP3 rs6953668 G?>?A polymorphisms may decrease genetic susceptibility to EGJA in eastern Chinese Han population. In addition, our findings also indicate that IGF1 rs5742612 A?>?G polymorphism may increase the susceptibility of LNM among patients with EGJA.
Project description:Stroke is currently the leading cause of functional impairments worldwide. Folate supplementation is inversely associated with risk of ischemic stroke. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism. The aim of this study is to examine whether genetic variants in MTHFR gene are associated with the risk of ischemic stroke and fasting total serum homocysteine (tHcy) level. We genotyped nine tag SNPs in the MTHFR gene in a case-control study, including 543 ischemic stroke cases and 655 healthy controls in China. We found that subjects with the rs1801133 TT genotype and rs1801131 CC genotype had significant increased risks of ischemic stroke (adjusted odds ratio (OR)=1.82, 95% confidence interval (CI): 1.27-2.61, p=0.004; adjusted OR=1.99, 95% CI: 1.12-3.56, p=0.01) compared with subjects with the major alleles. Haplotype analysis also found that carriers of the MTHFR CTTCGA haplotype (rs12121543-rs13306553-rs9651118-rs1801133-rs2274976-rs1801131) had a significant reduced risk of ischemic stroke (adjusted OR=0.53, 95% CI: 0.35-0.82) compared with those with the CTTTGA haplotype. Besides, the MTHFR rs1801133 and rs9651118 were significantly associated with serum levels of tHcy in healthy controls (p<0.0001 and p=0.02). These findings suggest that variants in the MTHFR gene may influence the risk of ischemic stroke and serum tHcy.
Project description:The aim of this case-control study was to assess the relationship between the tagging polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene and the susceptibility to colorectal cancer (CRC) in a Chinese Han population. A custom-by-design 48-Plex SNPscan Kit was used to determine the genotypes of MTHFR rs3753584 T>C, rs9651118 T>C, rs1801133 G>A, rs4846048 A>G and rs4845882 G>A polymorphisms in 387 CRC patients and 1,536 non-cancer controls. The results revealed that MTHFR rs1801133 G>A polymorphism was associated with a decreased risk of overall CRC. While MTHFR rs4845882 G>A polymorphism conferred an increased risk to overall CRC. In a stratified analysis by CRC region, we found MTHFR rs3753584 T>C and rs9651118 T>C polymorphisms were associated with the increased risk of colon cancer. In addition, a significantly increased risk of rectum cancer associated with MTHFR rs3753584 T>C polymorphism was overt. However, MTHFR rs1801133 G>A polymorphism conferred a decreased risk to colon cancer. In conclusion, findings of the present study reveal that the tagging polymorphisms in MTHFR gene (rs3753584 T>C, rs9651118 T>C and rs4845882 G>A) are associated with the increased risk of CRC. However, MTHFR rs1801133 G>A polymorphism confers a decreased risk to CRC. Additional studies with larger sample size are needed to confirm these findings.
Project description:Diabetes is a global public health crisis, and the prevalence is increasing rapidly. Folate supplementation is proved to be effective in reducing the risk of diabetes or improving its symptoms. Methylenetetrahydrofolate reductase is an important enzyme involved in folate metabolism. The aim of this study is to examine whether polymorphisms in the MTHFR gene are associated with risk of type 2 diabetes mellitus (T2DM) and fasting total serum homocysteine (tHcy) levels. We genotyped nine tagging SNPs in the MTHFR gene in a case-control study, including 595 T2DM cases and 681 healthy controls in China. We found that C allele of rs9651118 had significant decreased risk of T2DM (adjusted odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.55-0.87, P = 0.002) compared with T allele. Haplotype analysis also showed that MTHFR CTCCGA haplotype (rs12121543-rs13306553-rs9651118-rs1801133-rs2274976-rs1801131) had significant reduced risk of T2DM (adjusted OR = 0.71, 95% CI: 0.58-0.87, P = 0.001) compared with CTTTGA haplotype. Besides, the MTHFR rs1801133 was significantly associated with serum levels of tHcy in healthy controls (P = 0.0002). These associations were still significant after Bonferroni corrections (P < 0.0056). These findings suggest that variants in the MTHFR gene may influence the risk of T2DM and tHcy levels.
Project description:Previous reports implicated 5,10-ethylenetetrahydrofolate reductase (MTHFR) polymorphisms acted as a potential risk factor for several cancers. In order to explore the effect of MTHFR SNPs on non-small cell lung cancer (NSCLC), we selected MTHFR tagging single nucleotide polymorphisms (SNPs) and carried out a case-control study to determine the potential relationship of MTHFR SNPs with NSCLC risk. Our study consisted of 521 NSCLC patients and 1,030 non-cancer controls. MTHFR SNPs were genotyped by SNPscanTM genotyping assay. Using four genetic models (additive, Homozygote, dominant, recessive), the genotype frequencies were compared using the chi-squared (?2) test. Crude/adjusted odds ratios (ORs) with their 95% confidence intervals (CIs) were used to assess the difference for the genotype distribution. We found that MTHFR rs1801133 G>A polymorphism decreased the risk of overall NSCLC. In a subgroup analysis, MTHFR rs1801133 G>A polymorphism also decreased NSCLC risk in female, < 60 years and never smoking subgroups. However, we identified that MTHFR rs4845882 G>A polymorphism was associated with the development of NSCLC in female subgroup. In addition, MTHFR rs9651118 T>C polymorphism increased the risk of NSCLC in < 60 years, never smoking and BMI < 24 kg/m2 subgroups. In conclusion, the current study highlights MTHFR rs1801133 G>A variants decreases the risk of NSCLC. Nevertheless, MTHFR rs4845882 G>A and rs9651118 T > C polymorphisms may be associated with NSCLC susceptibility. Well-designed large-scale studies are needed to confirm these findings and explore the interactions of gene-gene and gene-environment involved in MTHFR SNPs and NSCLC.
Project description:The aim of this study was to investigate the relationship between the combined effect of MTHFR C677T (rs1801133) and EPHX2 G860A (rs751141) polymorphism and ischemic stroke in Chinese T2DM patients. This case-control study included a total of 626 Chinese T2DM patients (236 T2DM patients with ischemic stroke and 390 T2DM patients without ischemic stroke). The rs1801133 and rs751141 were genotyped using real-time polymerase chain reaction. Statistical analysis was performed with SPSS 17.0. Results showed that the combined effect of MTHFR TT and EPHX2 GG or GA + AA genotype has a higher risk of ischemic stroke compared with the control group (combined effect of MTHFR CC and EPHX2 GA + AA genotypes; OR = 3.46 and OR = 3.42, resp.; P = .001 and P = .002, resp.). The A allele showed marked association with a lower risk of ischemic stroke in patients with the lowest Hcy levels under additive, recessive, and dominant genetic models (OR = 0.45, OR = 0.11, and OR = 0.44, resp.; P = .002, P = .035, and P = .008, resp.), which was not observed in medium or high Hcy level groups. In conclusion, the T allele of rs1801133 and the G allele of rs751141 may be risk factors of ischemic stroke in the Chinese T2DM population.
Project description:We examined the association between high-density lipoprotein cholesterol (HDL-C), and exercise and vegetarian diets, in Taiwanese adults, based on the Methylenetetrahydrofolate reductase (MTHFR) rs1801133 polymorphism. Using regression models, we analyzed historical data collected from 9255 Taiwan Biobank (TWB) participants from 2008 through 2015. Exposure to exercise was associated with higher HDL-C (? = 1.0508 and 1.4011 for GG and GA + AA individuals, respectively), whereas a vegetarian diet was associated with lower HDL-C (? = -6.2793 and -4.6359 for those with GG and GA + AA genotype, respectively). We found an interaction between exercise and diet among GG individuals (p = 0.0101). Compared with no exercise/no vegetarian diet, vegetarian diet/no exercise was associated with a 5.1514 mg/dl reduction in HDL-C among those with GG genotype (? = -5.1514, p < 0.0001) and a 4.8426 mg/dl reduction (? = -4.8426, p < 0.0001) among those with GA + AA genotype. Vegetarian diets in combination with exercise predicted a 6.5552 mg/dl reduction in HDL-C among GG individuals (? = -6.5552) and a 2.8668 mg/dl reduction among GA + AA individuals (p < 0.05). These findings demonstrated that vegetarian diet alone was associated with lower HDL-C, no matter the rs1801133 genotype. However, the inclusion of regular exercise predicted much lower levels among GG individuals, whereas levels among GA + AA individuals were relatively higher.
Project description:Methylenetetrahydrofolate reductase gene (MTHFR), transcobalaminII (TCN2) and ring finger protein 213 (RNF213) are related to homocysteine (Hcy) level and are of great significance for hypertension. We aimed to evaluate the associations of MTHFR (rs1801133, rs1801131, rs9651118), TCN2 (rs117353193) and RNF213 (rs9916351) with hypertension and blood pressure (BP). A total of 953 patients with hypertension and 1103 controls were enrolled. Genotyping was performed by Taqman. Logistic regression analysis indicated that A allele of TCN2 rs117353193 under the dominant model had a significantly protective effect (P=0.045) after adjustment, which showed that AA+GA genotype has a lower risk than GG. Additionally, the average diastolic BP (DBP) (P=0.044) and mean arterial pressure (MAP) (P=0.035) levels were significantly different between genotypes of RNF213 rs9916351. Further pairwise comparison showed that the average systolic BP (SBP) level of the TT genotype carriers were significantly higher than in CC (P=0.024), and the average DBP and MAP levels of the TT genotype carriers were higher than in CT (P=0.044, P=0.012, respectively) and CC (P=0.048, P=0.010, respectively). In the recessive model, the average SBP (P=0.043), DBP (P=0.018) and MAP (P=0.017) levels with the TT genotype carriers were significantly higher than in CT+CC. Multiple linear regression analysis suggested that RNF213 rs9916351 in the recessive model had significant effects on SBP (P=0.025), DBP (P=0.017) and MAP (P=0.010) as a risk factor. However, no associations were observed between MTHFR and hypertension. TCN2 rs117353193 might serve as a protective factor in hypertension, and RNF213 rs9916351 might be a risk factor that is linked to increase BP level in Northeast Chinese population.
Project description:Accumulating evidence has suggested that leptin (LEP) is very important for the development of cancer. Recently, a number of case-control studies about the relationship of the rs2167270 G?>?A (G19A) variants in the LEP gene with the risk of cancer have yielded inconsistent results. In this study, we have carried out a case-control study [1063 esophagogastric junction adenocarcinoma (EGJA) cases and 1677 controls] in a Chinese population. Furthermore, we carried out a pooled-analysis of 13 studies involving 8059 cancer patients and 11?930 controls to assess whether the LEP G19A locus was associated with overall cancer susceptibility. Odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were harnessed to evaluate the potential association. In our case-control study, we found an association between the carriers of LEP 19A allele and EGJA risk. In addition, the results of meta-analysis also suggested significant associations with cancer risk (A vs G: OR?=?0.92, 95% CI?=?0.88-0.97, P?=?0.001; AA vs GG: OR?=?0.83, 95% CI?=?0.74-0.93, P?=?0.001, GA/AA vs GG: OR?=?0.93, 95% CI?=?0.88-0.99, P?=?0.023 and AA vs GG/GA: OR?=?0.83, 95% CI?=?0.74-0.92, P?<?0.001). Upon conducting a stratified analysis, we found that LEP 19A allele might decrease the susceptibility of non-Hodgkin lymphoma (NHL) and colorectal cancer (CRC). In a stratified-by-ethnicity analysis, significant associations were also found in Asians, Caucasians, and mixed populations. We can conclude that the LEP G19A polymorphism constitutes a decreased risk of cancer.