The effect of methylenetetrahydrofolate reductase polymorphisms on susceptibility to human papilloma virus infection and cervical cancer

Cervical cancer is the third most common cancer among women worldwide. Several factors lead to cervical cancer, among which human papilloma virus (HPV) infection has a prominent role. Methylenetetrahydrofolate reductase (MTHFR) is crucial in folate metabolic pathway and plays an important role in DNA synthesis and DNA methylation. MTHFR gene polymorphisms, including C677T and A1298C, lead to reduced enzyme activity. This case-control study aims to illustrate the association between MTHFR gene polymorphisms and the risk of cervical cancer.This study was conducted on 196 samples, which included 96 cervical biopsy samples compared to 100 Pap smear samples of normal healthy women without HPV infection. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for the MTHFR polymorphism detection, followed by fluorescent amplification-based specific hybridization PCR method to detect HPV16 and HPV18.The results show that the MTHFR 677TT genotype plays a protective role in cervical cancer (P = 0.0030) (OR = 0.21, 95% confidence interval [CI]: 0.07–0.59). Furthermore, there was a strong significant association between MTHFR 1298CC genotype and the risk of cervical cancer (OR = 10.69; 95% CI: 4.28–26.71, P = 0.0001).It can be concluded that A1298C polymorphism is a genetic risk factor for cervical cancer in the assessed Iranian population group. It seems that MTHFR 1298CC genotype is more susceptible to HPV 16 infection. Combination analysis of MTHFR C677T and A1298C polymorphisms revealed that combined MTHFR 677CC and 1298CC are strongly associated with a risk of cervical cancer.     

Significant association between methylenetetrahydrofolate reductase 677T allele and hyperuricemia among adult Japanese subjects

It is well known that high serum uric acid (SUA) is the cause of gout and a risk factor of cardiovascular diseases. Although SUA is thought to have an association with folate metabolism through elevated production and/or damaged renal excretion, studies on functional polymorphisms of folate metabolizing are still limited, showing inconsistent findings. We hypothesized that hyperuricemia would be associated with methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase (TS) 28-bp tandem repeat polymorphism. Subjects were 793 healthy health checkup examinees (272 male and 521 female Japanese) aged 39 years or older. There was no clear difference in SUA means among those with different genotypes of MTHFR and TS, but a significant association between hyperuricemia (SUA ≥7mg/dL) and MTHFR 677T allele carriers was observed. The odds ratio of harboring 677T allele adjusted for sex, age, body mass index, serum creatinine, systolic blood pressure, currents habits of smoking and drinking, and TS genotype was 2.77 (95% confidence interval, 1.38-5.56). The TS genotype was not significantly associated with hyperuricemia; the corresponding adjusted odds ratio was 1.36 (95% confidence interval, 0.75-2.48) for non–33 genotype relative to 33 genotype. Because MTHFR 677CC was rarer both in <4 mg/dL group and ≥7 mg/dL group, the comparisons of SUA means were not useful to elucidate the roles of the polymorphism. This new view may partly explain the inconsistent results on the association of the MTHFR polymorphism with SUA.     

Influence of the C677T Polymorphism of the MTHFR Gene on Oxidative Stress in Women With Overweight or Obesity: Response to a Dietary Folate Intervention

ABSTRACT

The C677T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR) is related to folate metabolism and can alter the levels of biochemical markers.

Objective: Investigate the influence of the MTHFR C677T polymorphism on the effects of a dietary folate intervention on oxidative stress in women with overweight or obesity.

Methods: Forty-eight adult women with overweight or obesity were subjected to a 24-hour dietary recall, anthropometric measurements, biochemical analysis, and genotyping of the MTHFR C677T polymorphism. They were allocated by convenience sampling to 2 groups, which received 300 g of folate-rich vegetables containing 191 µg/d (Group 1) (n = 24) or 95 µg/d (Group 2) (n = 24) of folate for 8 weeks.

Results: The dietary intervention increased the serum folic acid levels in the 2 analyzed groups. The intervention with 191 µg/d of folate led to relevant results in terms of homocysteine levels (p = 0.0005) and total antioxidant capacity (p = 0.0261); the effect was larger among carriers of the TT genotype.

Conclusions: The study demonstrated the beneficial effect of folate intake in terms of a TAC elevation for the CC and TT genotypes of the MTHFR C677T polymorphism, an increase in folic acid levels for all genotypes, and a reduction in the Hcy levels for the TT genotype in response to an intervention consisting of an intake of 191 µg/d of folate supplied by vegetables.     

Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T,MTHFR A1298C,MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency

Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28–75 were enrolled in this study from September 2005–December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk.     

Risk Factors for Colon Cancer in Northeastern Thailand: Interaction of MTHFR Codon 677 and 1298 Genotypes with Environmental Factors

Background

Polymorphisms in methylenetetrahydrofolate reductase (MTHFR), such as MTHFR C677T and A1298C, are associated with several cancers. This study aimed to evaluate the effects of MTHFR polymorphisms on colon cancer risk and possible interactions with environmental factors in a population from northeastern Thailand.

Methods

This hospital-based case–control study was conducted during 2002–2006; 130 colon cancer cases and 130 age- and sex-matched controls were enrolled. Information was collected and blood samples were obtained for assay of MTHFR C677T and A1298C polymorphisms by polymerase chain reaction with restriction fragment length polymorphism techniques. Associations between variables of interest and colon cancer were assessed using conditional logistic regression.

Results

Increased risk of colon cancer was associated with alcohol consumption and bowel habits. Alcohol drinkers who consumed ≤0.50 or >0.50 units of alcohol per day had elevated risks (OR_adj = 3.5; 95% CI: 1.19–10.25 and OR_adj = 1.71; 95% CI: 0.74–3.96, respectively). The risk was also higher in subjects with frequent constipation (11.69; 2.18–62.79) and occasional constipation (3.43; 1.72–6.82). An interaction was observed between the MTHFR C677T polymorphism and freshwater fish consumption on colon cancer risk (P value for interaction = 0.031). Interactions were observed between the MTHFR A1298C polymorphism and bowel habits, family history of cancer, alcohol consumption, and beef consumption on colon cancer risk (P-value for interaction = 0.0005, 0.007, 0.067, 0.003, respectively).

Conclusions

In a Thai population, colon cancer risk was associated with alcohol and beef consumption, bowel habits, and family history of cancer. Interactions between MTHFR polymorphisms and environmental factors were also observed.Key words: colon cancer, MTHFR, polymorphism, environmental factors, Thailand     

孕期环境危险因素以及母亲MTHFR677C→T、血浆Hcy与儿童先天性心脏病的关系

目的:分析儿童不分型先天性心脏病(CHD)致病的危险因素,探讨CHD与母亲亚甲基四氢叶酸还原酶(MTHFR)677C→T和血浆同型半胱氨酸(Hcy)的相关性。方法:采用病例对照研究方法,分析80对CHD患儿与对照儿父母所处的环境因素并检测其MTHFR677位点的多态性和血浆Hcy的水平,进行单因素及多因素Logistic回归分析。并且通过母子配对,分析MTHFR677位点多态性和血浆Hcy水平与CHD发生的相互关联。结果:①母孕早期发烧(OR=4.465)、孕期居住乡村(OR=2.234)、孕期吸烟环境(OR=20.529)、母子血浆Hcy水平增高(OR=3.342,OR=3.069)为不分型CHD的危险因素。②儿童与母亲MTHFR677位点基因型之间没有明显的关联,双方血浆Hcy水平亦无明显关联(P均>0.05)。③病例组与对照组MTHFR677位点基因型差异无统计学意义(P>0.05),病例组母子血浆Hcy水平均显著高于对照组相应值(P均<0.01)。结论:①母孕早期发烧、孕期居住乡村、孕期吸烟环境、母子血浆Hcy水平增高为不分型CHD的危险因素。②MTHFR基因677C→T对血浆Hcy水平影响有待于进一步研究。③在CHD发生上,母子MTHFR基因677位点基因型之间和血浆Hcy水平之间均没有相关性。     

MTHFR C677T genotype and cardiovascular risk in a general population without mandatory folic acid fortification

Purpose

Meta-analyses have suggested an effect of MTHFR C677T genotype (rs1801133), a proxy for blood total homocysteine, on cardiovascular disease (CVD) in populations with low population dietary folate. The aim was to examine the association and effect modification by serum folate and vitamin B12 levels between MTHFR and CVD-related outcomes in a general population with no mandatory folic acid fortification policy.

Methods

The study population included 13,748 adults retrieved from pooling of four population-based studies conducted in Denmark. MTHFR genotype, serum folate (measured in approximately 9,356 individuals), and serum vitamin B12 (9,215 individuals), hypertension, and dyslipidemia were measured at baseline, and participants were followed for a mean of 10.5–11.7 years in central registries for diagnoses of stroke (623 incidents), ischaemic heart disease (IHD) (835 incidents), and all-cause mortality (1,272 incidents).

Results

The MTHFR genotype (TT vs. CC/CT) was not associated with hypertension [OR (95 % CI) 1.09 (0.95–1.25)], dyslipidemia [OR (95 % CI) 0.97 (0.84–1.11)], stroke [HR (95 % CI) 0.92 (0.69–1.23)], and all-cause mortality [HR (95 % CI) 0.94 (0.77–1.14)], either overall, or in participants with low serum folate or B12 status (P values for interactions 0.15–0.94). Individuals with the MTHFR TT genotype had a higher risk of IHD (HR (95 % CI) 1.38 (1.11–1.71)), but this association was not modified by folate status (P value for interaction 0.45).

Conclusions

Our results do not support a causal relationship between homocysteine and CVD. However, we cannot exclude a direct causal effect of MTHFR C677T genotype on IHD.     

叶酸代谢相关基因MTHFR、MS基因多态与胰腺癌风险关联

目的 探讨亚甲基四氢叶酸还原酶（MTHFR）及甲硫氨酸合成酶（MS）基因多态与胰腺癌风险的关系.方法 采用以医院为基础的病例对照研究（胰腺癌新发病例101例,对照337人）方法,进行MTHFR C677T、A1298C及MS A2756G基因多态与胰腺癌风险关联分析,采用PCR-RFLP方法进行两候选基因分型.结果 携带MTHFR-677 CT及TT基因型者发生胰腺癌风险是CC基因型个体的2.17（95%CI：1.26～3.85）及3.53（95%CI：1.85～6.84）倍,呈明显的等位基因-效应关系;未观察到MTHFR 1298多态单独对胰腺癌发生的影响,但发现它与C677T有联合作用.MTHFR677CT与TT基因型与吸烟、饮酒有明显的正向交互,产生交互作用的ORint值分别为1.78（P=0.0010）和2.10（P=0.0051）.未发现MS A2756G多态与胰腺癌的发生之间存在统计学的显著关联.结论 MTHFR C677T多态与胰腺癌发生风险显著关联,且与吸烟、饮酒存在正向交互作用.     

Relationships between Maternal Gene Polymorphisms in One Carbon Metabolism and Adverse Pregnancy Outcomes: A Prospective Mother and Child Cohort Study in China

Background: To investigate relationships between five single nucleotide polymorphisms (SNP) in four maternal genes involved in one carbon metabolism and adverse pregnancy outcomes, including preterm birth (PTB), low birth weight (LBW), and small-for-gestational-age (SGA). Methods: This was a prospective mother and child cohort study in Wuqiang, China. Pregnant women (n = 939) were recruited from Jun 2016 to Oct 2018. Pregnancy outcomes (PTB, LBW, and SGA) were extracted from medical records and other information including age at childbearing, maternal education level, gravidity, parity, pre-pregnancy weight and height was collected by using a structured questionnaire. The maternal serum folate concentration was measured by using Abbott Architect i2000SR chemiluminescence analyzer in the first prenatal care visit. DNA genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase reductase (MTRR) A66G, methionine synthase (MTR) A2756G, and thymidylate synthetase (TYMS) rs3819102 was processed by Sequenom MassARRAY iPLEX Platform. Univariate and multivariate logistics regression analysis were used to test the relationships between 5 SNPs and PTB, LBW, SGA. Results: Totally, 849 dyads of women and infants were included in the analysis. The prevalence of PTD, LBW, and SGA were 3.76%, 1.58%, and 5.31% respectively. The homozygote frequencies of MTHFR C677T, MTHFR A1298C, MTRR A66G, MTR A2756G, and TYMS rs3819102 were 44.2%, 1.4%, 6.7%, 1.3%, and 3.2%, and the alt allele frequencies were 66.1%, 10.8%, 24.9%, 10.5%, and 20.5% respectively. The average serum folate concentration was 11.95 ng/mL and the folate deficiency rate was 0.47%. There were no significant associations between MTHFR C677T, MTHFR A1298C, MTRR A66G, MTR A2756G, TYMS rs3819102 alleles and PTD, LBW, SGA (p > 0.05). Conclusions: In the population with adequate folate status and low prevalence of adverse pregnancy outcomes, MTHFR C677T, MTHFR A1298C, MTRR A66G, MTR A2756G, TYMS rs3819102 alleles may not be related to PTD, LBW, and SGA.     

Association between genetic polymorphisms in folate-related enzyme genes and infertile men with non-obstructive azoospermia

Abstract

Polymorphisms in the genes encoding enzymes in the folate metabolism pathway have been associated with male infertility and chromosome abnormalities. The aim of this study was to analyze the distribution of the methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) polymorphisms in fertile men and infertile men with non-obstructive azoospermia (NOA). A case-control study comprising 85 infertile men with NOA and 246 fertile men as controls was carried out. MTHFR c.677C?>?T (rs1801133), MTHFR c.1298A?>?C (rs1801131), MTR c.2756A?>?G (rs1805087), and MTRR c.66A?>?G (rs1801394) polymorphisms were determined using the polymerase chain reaction restriction fragment length polymorphism technique. There were significant differences in AC?+?CC genotype (OR?=?1.9, 95% CI?=?1.1–3.2) and C allele frequencies (OR?=?1.8, 95% CI?=?1.2–2.8) of MTHFR c.1298A?>?C polymorphism between NOA patients and controls after applying the Bonferroni correction. Moreover, the 1298AC genotype, 1298AC?+?CC genotype, and 1298C allele frequencies were statistically significant in NOA with chromosomal abnormalities and/or a Y chromosome deletion compared to the controls (AC genotype: OR?=?3.0; AC?+?CC genotype: OR?=?3.0; C allele: OR?=?2.3). Considering the other polymorphisms, no differences were found between cases and controls. Our findings suggest the MTHFR c.1298A?>?C polymorphism is associated with an increased risk of male infertility, i.e., NOA.     

Effects of maternal 5,10-methylenetetrahydrofolate reductase C677T and A1298C Polymorphisms and tobacco smoking on infant birth weight in a Japanese population

Background

Intracellular folate hemostasis depends on the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. Because 5,10-MTHFR 677TT homozygosity and tobacco smoking are associated with low folate status, we tested the hypothesis that smoking in mothers with 5,10-MTHFR C677T or A1298C polymorphisms would be independently associated with lower birth weight among their offspring.

Methods

We assessed 1784 native Japanese mother-child pairs drawn from the ongoing birth cohort of The Hokkaido Study on Environment and Children’s Health. Data (demographic information, hospital birth records, and biological specimens) were extracted from recruitments that took place during the period from February 2003 to March 2006. Maternal serum folate were assayed by chemiluminescent immunoassay, and genotyping of 5,10-MTHFR C677T/A1298C polymorphisms was done using a TaqMan allelic discrimination assay.

Results

The prevalence of folate deficiency (<6.8 nmol/L) was 0.3%. The 5,10-MTHFR 677CT genotype was independently associated with an increase of 36.40 g (95% CI: 2.60 to 70.30, P = 0.035) in mean infant birth weight and an increase of 90.70 g (95% CI: 6.00 to 175.50, P = 0.036) among male infants of nonsmokers. Female infants of 677TT homozygous passive smokers were 99.00 g (95% CI: −190.26 to −7.56, P = 0.034) lighter. The birth weight of the offspring of smokers with 5,10-MTHFR 1298AA homozygosity was lower by 107.00 g (95% CI: −180.00 to −33.90, P = 0.004).

Conclusions

The results suggest that, in this population, maternal 5,10-MTHFR C677T polymorphism, but not the 5,10-MTHFR A1298C variant, is independently associated with improvement in infant birth weight, especially among nonsmokers. However, 5,10-MTHFR 1298AA might be associated with folate impairment and could interact with tobacco smoke to further decrease birth weight.Key words: birth weight, tobacco smoking, MTHFR SNPs, folate, Japan     

B-vitamins, homocysteine metabolism and CVD

The present review focuses on the B-vitamins, i.e. folate, vitamin B12, vitamin B6 and riboflavin, that are involved in homocysteine metabolism. Homocysteine is a S-containing amino acid and its plasma concentrations can be raised by various constitutive, genetic and lifestyle factors, by inadequate nutrient status and as a result of systemic disease and various drugs. Hyperhomocysteinaemia is a modest independent predictor of CVD and stroke, but causality and the precise pathophysiological mechanism(s) of homocysteine action remain unproven. The predominant nutritional cause of raised plasma homocysteine in most healthy populations is folate insufficiency. Vitamin B12 and, to a lesser extent, vitamin B6 are also effective at lowering plasma homocysteine, especially after homocysteine lowering by folic acid in those individuals presenting with raised plasma homocysteine. However, riboflavin supplementation appears to be effective at lowering plasma homocysteine only in those individuals homozygous for the T allele of the C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. This gene codes for the MTHFR enzyme that produces methyltetrahydrofolate, which, in turn, is a substrate for the remethylation of homocysteine by the vitamin B12-dependent enzyme methionine synthase. Individuals with the MTHFR 677TT genotype are genetically predisposed to elevated plasma homocysteine, and in most populations have a markedly higher risk of CVD.     

上海地区孕妇MTHFR C677T基因多态性与血浆同型半胱氨酸水平的关联性分析

目的 了解上海市孕妇MTHFR基因型的分布情况,分析MTHFR C677T基因多态性与高同型半胱氨酸血症的关联性,为高危孕妇的遗传筛查及围产期叶酸摄入的个性化提供依据。方法 选取上海市五所社区医院2015年1月~2015年6月门诊建卡孕妇1000例,随访了解基本信息、孕期危险因素暴露及叶酸摄入情况,以基因芯片法检测MTHFR基因型,循环酶法检测血浆同型半胱氨酸。结果 上海地区孕妇MTHFR C677T基因CC型、CT型、TT型的检出频率分别为33.0%、49.2%、17.8%,等位基因C、T的频率为57.6%、42.4%,样本人群处于H-W平衡状态。血浆同型半胱氨酸浓度为11.22（9.15,13.52）μmol/L,其中911例（91.6%）正常,84例（8.4%）属轻度高同型半胱氨酸血症。经多因素logistic回归分析,CT型与TT型发生高同型半胱氨酸血症的OR值分别为2.18（95%CI:1.11~4.25）和6.26（95%CI:3.13~12.53）。结论 MTHFR基因C677T多态性与孕妇血浆同型半胱氨酸水平存在关联,携带等位基因T者可视为高危孕妇,孕期叶酸补充可适量增加。     

C(1) metabolism and CVD outcomes in older adults

CVD is the most common cause of death in people over 65 years. This review considers the latest evidence for a potential protective effect of C(1) donors (folate and the metabolically related B-vitamins) in CVD. Such an effect may or may not be mediated via the role of these nutrients in maintaining plasma homocysteine concentrations within a desirable range. Despite predictions from epidemiological studies that lowering plasma homocysteine would reduce cardiovascular risk, several secondary prevention trials in at-risk patients published since 2004 have failed to demonstrate a benefit of homocysteine-lowering therapy with B-vitamins on CVD events generally. All these trials were performed in CVD patients with advanced disease; thus current evidence suggests that intervention with high-dose folic acid is of no benefit in preventing another event, at least in the case of heart disease. The evidence at this time, however, is stronger for stroke, with meta-analyses of randomised trials showing that folic acid reduces the risk of stroke, particularly in people with no history of stroke. Genetic studies provide convincing evidence to support a causal relationship between sub-optimal B-vitamin status and CVD. People homozygous for the common C677T variant in the gene encoding the folate-metabolising enzyme, methylenetetrahydrofolate reductase (MTHFR), typically have a 14-21% higher risk of CVD. Apart from folate, riboflavin is required as a co-factor for MTHFR. New evidence shows that riboflavin intervention results in marked lowering of blood pressure, specifically in patients with the MTHFR 677TT genotype. This novel gene-nutrient interaction may provide insights as to the mechanism that links C(1) metabolism with CVD outcomes.     

2型糖尿病合并冠心病患者的同型半胱氨酸水平及代谢关键酶基因多态性特点

目的探讨中国北方地区糖尿病合并冠心病者同型半胱氨酸(Hcy)及其代谢相关酶亚甲基四氢叶酸还原酶(MTHFR)C677T及胱硫醚β-合成酶(CBS)844 ins 68基因多态性的特点。方法研究对象均为北方汉族人群,包括无血缘关系的70名糖尿病合并冠心病患者、71名糖尿病患者和85名健康人群。应用荧光偏振免疫法(FPIA)测定Hcy水平,应用微粒子酶免分析免疫法(MEIA)测定血浆叶酸、维生素B12浓度,同时测定血脂。应用聚合酶链反应分析MTHFR C677T与CBS844 ins 68基因多态性。结果糖尿病合并冠心病组(DM+CHD组)Hcy中位数为14.8μmol/L,显著高于DM组(11.1μmol/L)和对照组(11.2μmol/L),(P<0.01),DM组与对照组之间差异无显著性(P>0.05)。DM+CHD组的T等位基因频率(45%)明显高于糖尿病组(26.8%)和对照组(31.2%),(P<0.01)。三组CBS844 ins 68的基因型及等位基因频率差异无显著性(P>0.05)。本研究定义Hcy>15μmol/L为高Hcy血症(HHcy)。Logistic回归分析显示HHcy的OR值为4.547(95%CI1.970～10.496),(P<0.01);MTHFR677携带T基因的OR值为2.369(95%CI1.160～4.841),(P=0.018);CBS844 ins 68基因的OR值为0.384(95%CI0.033～4.423),(P=0.443)。结论HHcy、MTHFR677携带T基因可能是中国北方地区汉族人2型糖尿病合并冠心病发生的危险因素。     

Serum folate and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism adjusted for folate intake

Background

Serum folate concentration is lower in individuals with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype than in those with the MTHFR 677CC or 677CT genotypes. Since studies considering folate intake are limited, we examined the association between folate intake and serum folate levels, according to the genotype.

Methods

The subjects comprised 170 Japanese persons (74 males and 96 females) aged 20-75 years who visited a clinic to test for Helicobacter pylori infection. Folate intake was estimated using a semiquantitative food-frequency questionnaire, and serum folate was measured in the residual fasting blood samples of the subjects. MTHFR C677T was genotyped using polymerase chain reaction.

Results

The geometric means of serum folate level were 6.19, 6.20, and 5.17 ng/mL among the 60 participants with the 677CC genotype, 90 participants with the 677CT genotype, and 20 participants with the 677TT genotype, respectively. No difference was noted in the mean folate intake estimated using the food-frequency questionnaire. Regression analysis showed that log_e(serum folate) adjusted for age, sex, and log_e(folate intake) was significantly lower among those with the 677TT genotype than among those with the 677CT or 677CC genotypes (p = 0.01). The adjusted reduction in serum folate was 20.2% (95% confidence interval, 5.4-32.6%) in the case of the 677TT genotype relative to the levels in the case of the 677CC/677CT genotypes. When folate intake was adjusted for total energy intake, using the residual method, the slope of the regression line for 677TT was smaller than those of the regression lines for 677CC and 677CT.

Conclusion

Individuals with the 677TT genotype may need to consume more folate to maintain serum folate levels similar to those found in individuals with the 677CC/677CT genotypes.Key words: Eating, Folic Acid, MTHFR C677T, Japanese     

Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review

Epidemiologic and mechanistic evidence suggests that folate is involved in colorectal neoplasia. Some polymorphic genes involved in folate metabolism--methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), cystathionine beta-synthase (CBS exon 8, 68-base-pair insertion), and thymidylate synthase (TS enhancer region and 3' untranslated region)--have been investigated in colorectal neoplasia. For MTHFR C677T and A1298C, the variant allele is associated with reduced enzyme activity in vitro. For the other polymorphisms, functional data are limited and/or inconsistent. Genotype frequencies for all of the polymorphisms show marked ethnic and geographic variation. In most studies, MTHFR 677TT (10 studies, >4,000 cases) and 1298CC (four studies, >1,500 cases) are associated with moderately reduced colorectal cancer risk. In four of five genotype-diet interaction studies, 677TT subjects who had higher folate levels (or a "high-methyl diet") had the lowest cancer risk. In two studies, 677TT homozygote subjects with the highest alcohol intake had the highest cancer risk. Findings from six studies of MTHFR C677T and adenomatous polyps are inconsistent. There have been only one or two studies of the other polymorphisms; replication is needed. Overall, the roles of folate-pathway genes, folate, and related dietary factors in colorectal neoplasia are complex. Research priorities are suggested.     

叶酸、蛋氨酸摄入量,MTHFR多态性与结直肠癌关系的病例对照研究

目的:研究亚甲基四氢叶酸还原酶(MTHFR)基因多态,叶酸、蛋氨酸摄入量与结直肠癌易感性的关系。方法:应用PCR-RFLP法,检测126例结直肠癌患者和343例正常对照者的MTHFRC 677T和A1298C两个位点基因多态,比较不同基因型与结直肠癌风险的关系,以及两个多态位点与叶酸、蛋氨酸的联合作用。结果: MTHFR C677T和A1298C突变基因在对照组中的频率分别为39.7%和17.1%。MTHFR A1298C突变基因携带者与野生型相比,患结直肠癌的风险显著降低(OR=0.51,95% CI:0.27～0.95);在叶酸个别摄入量组,MTHFR C677T多态使结直肠癌的风险显著降低(OR=0.23,95% CI:0.06～0.93)。结论: MTHFR A1298C位点多态性是直肠癌的保护因素 ,在叶酸摄入充足的条件下,MTHFR C677T多态是结肠癌的保护因素。     

Lack of association between the C677T single nucleotide polymorphism of the MTHFR gene and glaucoma in Iranian patients

Glaucoma is a major cause of blindness worldwide. A single nucleotide polymorphism of the MTHFR gene (C677T) has been associated with susceptibility to this disease, although this is controversial in the last decade. In this study, the possible association between the MTHFR C677T polymorphism and the risk of developing primary open angle (POAG) and pseudoexfoliation glaucoma (PEXG) was investigated. For this, a prospective study consisting of 73 POAG, 85 PEXG and 90 matched controls was undertaken in an Iranian population. Genomic DNA was extracted from whole blood. Genotyping of all individuals for the MTHFR C677T polymorphism was conducted using the PCR-RFLP technique. Our findings revealed no significant association between the MTHFR C677T polymorphism in POAG and PEXG compared with controls. Consistent with several other studies, our analysis suggests that the MTHFR C677T polymorphism is unlikely to be a factor contributing to the risk of developing specific forms of glaucoma.     

Polymorphisms in cytoplasmic serine hydroxymethyltransferase and methylenetetrahydrofolate reductase affect the risk of cardiovascular disease in men

Genetic variation in folate-regulating enzymes contributes to the risk of cardiovascular disease (CVD). The cytoplasmic serine hydroxymethyltransferase (cSHMT) enzyme is proposed to regulate a key metabolic intersection in folate metabolism. We hypothesized that a variant in cSHMT (cSHMT 1420C-->T) affects CVD risk, and that the effect depends on a linked step in the metabolic pathway catalyzed by methylenetetrahydrofolate reductase (MTHFR). A nested case-control study of incident CVD was conducted within the all-male Normative Aging Study cohort. Of the incident CVD cases, 507 had DNA samples; 2 controls/case were selected by risk set sampling (matched on age and birth year). A significant gene-gene interaction (P-values 0.0013, 0.0064) was found between MTHFR and cSHMT, and there was little or no change in the coefficients in covariate-adjusted models. The effect of MTHFR 677C-->T genotype on CVD risk varied by cSHMT 1420C-->T genotype. Among men with cSHMT 1420C-->T TT genotype, the odds ratios (OR) for CVD risk for MTHFR 677C-->T CT and TT genotypes compared with the MTHFR 677C-->T CC genotype were 3.6 (95% CI, 1.7-7.8) and 10.6 (95% CI, 2.5-46.0), respectively. Among men with the cSHMT 1420C-->T CC/CT genotype, the corresponding ORs were 1.0 (95% CI, 0.8-1.2) and 1.3 (95% CI, 0.9-1.8). Plasma total homocysteine concentrations were highest in the subgroup of men with both polymorphisms, MTHFR 677C-->T TT and cSHMT 1420C-->T TT, consistent with a higher risk of CVD in this subgroup. A more complete understanding of the molecular mechanism awaits identification of the functional effect of the polymorphism.