The common MTHFR C677T and A1298C variants are not associated with the risk of non-syndromic cleft lip/palate in northern Venezuela

Non-syndromic cleft lip with or without cleft palate （nsCL/P） is among the most common major birth defects, with complex inheritance involving multiple genes and environmental factors. Numerous studies of MTHFR, encoding methylenetetrahydrofolate reductase, which catalyzes the rate-limiting step of folic acid biosynthesis, have shown inconsistent association of two common hypomorphic allelic variants, C677T and A1298C, in nsCL/P patients and, in some cases, their mothers. We have studied the MTHFR C677T and A1298C polymorphisms in nsCL/P patients, their mothers, and population-matched controls from northern Venezuela. We found no evidence for contribution of the MTHFR C677T and A1298C variants to the risk of nsCL/P in northern Venezuela. Overall, our findings fail to support a causal role of either the MTHFR C677T or A 1298C variants in the pathogenesis of nsCL/P in northern Venezuela.     

Lower incidence of nonsyndromic cleft lip with or without cleft palate in females: Is homocysteine a factor?

In India, as in other parts of the world, nonsyndromic cleft lip with or without cleft palate (NSCL±P) is a highly prevalent birth defect, its incidence in males being twice that in females. A case–control association study has been carried out with respect to homocysteine level and MTHFR C677T, A1298C and SLC19A1 (RFC1) G80A genotypes from an eastern Indian cohort to investigate whether Hcy and other Hcy-pathway genes also contribute to the risk level. While MTHFR 677T and SLC19A1 80G are individually and cumulatively risk factors, SLC19A1 80A appears to be protective against MTHFR 677T risk allele. Elevated Hcy associates with NSCL±P both in case mothers and cases. Significantly, this difference shows a gender bias: the level of elevation of Hcy in female cases is distinctly higher than in males, and more case females are hyperhomocyteinemic than the case males. It implies that compared with the males, higher level of Hcy is needed for NSCL±P to manifest in the females. We consider this as one of the possible factors why the incidence of this disorder in females is much lower than in males.     

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 between MTHFR polymorphisms and orofacial clefts risk: A meta‐analysis

BACKGROUND The roles of C677T and A1298C polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene in orofacial clefts (OFCs) risk have been substantially explored, but the results remain conflicting. To address this gap, we conducted a meta‐analysis involving all eligible studies. METHODS: Electronic literature searches of the PubMed, EmBase, and Medline databases were performed up to October 31, 2011. Fixed‐effects or random‐effects models were used to calculate the pooled odds ratios (ORs) for two genetic comparisons (heterozygous mutation vs. wild type, homozygous mutation vs. wild type). RESULTS A total of 18 studies were ultimately identified. The pooled results revealed no statistical association between infant and maternal C677T and A1298C variants and risk of cleft lip with or without palate (CL/P) or cleft palate only (CPO), except for the maternal 677TT genotype for CL/P, the OR was 1.32 (95% confidence interval [CI], 1.06–1.63) as compared to the normal 677CC genotype. In the subgroup analyses on CL/P data based on ethnicity and source of control subjects, almost all of the results were replicated as nonsignificant associations in both examined polymorphisms, whereas the pooled risk estimate calculated for maternal 677TT genotype in the white population remained statistically significant, with an OR of 1.36 (95% CI, 1.05–1.76). CONCLUSIONS This meta‐analysis suggests that maternal MTHFR 677TT genotype might increase the risk of having a CL/P offspring in the white population. However, these findings remain to be confirmed by additional investigations. Birth Defects Research (Part A) 2012. © 2012 Wiley Periodicals, Inc.     

MTHFR C677T and A1298C gene polymorphisms and their relation to homocysteine level in Egyptian children with congenital heart diseases

Objective

To investigate the association of combined MTHFR C677T and A1298C gene polymorphisms with congenital heart diseases (CHD) in Egyptian children and their mothers and to determine their effect on homocysteine level in these children.

Material and methods

MTHFR C677T and A1298C polymorphisms were genotyped in 160 Egyptian children (80 patients with CHD and 80 healthy controls) and their mothers using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP), while, homocysteine (Hcy) level was measured optically by enzymatic method.

Results

We found that MTHFR 677TT genotype, T allele, 1298CC genotype, and C allele were associated with 2.61, 2.0, 2.91 and 1.99 fold increased risk of CHD in Egyptian children respectively. Furthermore, the frequencies of MTHFR 1298AC and CC genotypes and C allele significantly increased in mothers with CHD affected children. The homocysteine levels were significantly increased in MTHFR 677TT and 1298CC genotypes in children with CHD.

Conclusions

Our study demonstrated an association of MTHFR A1298C polymorphisms with CHD in Egyptian children and their mothers, while, MTHFR C677T polymorphisms were significantly associated with the risk of CHD in the children only. An association between combined MTHFR A1298C and C677T polymorphisms and CHD was recorded in the children and their mothers. Also, homocysteine levels were significantly increased with both MTHFR 677TT and 1298CC genotypes in Egyptian children with CHD.     

Methylenetetrahydrofolate reductase gene polymorphisms contribute to acute myeloid leukemia and chronic myeloid leukemia susceptibilities: Evidence from meta-analyses

PurposeThe expression of methylenetetrahydrofolate reductase (MTHFR) is associated with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Most studies have linked the common functional C677T and A1298C polymorphisms of the MTHFR gene and susceptibility to AML and CML, but the results were not consistent. The aim of the present study was to derive a more precise estimation of the relationship.MethodsMeta-analyses assessing the association of MTHFR C677T and A1298C variations with AML and CML were conducted. Eligible articles were identified from the PubMed and EMBASE databases. All statistical analyses were conducted using Review Manager Software.Results10 and 10 studies were included in the meta-analysis about the role of C677T polymorphism on the AML and CML risks, respectively; 6 and 4 studies were included about the role of A1298C polymorphism on the AML and CML risks, respectively. Overall, both the C677T and A1298C polymorphisms were significantly associated with CML risk under the recessive model (P = 0.04, OR = 1.35, 95% CI = 1.02–1.79 for C677T and P = 0.003, OR = 2.17, 95% CI = 1.29–3.63 for A1298C). In addition, the risk of CML was higher in 1298CC genotype carriers than in 1298AA genotype carriers (P = 0.004, OR = 2.17, 95% = 1.28–3.69). Conversely, the overall data failed to indicate a significant association of C677T or A1298C polymorphisms with AML risk under any model.ConclusionsThe findings provide evidence that C677T and A1298C polymorphisms are risk factors for CML risk.     

Methylenetetrahydrofolate reductase gene C677T,A1298C polymorphisms and pre-eclampsia risk: a meta-analysis

To determine whether methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with pre-eclampsia susceptibility. Literature searches of the Pubmed, Embase, BIOSIS Previews and Web of Science were conducted to identify all eligible articles up to January 18th, 2013. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) of five genetic models were calculated by fixed-effects or random-effects model. Publication bias, subgroup analysis, meta-regression and sensitivity analysis were also performed. A number of 49 studies including 51 samples consisted of 18,009 subjects (6,238 patients and 11,771 controls) were finally included. MTHFR C677T allele (TT or CT) carriers were 1.12 times more likely to develop pre-eclampsia (95 % CI 1.04–1.21) compared with 677CC homozygous individuals. Similar results were obtained under other genetic models. Restricted to severe pre-eclampsia, there was an increased risk for 677TT homozygotes compared with 677CC homozygotes (OR 1.43; 95 % CI 1.12–1.83). Subgroup analysis revealed a significant positive association between the C677T polymorphism (TT or CT) and pre-eclampsia in Asians (OR 1.41; 95 % CI 1.11–1.79) and white population (OR 1.14; 95 % CI 1.03–1.25). Meta-regression showed that study population, blinded genotyping, matching of cases and controls were not substantial sources of heterogeneity. For the MTHFR A1298C, ORs for all genetic models yielded a null association. This meta-analysis suggests that the MTHFR 677T allele might be associated with increased pre-eclampsia risk in Asian and white ethnicity and the subgroup of severe pre-eclampsia, while no association is observed between the MTHFR A1298C polymorphism and pre-eclampsia.     

MTHFR Gene variants C677T, A1298C and association with Down syndrome: A Case-control study from South India

BACKGROUND:

The 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and low folate levels are associated with inhibition of DNA methyltransferase and consequently DNA hypomethylation. The expanding spectrum of common conditions linked with MTHFR polymorphisms includes certain adverse birth outcome, pregnancy complications, cancers, adult cardiovascular diseases and psychiatric disorders, with several of these associations remaining still controversial. Trisomy 21 or Down syndrome (DS) is the most common genetic cause of mental retardation. It stems predominantly from the failure of chromosome 21 to segregate normally during meiosis. Despite substantial research, the molecular mechanisms underlying non-disjunction leading to trisomy 21 are poorly understood.

MATERIALS AND METHODS:

Two common variants C677T and A1298C of the MTHFR gene were screened in 36 parents with DS children and 60 healthy couples from Tamil Nadu and Karnataka. The MTHFR genotypes were studied by RFLP analysis of PCR-amplified products and confirmed by sequencing.

RESULTS:

The CT genotype was seen in three each (8.3%) of case mothers and fathers. One case father showed TT genotype. All the control individuals exhibited the wild type CC genotype. A similar frequency for the uncommon allele C of the second polymorphism was recorded in case mothers (0.35) and fathers (0.37) in comparison with the control mothers (0.39) and fathers (0.37).

CONCLUSION:

This first report on MTHFR C677T and A1298C polymorphisms in trisomy 21 parents from south Indian population revealed that MTHFR 677CT polymorphism was associated with a risk for Down syndrome.     

Meta-analysis of Methylenetetrahydrofolate reductase maternal gene in Down syndrome: increased susceptibility in women carriers of the MTHFR 677T allele

Because a number of data studies include some controversial results about Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Down syndrome (DS), we performed a meta-analysis to determine a more precise estimation of this association. Studies were searched on PubMed, EMBASE and Lilacs–Scielo, up to April 2013, and they were eligible if they included case mothers (DSM) that have gave birth to children with DS, and controls mothers (CM) that have gave birth to healthy children without chromosomal abnormality, syndrome or malformation. The combined odds ratio with 95 % confidence intervals was calculated by fixed or random effects models to assess the strength of associations. Potential sources of heterogeneity between studies were evaluated using Q test and the I². Publication bias was estimated using Begg’s test and Egger’s linear regression test. Sensitivity analyses were performed by using allelic, dominant, recessive and codominant genetic models, Hardy–Weinberg equilibrium (HWE) and ethnicity. Twenty-two studies with 2,223 DSM and 2,807 CM were included for MTHFR C677T and 15 studies with 1,601 DSM and 1,849 CM were included for MTHFR A1298C. Overall analysis suggests an association of the MTHFR C677T polymorphism with maternal risk for DS. Moreover, no association between the MTHFR A1298C polymorphism and maternal risk for DS was found. There is also evidence of higher heterogeneity, with I² test values ranging from 8 to 89 %. No evidence of publication bias was found. Taken together, our meta-analysis implied that the T allele carriers might carry an increased maternal risk for DS.     

Geographical Distribution of MTHFR C677T,A1298C and MTRR A66G Gene Polymorphisms in China: Findings from 15357 Adults of Han Nationality

Background

Methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms are important genetic determinants for homocysteine (Hcy) levels, and are associated with several disorders. These polymorphisms are heterogeneously distributed worldwide. Our objective was to explore the geographical distributions of these polymorphisms in China.

Methodologies

15357 healthy adults were recruited from 10 regions. Buccal samples were collected and genomic DNA was isolated. Genotyping was performed using the fluorogenic 5′-nuclease assay.

Principal Findings

The prevalence of the three polymorphisms among different populations from China varied significantly and showed apparent geographical gradients. For MTHFR C677T, the frequencies of the 677T allele and the 677TT genotype were significantly higher among northern populations and ranged from the lowest values (24.0% and 6.4%, respectively) in Hainan (southern) to the highest values (63.1% and 40.8%, respectively) in Shandong (northern). For MTHFR A1298C, the 1298C allele and the 1298CC genotype frequencies were significantly higher among southern populations and increased from low values (13.1% and 1.4%, respectively) in Shandong to high values (25.7% and 6.7%, respectively) in Hainan. For A66G, the 66G allele and the 66GG genotype frequencies increased from lower values (23.7% and 5.4%, respectively) in Shandong to higher values (29.2% and 8.6%, respectively) in Hainan. The overall frequency of the 677T allele, 677TT genotype, 1298C allele, 1298CC genotype, 66G allele and 66GG genotype in the Chinese Han population was 45.2%, 23.2%, 18.6%, 3.9%, 25.7%, and 6.6%, respectively. No gender differences were found in the prevalence of both the MTHFR C677T and MTRR A66G polymorphisms.

Conclusions

This study indicates that there are marked geographical variations in the prevalence of the three polymorphisms among Chinese Han populations. Our baseline data may be useful for future researches in related fields.     

Associations of variants in MTHFR and MTRR genes with male infertility in the Jordanian population

Folate pathway is expected to play an important role in spermatogenesis since it is involved in DNA synthesis, repair and methylation. The purpose of this study was to examine the association between male infertility and the MTHFR (C677T and A1298C) and MTRR (A66G) polymorphisms. A group of 300 males was recruited in this study from different Jordanian infertility clinics. Of these, 150 cases of infertile men that included oligozoospermia cases (n = 45), severe oligozoospermia (n = 71) and azoospermia (n = 34) were studied. The other 150 males were age matched fertile controls. Genotyping of MTHFR and MTRR polymorphisms was performed using PCR-RFLP technique. The results showed an association between MTHFR 677TT genotype and male infertility (P < 0.05). However, the distribution of MTHFR A1298C and MTRR A66G genotypes were not different between the fertile and infertile groups (P > 0.05). In addition, none of the examined polymorphisms was related to any of the semen parameters in the infertile group. In conclusion, this study showed that MTHFR C677T polymorphism is associated with male infertility in Jordanians.     

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and variations of homocysteine concentrations in patients with Behcet's disease

Background

Behcet's disease (BD) is a chronic, relapsing, multi-systemic inflammatory disorder of unknown causes. This disease is mainly characterized by mucocutaneous, ocular, vascular, and central nervous system manifestations. The aim of this study is to investigate the associations between C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and the plasma homocysteine (Hcy), folate, and B12 levels in a relatively large cohort of Tunisian patients with BD.

Methods

The study included 142 patients with BD and 172 healthy controls. The C677T and A1298C polymorphisms were genotyped using PCR-RFLP. Serum Hcy level was determined using a fluorescence polarization immunoassay. Serum folate and vitamin B12 levels were measured by electrochemiluminescence immunoassay.

Results

Genotype and allele frequencies of the two studied MTHFR polymorphisms did not show any significant differences among BD patients compared to controls. Patient carriers of the 677TT variant and the 677 T allele displayed significantly higher Hcy concentration. Moreover, no significant association was found between neither A1298C polymorphism nor the C allele and Hcy, folate, and B12 levels. In multivariate analyses, we reported that 677 T allele, male gender, and creatinine level were independent risk factors for hyperhomocysteinemia (HHC).

Conclusions

In the present study, we report the absence of any significant differences between genotype and allele frequencies for both studied polymorphisms among BD patients compared to healthy controls. Besides, we showed that the T allele of MTHFR C677T polymorphism influenced the Hcy level which is an independent risk factor for HHC in Tunisian BD patients.     

Association of the MTHFR A1298C variant with unexplained severe male infertility

The methylenetetrahydrofolate reductase (MTHFR) gene is one of the main regulatory enzymes involved in folate metabolism, DNA synthesis and remethylation reactions. The influence of MTHFR variants on male infertility is not completely understood. The objective of this study was to analyze the distribution of the MTHFR C677T and A1298C variants using PCR-Restriction Fragment Length Polymorphism (RFLP) in a case group consisting of 344 men with unexplained reduced sperm counts compared to 617 ancestry-matched fertile or normozoospermic controls. The Chi square test was used to analyze the genotype distributions of MTHFR polymorphisms. Our data indicated a lack of association of the C677T variant with infertility. However, the homozygous (C/C) A1298C polymorphism of the MTHFR gene was present at a statistically high significance in severe oligozoospermia group compared with controls (OR = 3.372, 95% confidence interval CI = 1.27–8.238; p = 0.01431). The genotype distribution of the A1298C variants showed significant deviation from the expected Hardy-Weinberg equilibrium, suggesting that purifying selection may be acting on the 1298CC genotype. Further studies are necessary to determine the influence of the environment, especially the consumption of diet folate on sperm counts of men with different MTHFR variants.     

The Association of Methylenetetrahydrofolate Reductase Genotypes with the Risk of Childhood Leukemia in Taiwan

Background

Acute lymphoblastic leukemia (ALL) is the most prevalent type of pediatric cancer, the causes of which are likely to involve an interaction between genetic and environmental factors. To evaluate the effects of the genotypic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) on childhood ALL risk in Taiwan, two well-known polymorphic genotypes of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed to examine the extent of their associations with childhood ALL susceptibility and to discuss the MTHFR genotypic contribution to childhood ALL risk among different populations.

Methodology/Principal Findings

In total, 266 patients with childhood ALL and an equal number of non-cancer controls recruited were genotyped utilizing PCR-RFLP methodology. The MTHFR C677T genotype, but not the A1298C, was differently distributed between childhood ALL and control groups. The CT and TT of MTHFR C677T genotypes were significantly more frequently found in controls than in childhood ALL patients (odds ratios=0.60 and 0.48, 95% confidence intervals=0.42–0.87 and 0.24–0.97, respectively). As for gender, the boys carrying the MTHFR C677T CT or TT genotype conferred a lower odds ratio of 0.51 (95% confidence interval=0.32–0.81, P=0.0113) for childhood ALL. As for age, those equal to or greater than 3.5 years of age at onset of disease carrying the MTHFR C677T CT or TT genotype were of lower risk (odds ratio= 0.43 and 95% confidence interval=0.26–0.71, P=0.0016).

Conclusions

Our results indicated that the MTHFR C677T T allele was a protective biomarker for childhood ALL in Taiwan, and the association was more significant in male patients and in patients 3.5 years of age or older at onset of disease.     

Frequencies of C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene at the early stage of human development

In most cases, the cause of embryo and fetus death remains unclear although the multifactorial reasons are suspected. The polymorphic C677T and A1298C variants of the MTHFR gene are associated with hyperhomocysteinemia, which is a risk factor of early pregnancy loss. The aim of this study is analysis of genotypes and haplotypes of C677T and A1298C polymorphic variants of MTHFR genes in the groups of spontaneous abortions with normal karyotype and newborns in the Tomsk population. Between these groups, no statistically significant differences were determined in the allele, genotype, and haplotype distributions of C677T and A1298C polymorphisms of the MTHFR gene. The haplotype frequencies of C677T and A1298C polymorphic variants of MTHFR gene in the Russian populations, which proved to be similar to those in most European populations, are presented for the first time.     

Association between MTHFR polymorphisms and orofacial clefts risk: a meta-analysis

BACKGROUND The roles of C677T and A1298C polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene in orofacial clefts (OFCs) risk have been substantially explored, but the results remain conflicting. To address this gap, we conducted a meta-analysis involving all eligible studies. METHODS: Electronic literature searches of the PubMed, EmBase, and Medline databases were performed up to October 31, 2011. Fixed-effects or random-effects models were used to calculate the pooled odds ratios (ORs) for two genetic comparisons (heterozygous mutation vs. wild type, homozygous mutation vs. wild type). RESULTS A total of 18 studies were ultimately identified. The pooled results revealed no statistical association between infant and maternal C677T and A1298C variants and risk of cleft lip with or without palate (CL/P) or cleft palate only (CPO), except for the maternal 677TT genotype for CL/P, the OR was 1.32 (95% confidence interval [CI], 1.06-1.63) as compared to the normal 677CC genotype. In the subgroup analyses on CL/P data based on ethnicity and source of control subjects, almost all of the results were replicated as nonsignificant associations in both examined polymorphisms, whereas the pooled risk estimate calculated for maternal 677TT genotype in the white population remained statistically significant, with an OR of 1.36 (95% CI, 1.05-1.76). CONCLUSIONS This meta-analysis suggests that maternal MTHFR 677TT genotype might increase the risk of having a CL/P offspring in the white population. However, these findings remain to be confirmed by additional investigations.     

Association between folate metabolism polymorphisms and breast cancer: a case-control study

We investigated the association between methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthetase (MTR A2756G), and methionine synthase reductase (MTRR A66G) polymorphisms involved in folate pathway and breast cancer risk, and the interaction between these polymorphisms and tobacco and alcohol consumption. Furthermore, we evaluated the association between these polymorphisms and clinicopathological variables. This case-control study included 606 Brazilian women, comprising 128 patients with breast cancer and 478 controls. MTHFR and MTR polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and MTRR polymorphisms using real-time PCR. Age ≥50 years (odds ratio [OR]: 2.65; 95% confidence interval [CI]: 1.65-4.26; p<0.001) and alcohol consumption (OR: 1.76; 95% CI: 1.0-2.85; p=0.021) were associated with an increased risk of breast cancer. For MTHFR A1298C, we observed a reduced risk of developing breast cancer in the codominant model (genotype CC-OR: 0.22; 95% CI: 0.06-0.74; p=0.014), recessive model (OR: 0.22; 95% CI: 0.07-0.76 p=0.004), and log-additive model (OR: 0.70; 95% CI: 0.49-0.98; p=0.035). Women aged ≥50 years and those who are alcohol consumers had increased susceptibility to breast cancer, and MTHFR A1298C modulated the risk for this disease. This is the first study to evaluate the association between polymorphisms in folate metabolism and breast cancer in the northwest region of São Paulo State, Brazil.     

Polymorphisms and haplotypes in methylenetetrahydrofolate reductase gene and head and neck squamous cell carcinoma risk

Functional polymorphisms in genes encoding enzymes involved in folate metabolism might modulate head and neck carcinoma risk because folate participates in DNA methylation and synthesis. We therefore conducted a case–control study of 853 individuals (322 head and neck cancer cases and 531 non-cancer controls) to investigate associations among MTHFR C677T and MTHFR A1298C polymorphisms and head and neck squamous cell carcinoma risk. Interactions between these two polymorphisms and risk factors and clinical histopathological parameters were also evaluated. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to genotype the polymorphisms and Chi-square test and multiple logistic regression were used for statistical analyses. The variables age ≥49 years, male gender, tobacco habits and alcohol consumption, MTHFR 1298 AC or CC genotypes, combined genotypes with two or more polymorphic alleles and 677T and 1298C polymorphic alleles were associated with increased risk for this disease (P < 0.05). Furthermore, we found that 1298 AC or CC genotypes were associated with age ≥49 years, tobacco and alcohol habits (P < 0.05). Regarding clinical histopathological parameters, the A1298C polymorphism was more frequent in patients with oral cavity as primary site (P < 0.05). MTHFR polymorphisms may contribute for increase risk for head and neck carcinoma and the variables age ≥49 years, male gender, tobacco and alcohol habits were associated with MTHFR 1298AC or CC genotypes, confirming that individuals with these variables and MTHFR A1298C polymorphism has higher risk for this disease.     

Methylenetetrahydrofolate reductase,MTHFR, polymorphisms and predisposition to different multifactorial disorders

Gene polymorphisms involved in homocysteine-methionine pathway result in hyperhomocysteinemia, a predisposing condition to several diseases. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate and homocysteine metabolism. The two known functional polymorphisms of MTHFR gene, 677C>T and 1298A>C have been implicated in a variety of multifactorial diseases: cardio-cerebrovascular and neurodegenerative disorders, autoimmune diseases, birth defects, diabetes, neuropsychiatric disorders, cancer and renal disease. C667T, and to a lesser extent A1298C polymorphisms, have been also reported to have a pharmacogenetic role in predicting drug toxicity in cancer and rheumatoid arthritis treatment. We review here the principal effects of the MTHFR gene variations in different clinical conditions.     

SUMO1 polymorphisms are associated with non-syndromic cleft lip with or without cleft palate

Small ubiquitin-like modifier 1 (SUMO1) haploinsufficiency results in cleft lip and palate in animal models. However, no studies have linked SUMO1 to non-syndromic cleft lip with or without cleft palate (NSCLP) in humans. In the present study, we investigated the potential association between SUMO1 single nucleotide polymorphisms (SNPs) and risk for human NSCLP. From 181 patients and 162 healthy controls, we found statistically significant correlations between a 4-SNP SUMO1 haplotype and NSCLP. These data are the first to suggest a role for SUMO1 gene variation in human NSCLP development.