Methylenetetrahydrofolate Reductase Polymorphisms Research Articles

Lack of Association of C677T Methylenetetrahydrofolate Reductase Polymorphism with Breast Cancer Risk in Mali.

Methylenetetrahydrofolate reductase (MTHFR) plays a major role in the metabolism of folates and homocysteine, which in turn can affect gene expression and ultimately promote the development of breast cancer. Thus, mutations in the MTHFR gene could influence homocysteine, methionine, and S-adenosylmethionine levels and, indirectly, nucleotide levels. Imbalance in methionine and S-adenosylmethionine synthesis affects protein synthesis and methylation. These changes, which affect gene expression, may ultimately promote the development of breast cancer. We therefore hypothesized that such mutations could also play an important role in the occurrence and pathogenesis of breast cancer in a Malian population. In this study, we used the PCR-RFLP technique to identify the different genotypic profiles of the C677T MTHFR polymorphism in 127 breast cancer women and 160 healthy controls. The genotypic distribution of the C677T polymorphism in breast cancer cases was 88.2% for CC, 11.0% for CT, and 0.8% for TT. Healthy controls showed a similar distribution with 90.6% for CC, 8.8% for CT, and 0.6% for TT. We found no statistical association between the C677T polymorphism and breast cancer risk for the codominant models CT and TT (p > 0.05). The same trend was observed when the analysis was extended to other genetic models, including dominant (p = 0.50), recessive (p = 0.87), and additive (p = 0.50) models. The C677T polymorphism of MTHFR gene did not influence the risk of breast cancer in the Malian samples.

The association between MTHFR polymorphism, dietary methyl donors, and childhood asthma and atopy.

Studies investigating the genetic association of the C677T methylenetetrahydrofolate reductase (MTHFR) genotype and dietary methyl donors with asthma and atopy are limited, and have variable results. To investigate the effect of dietary methyl donor intake on the risk of childhood asthma and atopy, based on the C677T polymorphism in the MTHFR gene. This cross-sectional study included 2,333 elementary school children aged 6-8 years across Korea during 2005 and 2006, as part of the first Children's Health and Environmental Research survey. Genotyping for the MTHFR (rs1801133) polymorphism was performed using the TaqMan assay. Multivariable-adjusted logistic regression analysis was performed to determine a descriptive association between the dietary methyl donor intake, MTHFR polymorphism, and childhood asthma and atopy. Intake of dietary methyl donors like folates was significantly associated with a decreased risk of the wheezing symptom, in the past 12 months, and "ever asthma" diagnosis, respectively. Vitamin B6 intake was also associated with a decreased atopy risk. The T allele of the MTHFR (rs1801133) gene was significantly associated with a decreased risk of atopy. Increased intakes of folate, vitamin B2, and vitamin B6 were protective factors against atopy, especially in children with the T allele on the MTHFR gene, compared to those with lower intakes and the CC genotype. High intakes of dietary methyl donors were associated with reduced risk of atopy and asthma symptoms. These may have additive effects related to the susceptibility alleles of the MTHFR gene. The clinical implications require evaluation.

The Association between Methylenetetrahydrofolate Reductase (MTHFR) Mutations and Serum Biomarkers of Cardiac Health

Background: Homocysteine (tHcy) has emerged as a new risk factor for cardiovascular diseases (CVD) The Methylenetetrahydrofolate reductase (MTHFR) polymorphisms are seen to give rise to high levels of tHcy which can be a causative factor in the progression of CVD due to its thrombogenic effect. Serum cardiac biomarkers help in the diagnosis, prognosis, or surveillance of CVD. The present study evaluated the association of the two MTHFR mutations, rs1801133 and rs1801131 with 16 well-established serum cardiac markers. Additionally, the influence of age and gender on the association of the two MTHFR polymorphisms with serum cardiac marker levels was also investigated. Methods: The study was carried out on 1295 individuals who visited Vibrant America Clinical Lab for regular or suspected CVD check-ups. The serological markers and genomic variant analysis were carried out as per the standard laboratory protocol under CLIA. The association between serological markers and the rs1801133 and rs1801131 genetic variants with respect to age and gender was evaluated using a one-way ANNOVA test. Results: No significant association was observed in tHcy levels with respect to gender, however, plasma total tHcy levels were higher in males than females. tHcy levels increased with increasing age in the wild and heterozygous genotypes for the mutations, rs1801133 and rs1801131. Additionally, the serum cardiac markers, High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Cholesterol (CHOL), Apolipoprotein A (APOA), Apolipoprotein B (APOB), N-terminal (NT)-pro hormone BNP (BNPNT), LDL calculated (LDLCAL), Small Density Low Density Lipoprotein (SDLDL), APOBAR, Oxidised Low Density Lipoprotein (OXLDL), Lipoprotein (A) (LPA), Triglycerides (TRIG), and Lipoprotein-Associated Phospholipase (Lp-PLA2) Test (PLAC) showed significant associations with respect to gender and age for rs1801133 and rs1801131 (P < 0.05) However, these markers were seen to have different trends in correlation with gender and age. Conclusions: The present study reports the association of tHcy, HDL, LDL, CHOL, APOA, APOB, BNPNT, LDLCAL, SDLDL, APOBAR, OXLDL, LPA, TRIG, and PLAC with respect to age and gender for the mutations, rs1801133 and rs1801131. We observed that tHcy levels were high in males and the levels increased with increasing age in males for both polymorphisms. rs1801131 mutant males have high levels of triglyceride whereas rs1801133 mutant postmenopausal females showed high levels of cholesterol. Further analysis will be required to understand the pattern of association of the rest of the serum cardiac markers with age and gender for rs1801133 and rs1801131 mutations.

Association of C677T Polymorphism of Methylenetetrahydrofolate Reductase with Metabolic Syndrome among Eastern Indian Women: A Case-control Study

Introduction: Polymorphisms of Methylene Tetrahydrofolate Reductase (MTHFR) gene have been associated with hyperhomocysteinaemia, which in turn may lead to hypertension, insulin resistance and abnormality of lipid metabolism. All these abnormalities are also components of Metabolic Syndrome (MetS). Thus, there is possibility of an association between MetS and MTHFR polymorphism. Literature search revealed paucity of data on this association, particularly from India. Aim: To evaluate the association of C677T polymorphism of MTHFR gene with MetS, among women of eastern Indian population. Materials and Methods: A hospital-based case-control study was conducted in the Department of Biochemistry, Calcutta National Medical College, Kolkata, West Bengal, India, between December 2016 to June 2018. Anthropometric and biochemical profiling of all 417 study subjects were done. Genetic workup was done by Polymerase Chain Reaction (PCR), using suitable primer, followed by restriction fragment length polymorphism analysis using Hinf 1 enzyme to identify MTHFR C677T polymorphism. Subjects were divided into two groups according to presence or absence of MetS as per International Diabetic Federation worldwide definition and compared with Mann-Whitney U Test. Logistic regression analysis was also performed. Results: Out of enrolled 417 female subjects, 243 were categorised as MetS group. Mean age (in years), of MetS group (48.70±9.03) was found to be significantly higher (p&lt;0.001) than that of control group (42.83±10.90). A total of 45 (25%) females with MetS exhibited the presence of heterozygous CT genotype; that was significantly higher (p=0.026) than the non MetS group 21 (14.9%). The mutant T allele frequency was also significantly higher among the subjects suffering from MetS; 45 (12.5%)compared to 21 (7.4%) in the control group (p=0.036). Multiple logistic regression analysis revealed the odds of developing MetS among subjects with heterozygous CT genotype was 7.721 times (CI: 2.38-25.05) compared to those with wild genotype. Conclusion: C677T polymorphism of MTHFR gene was associated with the occurrence of MetS among woman.

Association of methylenetetrahydrofolate reductase polymorphism and male infertility in type 2 diabetes mellitus patients

INTRODUCTION: As per World Health Organization, Infertility is a condition which is characterized by not getting conceived with more than 1-year of unprotected sexual intercourse without usage of any contraceptive aids. Folate has a significant role in the metabolism of the cells, like nucleic acids synthesis, gene expression by means of remethylation of the homocysteine into methionine. In the males, deficiency of folate leads to reduced proliferation of the sperm cells. Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase genes result in alterations of the methylations resulting pathological conditions being a potential risk factor for male infertility. MATERIALS AND METHODS: A total of 100 diabetic infertile males were selected as the study group and 100 nondiabetic fertile males were included as the control group. Blood samples were analyzed for the MTHFR polymorphisms. DNA extraction was done and the extract is subjected to polymerase chain reaction amplification. The resultant is subjected to electrophoresis for MTHFR gene allele confirmation. Statistical analysis was done using IBM SPSS Statistics 20 package. Chi-square test, odds ratio has been done and P &lt; 0.05 is considered statistically significant. RESULTS: Genotype frequencies of MTHFR C677T, A1298C in all the subjects were analyzed for the Hardy–Weinberg law of genetic equilibrium. Mutant polymorphisms of MTHFR C677T, i.e., thymine-thymine and cytosine-thymine were increased significantly. Similarly, MTHFR A1298C mutant polymorphisms, i.e. adenine-cytosine, cytosine-cytosine were increased significantly in the infertile group than in the fertile group. DISCUSSION: Mutations of both MTHFR C677T, A1298C are found to be linked with lowered enzyme activity. We found that the occurrence of mutant homozygous and mutant heterozygous genotypes was increased in a diabetic male infertile group when compared to nondiabetic fertile group. Hence, it can be concluded that presence of single-nucleotide polymorphisms of MTHFR will increase the risk of infertility in diabetic male population.

Homocysteine Reduction for Stroke Prevention: Regarding the Recent AHA/ASA 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack.

Reduction of secondary ischemic stroke risk following an initial stroke is an important goal. The 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack assembles opportunities for up to 80% secondary stroke reduction. Homocysteine reduction was not included in the recommendations. The reduction of homocysteine with low doses of folic acid has been shown to reduce ischemic stroke and all stroke. This has been obscured by studies using high doses of folic acid and cyanocobalamin in patients with renal failure and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. The confounding impacts of high dose folic acid and cyanocobalamin toxicity in renal failure and MTHFR C677T subgroups are discussed. New studies show that their toxicity is due to non-bioequivalence to the natural dietary forms, L-methylfolate and methylcobalamin. Low doses of folic acid and cyanocobalamin are safer than high doses for these subpopulations. Even lower toxicity with greater effectiveness for reducing homocysteine is seen with L-methylfolate and methylcobalamin, which are safe at high doses. Retinal vascular imaging is a noninvasive method for evaluating central nervous system (CNS) microangiopathy. A formulation containing l-methylfolate and methylcobalamin has been shown to reduce homocysteine and increase perfusion in diabetic retinopathy. This supports homocysteine intervention for CNS ischemia. Future ischemic stroke intervention studies could benefit from monitoring retinal perfusion to estimate the impact of risk reduction strategies. The omission of a recommendation for homocysteine and secondary stroke reduction through the use of B vitamins should be reconsidered in light of re-analysis of major B vitamin intervention studies and new technologies for monitoring CNS perfusion. We recommend revision of the 2021 Guideline to include homocysteine reduction with low doses of folic acid and cyanocobalamin, or better yet, L-methylfolate and methylcobalamin, making a good clinical guideline better.

Association Between Plasma Homocysteine Level and Mortality: A Mendelian Randomization Study.

In previous studies, high homocysteine levels were associated with high cardiovascular mortality. However, these results were inconsistent with those of randomized controlled trials. We aimed to evaluate the causal role of homocysteine on all-cause and cardiovascular mortality using Mendelian randomization (MR) analysis. This study included the 10,005 participants in the Namwon Study. In conventional observational analysis, age, sex, survey years, lifestyles, body mass index, comorbidities, and serum folate level were adjusted using multivariate Cox proportional regression. MR using 2-stage least squares regression was used to evaluate the association between genetically predicted plasma homocysteine levels and mortality. Age, sex, and survey years were adjusted for each stage. The methylenetetrahydrofolate reductase (MTHFR) polymorphism was used as an instrumental variable for predicting plasma homocysteine levels. Observed homocysteine levels were positively associated with all-cause (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.26-1.54) and cardiovascular (HR, 1.62; 95% CI, 1.28-2.06) mortality when plasma homocysteine levels doubled. However, these associations were not significant in MR analysis. The HRs of doubling genetically predicted plasma homocysteine levels for all-cause and cardiovascular mortality were 0.99 (95% CI, 0.62-1.57) and 1.76 (95% CI, 0.54-5.77), respectively. This MR analysis did not support a causal role for elevated plasma homocysteine concentrations in premature deaths.

Effects of Folic Acid Supplementation on Liver Enzymes, Lipid Profile, and Insulin Resistance in Patients with Non-Alcoholic Fatty Liver Disease: A Randomized Controlled Trial.

Previous evidence revealed an association between folate deficiency and non-alcoholic fatty liver disease (NAFLD). This study is the first one investigating the effects of folic acid on hepatic steatosis grade, liver enzymes, insulin resistance, and lipid profile in NAFLD cases. Sixty-six participants with NAFLD were allocated randomly to take either a placebo or one oral tablet of folic acid (1 mg) on a daily basis within eight weeks. Serum folate, homocysteine, glucose, aminotransferases, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and lipids were assessed. Ultrasonography was used for assessing the liver steatosis grade. The serum alanine transaminase, grade of hepatic steatosis, and aspartate transaminase significantly were decreased within both study groups; however, the between-group comparison was not statistically significant. Of note, the decrease in ALT was more pronounced in folic acid compared with the placebo group (-5.45 ± 7.45 vs. -2.19 ± 8.6 IU/L). The serum homocysteine was decreased after receiving folic acid compared to the placebo (-0.58 ± 3.41 vs. +0.4 ± 3.56 μmol/L; adjusted P = 0.054). Other outcomes did not significantly change. Supplementation with folic acid (1 mg/d) for eight weeks among cases with NAFLD did not change significantly the serum levels of liver enzymes, the hepatic steatosis grade, insulin resistance and lipid profile. However, it was able to prevent the increase in homocysteine in comparison with the placebo. Conducting further research is suggested with the longer duration and different doses of folic acid, adjusted to the genotypes of methylenetetrahydrofolate reductase polymorphism, among NAFLD patients.

MTHFR polymorphism's influence on the clinical features and therapeutic effects in patients with migraine: An observational study.

Our study aimed to evaluate the influence of methylenetetrahydrofolate reductase (MTHFR) polymorphism on the clinical features and therapeutic effects in patients with migraine. The data of 135 patients with migraine were collected from January 2021 to December 2021. The MTHFR C677T polymorphism was analyzed. The pain intensity was evaluated using a numerical rating scale (NRS) during treatment. The levels of folic acid, homocysteine (Hcy), vitamin B12, interleukin-2 (IL-2), IL-4, and ferritin, and changes of NRS were compared between folic acid and conventional treatment groups stratified by different genotypes of MTHFR in migraine patients. The levels of Hcy and ferritin in male patients were higher than that in female patients (P < 0.05); Compared with CC and CT genotype groups, the TT genotype group showed significantly higher Hcy levels (P < 0.05) and lower folic acid levels (P < 0.05); In both folic acid and conventional treatment groups, a significant decrease in NRS score was observed in different genotypes post-treatment (P < 0.05). Patients with TT genotype in the folic acid treatment group showed better therapeutic efficacy than conventional treatment group (P < 0.05). There is no significant difference in the therapeutic efficacy in other genotypes between the two groups (P > 0.05). The MTHFR C677T genotyping may provide a new method to guide and optimize individualized medication for migraine patients.

Association of paternal MTHFR polymorphisms (C677T) with clinical outcomes in ICSI treatment.

This study aims to investigate the association between paternal methylenetetrahydrofolate reductase (MTHFR) polymorphisms (C677T) and embryonic development, pregnancy, and neonatal outcomes in intracytoplasmic sperm injection (ICSI) treatment. A total of 191 infertile men undergoing ICSI treatment at the Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, were recruited between January 2020 and June 2021. The MTHFR C677T polymorphism genotyping was evaluated in these male patients, and they were stratified into three groups according to genotyping results: Control (CC), heterozygote mutated (CT), and mutated homozygote (TT). In addition, we conducted a comparative analysis of embryonic development, pregnancy, and neonatal outcomes among these three groups. The embryonic development (including normal fertilization rate (80.14% vs. 83.06% vs. 85.10%; p = 0.37), high-quality embryo rate (45.26% vs. 43.69% vs. 46.04%; p = 0.72), blastocyst formation rate (42.47% vs. 43.18% vs. 39.38%; p = 0.62), implantation rate (42.47% vs. 36.25% vs. 41.22%; p = 0.62), and clinical pregnancy rate (64.71% vs. 58.75% vs. 66.67%; p = 0.59) were not comparable among these three groups. Moreover, no significant difference was observed in terms of pregnancy outcomes (including miscarriage rate (24.24% vs. 12.77% vs. 22.5%; p = 0.35) and live birth rate (49.02% vs. 51.25% vs. 51.66%; p = 0.96)). Additionally, no marked difference was observed in terms of neonatal outcome (including, preterm delivery rate (24% vs. 14.63% vs. 9.67%; p = 0.35), birth height (p = 0.75), birth weight (p = 0.35), neonatal sex (p = 0.48), gestational age at delivery (p = 0.24), Apgar score (p = 0.34), and birth defects (0% vs. 2% vs. 9%; p = 0.23) among the study groups. The paternal MTHFR C677T polymorphism is not associated with embryo quality, pregnancy, or neonatal outcomes in ICSI treatment. Therefore, in our population, MTHFR polymorphisms do not provide helpful information in explaining ICSI failure.

Association of homocysteine and polymorphism of methylenetetrahydrofolate reductase with early-onset post stroke depression.

Homocysteine (Hcy) has been indicated to be involved in pathophysiology of post stroke depression (PSD). There is a lack of research to study the relationship between Hcy metabolism genes and PSD. Our study aims to investigate the relationship among Hcy metabolism genes, Hcy, and early-onset PSD. We recruited 212 patients with stroke and collected their peripheral blood sample, clinical data, and laboratory test on admission. 12 single nucleotide polymorphisms (SNPs) in methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), and methionine synthase (MTR) genes were genotyped by high-resolution melt analysis. PSD was diagnosed by DSM-V at 2 weeks after stroke. Binary logistic regression and haplotype analysis were used to examine the association between Hcy metabolism genes and PSD. Mediation analysis was performed to clarify whether the SNPs exerted their effect on PSD by affecting the Hcy level. 81 patients were diagnosed with PSD, and the incidence rate was 38.2%. Hcy level in PSD group was significantly higher than it in non-PSD group (p = 0.019). MTHFR rs1801133 AA genotype an A allele were associated with an elevated risk of PSD after adjustment for some confounding factors (OR = 4.021, 95% CI: 1.459∼11.080, p = 0.007 for AA genotype; OR = 1.808, 95% CI: 1.172∼2.788, p = 0.007 for A allele). Furthermore, the effect of MTHFR rs1801133 AA genotype on PSD was mediated by Hcy (OR = 1.569, 95% CI: 0.013∼3.350, p < 0.05). MTHFR rs1801133 and Hcy were associated with PSD, and MTHFR rs1801133 may exert an effect on PSD via mediating Hcy level. This offers a new perspective for treating PSD and understanding the mechanism of PSD.

Association of small dense low-density lipoprotein cholesterol with H-type hypertension and MTHFR gene polymorphism

To investigate the expression of small dense low-density lipoprotein cholesterol (sdLDL-C) in patients with H-type hypertension and its association with H-type hypertension and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms. The retrospective study method was used,and a total of 207 hospitalized hypertensive patients (76 males and 131 females, aged 40-82 years, median age 66 years) admitted to the Zibo First Hospital from March 2021 to March 2022 were enrolled in this study. The levels of homocysteine (Hcy), sdLDL-C, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TG) and lipoprotein (a) [Lp(a)] were measured. The patients were divided into H-type hypertensive group (n=105, 40 males and 65 females) and non-H-type hypertensive group (n=102, 36 males and 66 females) according to Hcy levels. The C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene was detected in each group. Logistic regression analysis was performed for the related factors of H-type hypertension. The serum sdLDL-C levels were (0.92±0.31) and (0.65±0.28) mmol/L in H-type hypertension group and non-H-type hypertension group, respectively. The sdLDL-C levels in H-type hypertension group were significantly higher than those in non-H-type hypertension group (t=6.500, P<0.01). There was no significant difference in the serum sdLDL-C levels between males and females in H-type hypertension group (t=-1.543, P=0.129). The CC, CT, TT genotypes and C and T allele frequencies of MTHFR C677T in H-type hypertension group were significantly different from those in non-H-type hypertension group (P<0.05). The Hcy and sdLDL-C levels in different genotypes of MTHFR in H-type hypertension group were significantly different (H=12.742, P=0.002; F=3.345, P=0.042). Among them, Hcy levels were higher in TT genotype than in CT and CC genotypes, respectively (Z=-28.099, P=0.003; Z=-16.112, P=0.040), and sdLDL-C levels were higher in TT genotype than in CC genotype (t=-2.587, P=0.012). Logistic regression analysis showed that age, sdLDL-C, and MTHFRC677T TT genotypes were associated with the development for H-type hypertension. In conclusion, the level of sdLDL-C is associated with MTHFR gene polymorphisms and may be associated with the development of H-type hypertension.

WITHDRAWN: Maternal MTHFR Gene Polymorphisms and the Risk of Cancer Disease

The etiology of Cancer disease has been related to polymorphisms in the genes encoding the folate metabolizing enzymes methylenetetrahydrofolate reductase (MTHFR). Despite several studies having linked Down syndrome to genetic factors, the specific etiology remained unclear. Our study aimed to investigate maternal MTHFR gene polymorphism and its risk of Cancer disease. This study was done during the period November 2019 and October 2020. We investigated 132 (80 newborn babies with and 52 healthy individuals as a control) their ages ranging from 14 to 22 years old at (Hiwa Institute for Deaf and Mutes) in Arbil city, Kurdistan/Iraq. Our study revealed that maternal genetic polymorphism of MTHFR EXON8-1261-1395 gene among all samples was only seen among patient samples rather than the control group were detected by PCR. In addition, sequencing results showed the presence of some mutation among polymorphism group (Deletion A) in two different nucleotide regions and there are two sites of (Substation C to T) in other nucleotide regions (105-108). The present finding supports the association of maternal MTHFR genotype polymorphism and risk factors and is associated with the presence of many abnormalities such as Cancer disease in the offspring. We suggest that the identification of maternal MTHFR genotype polymorphism should be taken concern and should be used as a critical marker for diagnosis of DS in babies.

Short-Term Combined Intake of Vitamin B2 and Vitamin E Decreases Plasma Homocysteine Concentrations in Female Track Athletes

Female athletes who endure physical strain on the same bone area are prone to stress fractures. Preventing these improves their quality of life. Blood vitamin B2 (V.B2) and E (V.E) levels influence blood homocysteine (Hcy) levels, which, when elevated, increase the risk of stress fractures. We aimed to determine the effects of V.B2 and V.E supplementation on plasma Hcy concentrations in these athletes carrying the C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR). This study is a before–after study in 16 female athletes. It was divided into three intervention periods of V.B2 (28 mg/day), V.E (60 mg/day), and V.B2 + V.E intake, and each period was 14 days. Blood samples were collected before and after each period, and plasma Hcy concentration and each blood vitamin concentration were measured. Plasma Hcy concentration significantly decreased in all periods, but the maximum lowering effect was obtained when V.B2 and V.E were used in combination. The administration of V.B2 might have lowered the plasma Hcy level by maximizing the catalytic activity of MTHFR; V.E might have suppressed cell oxidation, increasing the efficiency of folate in lowering the plasma Hcy level. We propose the combined intake of V.B2 and V.E as effective nutrients to reduce plasma Hcy concentrations in female athletes with MTHFR polymorphisms.

Homocysteine in CAD patients-Does it matter?

Introduction and Aim: Homocysteine (Hcy) is considered as an independent risk factor for coronary artery disease (CAD). Hyperhomocysteinemia (HHcy) may be caused due to the deficiency of vitamin B12, folic acid (FA), and pyridoxine (B6) or due to genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR). A pilot study was undertaken to investigate Hcy levels and its association with lipid profile in patients with CAD. Methods: Lipid profile values were obtained from laboratory reports and the Hcy levels were estimated by enzymatic cycling assay using the commercial kits in autoanalyzer in subjects with CAD (n=12). Results: Hcy (14.58 ± 8.32 µmol/L), LDL (134.75 ± 45.02 mg/dl) and non-HDL (150.25 ± 56.89 mg/dl) levels were found to be elevated in patients with CAD. Conclusion: Dyslipidemia was associated with variable Hcy levels. Few patients with HHcy showed concurrent upsurge in LDL and non-HDL levels.

The Roles of MTRR and MTHFR Gene Polymorphisms in Colorectal Cancer Survival.

Paradoxically epidemiological data illustrate a negative relationship between dietary folate intake and colorectal cancer (CRC) risk. The occurrence and progression of CRC may be influenced by variants in some key enzyme coding genes in the folate metabolic pathway. We investigated the correlation between genetic variants in methionine synthase reductase (MTRR) and methylenetetrahydrofolate reductase (MTHFR) and CRC survival. This study used data collected from the Newfoundland Familial Colorectal Cancer Study. A total of 532 patients diagnosed with CRC for the first time from 1999 to 2003 were enrolled, and their mortality were tracked until April 2010. DNA samples were genotyped by Illumina's integrated quantum 1 million chip. Cox models were established to assess 33 tag single-nucleotide polymorphisms in MTRR and MTHFR in relation to overall survival (OS), disease-free survival (DFS) and CRC-specific survival. The MTRR and MTHFR genes were associated with DFS and CRC-specific survival in CRC patients at the gene level. After multiple comparison adjustment, MTRR rs1801394 A (vs. G) allele was associated with increased DFS (p = 0.024), while MTHRT rs3737966 (G vs. A), rs4846049 (T vs. G), rs1476413 (A vs. G), rs1801131 (C vs. A), rs12121543 (A vs. C), rs1801133 (C vs. T), rs4846052 (T vs. C), rs2066471 (A vs. G) and rs7533315 (T vs. C) were related to worse CRC-specific survival. Additionally, significant interactions were seen among pre-diagnostic alcohol consumption with MTRR rs1801394, rs3776467, rs326124, rs162040, and rs3776455, with superior OS associated with those protective variant alleles limited to patients with alcohol consumption under the median. The MTHFR rs3737966 (G vs. A) allele seemed to be detrimental to CRC survival only among subjects with fruit intake below the median. Polymorphic variants in MTRR and MTHFR genes that code for key enzymes for folate metabolism may be associated with survival in patients with CRC. The gene-CRC outcome association seems modulated by alcohol drinking and fruit intake.

Genes predisposing tunneled catheter thrombosis in hemodialysis patients.

This study aims to investigate the association of genes predisposing thrombophilia with tunneled catheter thrombosis in hemodialysis patients. Between October 2018 and December 2020, we compared the frequencies of genetic polymorphisms causing thrombophilia, including prothrombin G20210A, factor V Leiden, methylene tetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, plasminogen activator inhibitor (PAI), factor XIII V34L and clinical characteristics of 52 patients with a history of 2 tunneled2 tunneled catheter thrombosis occlusions within a year (Group 1; 24 males, 28 females; mean age: 62±8.9 years; range, 45 to 77 years), 52 patients who underwent their first tunneled catheter thrombosis insertion (Group 2; 29 males, 23 females; mean age: 63±15.2 years; range, 22 to 87 years), and 51 healthy controls (Group 3; 26 males, 25 females; mean age: 34±9.2 years; range, 19 to 54 years). Groups 1 and 2 carried the MTHFR A1298C (p=0.048) and compound heterozygous MTHFR A1298C and C677T (p=0.048) polymorphisms more frequently than Group 3. However, subgroup analysis results were not statistically significant. The other polymorphisms were distributed similarly in all three groups. The MTHFR polymorphisms had a weak effect on tunneled hemodialysis catheter thrombosis in neural network analysis. Our study results indicated that there was a concomitance of MTHFR polymorphisms with hemodialysis-dependent chronic kidney disease. The MTHFR A1298C and compound heterozygous MTHFR polymorphisms may be associated with tunneled hemodialysis catheter thrombosis. Thrombophilia gene screening may be recommended in hemodialysis patients undergoing tunneled hemodialysis catheter thrombosis at least twice in a year.

APOE Genetic Polymorphism rs7412 T/T Genotype May Be a Risk Factor for Essential Hypertension among Hakka People in Southern China.

Objective One of the causes of hypertension is a genetic factor. The purpose of this study was to look at the relationship between apolipoprotein E (APOE) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms and essential hypertension in the Hakka population. Methods The study included 2,850 patients with hypertension and 2,034 controls. APOE rs429358, rs7412, and MTHFR rs1801133 were genotyped by polymerase chain reaction (PCR)-microarray. The differences in these polymorphisms between the two groups were analyzed. Results The genotype and allele frequency of APOE and MTHFR polymorphisms did not differ significantly between hypertensive patients and controls. Patients with hypertension who were APOE rs429358C/C homozygous had higher TG, TC, LDL-C, and Apo-B levels, whereas patients with the T/T genotype had higher HDL-C levels. Patients with hypertension who were APOE rs7412T/T homozygous had higher TG and TC levels and lower LDL-C and Apo-B levels. Homocysteine (Hcy) levels in patients with MTHFR CC, CT, and TT genotypes were increased, while patients with the TT genotype and T allele had higher Hcy levels than those of patients with other genotypes and the C allele. The APOE rs7412T/T genotype in the co-dominant model (APOE rs7412T/T vs. C/C) (gender-, age-, smoking-, and drinking-adjusted OR 2.682, 95% CI, 1.072–6.710, P=0.035) was a significant risk factor for hypertension. The APOE rs429358 and MTHFR rs1801133 genotypes in co-dominant, dominant, and recessive models were not significant risk factors for hypertension. Conclusions It supports that APOE polymorphisms are related to hypertension in the Hakka population. Specifically, the APOE rs7412T/T genotype may be a risk factor for hypertension.

Possible effect of genetic background in thrombophilia genes on clinical severity of patients with coronavirus disease-2019: A prospective cohort study

Background and objective: Thrombotic and microangiopathic effects have been reported in Coronavirus Disease-2019 (COVID-19) patients. In the present study, we aimed to examine the relationship between hereditary thrombophilia factors and the clinical picture severity of COVID-19 patients. Methods: Ninety COVID-19 patients were included and grouped according to the severity to three groups: severe/critical (n=30), mild/moderate (n=30) and asymptomatic (n=30). Hereditary thrombophilia genetic markers [prothrombin (FII) G20210A, factor V Leiden (FVL) G1691A, factor XIII (FXIII) V34L, methylene tetrahydrofolate reductase (MTHFR) A1298C and C677T, and plasminogen activator inhibitor-1 (PAI-1) 4G &amp; 5G] were genotyped for all patients. Results: Seventeen (18.9%) patients had the polymorphism 4G/4G PAI-1 and 48 (53.3%) had 4G/5G. In addition, the heterozygous GA FVL, MTHRF677CT, and MTHRF1298AC polymorphisms were detected in 11 (12.2%), 26 (28.9%), and 38 (42.2%) patients, respectively. The rate of severe/critical patients with PAI 4G/5G gene polymorphism was higher than the asymptomatic+moderate/mild patients, and the rate of severe/critically ill patients with PAI 4G/4G polymorphism was found to be lower than the asymptomatic+moderate/mild patients. No difference was evidenced between the distribution of deceased and survivors of the genotype groups. Conclusions: In the present study, we found that heterozygous 4G/5G PAI-1 polymorphism is associated with critical or severe COVID-19 picture, and that FVL, MTHFR, FXIII, and prothrombin polymorphisms were not directly related to COVID-19 severity.

Association of MTHFR 677C>T polymorphism with pregnancy outcomes in IVF/ICSI-ET recipients with adequate synthetic folic acid supplementation.

Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphism rs1801133 (677C>T) will decrease the utilization of folate. Folate deficiency and its resulting homocysteine (HCY) accumulation can impair female fertility. Folic acid (FA) supplementation is necessary in pregnant women who are undergoing in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) - embryo transfer (ET), and especially in women with MTHFR rs1801133 C-to-T mutations. At present, affordable and accessible synthetic FA is mainly used. However, some studies have suggested that 5-methylenetetrahydrofolate (5-MTHF), a type of active FA, may be more suitable for women with the MTHFR 677C>T polymorphism, since it is safer and more effective. This retrospective study aimed to evaluate whether the MTHFR rs1801133 gene polymorphism is related to the pregnancy outcomes of IVF/ICSI-ET recipients after sufficient supplementation with FA instead of 5-MTHF. Data on 692 women undergoing IVF/ICSI-ET and taking adequate FA were collected. Participant characteristics were compared using the Kruskal-Wallis test and Pearson chi-square test. Logistic regressions were used to calculate the odds ratio (OR) and 95% confidence interval (95% CI), after adjusting for age, BMI, method of fertilization, method of embryo transfer and number of embryos transferred. An additive model (T/T vs. C/C), dominant model (C/T + T/T vs. C/C), and recessive model (T/T vs. C/T + C/C) were evaluated. Analysis revealed that MTHFR rs1801133 in IVF/ICSI-ET women with adequate FA supplementation was not associated with the pregnancy rate but with age (OR = 0.91, 95% CI = 0.88, 0.94, P < 0.001) and BMI (OR = 0.95, 95% CI = 0.90, 0.997, P = 0.037). In 349 clinically pregnant women, no association of the MTHFR 677C>T with pregnancy outcomes was found in the additive model, dominant model, or recessive model. Of the 273 women with positive pregnancy outcomes, 34 had a preterm delivery. MTHFR 677C>T was not associated with a preterm delivery after adjusting for age and BMI. The current results indicated that MTHFR polymorphism rs1801133 was not related to the pregnancy rate or pregnancy outcomes of women undergoing IVF/ICSI-ET with adequate synthetic FA supplementation, suggesting that simple supplementation with less expensive and readily available FA, rather than expensive 5-MTHF, appeared to be appropriate.