Methylenetetrahydrofolate reductase polymorphisms as risk factors for retinal venous occlusive disease: A literature review

The role of polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene in retinal vein occlusion (RVO) is a theme of discussion since the first reports of RVO in patients with MTHFR C677T mutation and without classic acquired risk factors for retinal vascular disease. The association between MTHFR polymorphisms and RVO has been studied over the last 20 years producing conflicting results. This review aims to summarize the literature concerning the role MTHFR polymorphisms as risk factors for RVO.

MTHFR Gene Polymorphisms Prevalence and Cardiovascular Risk Factors Involved in Cardioembolic Stroke Type and Severity

Background: Cardioembolic stroke (CES), generally known as the most severe subtype of ischemic stroke, is related to many factors, including diabetes mellitus (DM), hypertension (HTN), smoking, hyperlipidemia and atrial fibrillation (AF). Genetic mutations of the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C have been recently associated with ischemic stroke. The purpose of this study was to analyze the prevalence of MTHFR gene polymorphisms correlated with cardiovascular risk factors in a selected population of patients with CES due to non-valvular AF (NVAF). Methods: This cross-sectional study was performed on 67 consecutive patients with acute cardioembolic stroke admitted to our hospital. The protocol included general physical examination, neurological clinical status and stroke severity evaluation, imagistic evaluation and genetic testing of MTHFRC677T and A1298C polymorphisms. Results: The prevalence of MTHFR polymorphisms in the study population was 38.2% for C677T and 40.3% for A1298C. The C677T mutation was significantly correlated with increased diastolic blood pressure (DBP) values (p = 0.007), higher total cholesterol (TC) (p = 0.003), low-density lipoprotein cholesterol (LDLc) (p = 0.003) and triglycerides (TGL) (p = 0.001), increased high-sensitive C-reactive protein (hsCRP) values (p = 0.015), HbA1c (p = 0.004) and left ventricle ejection fraction (LVEF) (p = 0.047) and lower high-density lipoprotein cholesterol (HDLc) (p < 0.001) compared to patients without this genetic variant. This genetic profile also included significantly higher CHA2DS2VASC (p = 0.029) and HASBLED (Hypertension, Abnormal liver/renal function, Stroke, Bleeding, Labile INR, Elderly age(>65 years), Drug/Alcohol usage history/Medication usage with bleeding predisposition) (p = 0.025) scores. Stroke severity in patients with MTHFRA1298C mutation was significantly increased when applying National Institutes of Health Stroke Scale (NIHSS) (p = 0.006) and modified Rankin scale (mRS) (p = 0.020) scores. The presence of A1298C mutation as a dependent variable was associated with significantly higher TGL values (odds ratio (OR) = 2.983, 95%CI = (1.972, 7.994)). Conclusions: The results obtained in this study demonstrate that MTHFR gene polymorphisms have a high prevalence in an NVAF cardioembolic stroke population. Moreover, an association between C677T mutation and stroke severity was highlighted. The C677T mutation in patients with NVAF was correlated with a higher incidence of cardiovascular comorbidities (hypertension HTN, heart failure (HF), dyslipidemia, type II diabetes mellitus (T2DM) with high HbA1c and increased inflammatory state). The A1298CMTHFR gene mutation was associated with a higher incidence of previous lacunar stroke and stroke recurrence rate, while dyslipidemia was the main cardiovascular comorbidity in this category.

Methylenetetrahydrofolate reductase C677T polymorphism and toxicity to 5-FU-based chemotherapy in colorectal cancer

Purpose: To investigate the toxicity of methylenetetrahydrofolate reductase (MTHFR) polymorphism in colorectal cancer patients treated with 5-fluorouracil (5-FU).Methods: A total of 105 patients with colorectal cancer who underwent 5-FU therapy were included in this study. MTHFR C677T polymorphisms were determined using direct sequencing. Physical examination and the results of blood and urine tests were used to evaluate the toxicities, including gastrointestinal toxicity, hematopoietic toxicity, hair-skin toxicity and hand-foot syndrome.Results: In 90.5 % of all patients, 5-FU toxicity was observed. With regard to MTHFR C677T mutation, 45.7 % heterozygote mutants and 19.0 % homozygote mutants were observed. MTHFR C677T polymorphism was statistically related to 5-FU toxicity (p = 0.000). In addition, MTHFR C677T mutation was closely related to hematopoietic toxicity (p = 0.005).Conclusion: MTHFR C677T can be used for the prediction of 5-FU toxicity, and can also predict hematopoietic toxicity in patients with colorectal cancer. Keywords: MTHFR genes, Polymorphism, Colorectal cancer, Biomarker, Toxicity

Intrauterine upper limb thrombosis: an unusual presentation

Intrauterine thrombosis with extremity ischemia presenting at birth in a newborn is a rare event. A 29 year old mother, 2nd gravida with one first trimester spontaneous abortion delivered a 33week gestation male preterm baby. On Examination, the entire left upper limb was ischemic and edematous with an absent flow on Doppler USG. Low molecular weight heparin (LMWH) was started after which gradually the limb turned pink with good volume pulsations. Thrombophilia mutation studies revealed the heterozygous state for the MTHFR (C677T) mutation only in the mother. Prompt diagnosis and early treatment has a favourable outcome in cases of intra-uterine thrombo-embolism.

Prevalence of the MTHFR C677T Mutation in Fertile and Infertile Women

Introduction The importance of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in infertile women remains controversial. Objective To evaluate if the MTHFR C677T mutations are more frequent in infertile women, and if they can be associated with the occurrence of infertility in the Brazilian population. Methods This case-control study included 130 infertile women consulting at a private clinic between March 2003 and March 2005 (data previously published), and 260 fertile women attending the family planning outpatient clinic of our institution between April 2012 and March 2013. Data analysis The Chi-squared and Fisher Exact tests were used to evaluate the association between the presence of the MTHFR C677T mutation and a history of infertility. Results The frequency of the mutation was of 58.5% for the case group (n = 76) and of 49.2% for the fertile controls (n = 128). The mutation was homozygous in 13 women in the case group (10%) and in 23 of the fertile women in the control group (8.8%). These differences were not statistically significant. Conclusions These results suggest that the presence of the MTHFR C677T mutation does not constitute a risk factor for infertility, even when the mutation is homozygous. Further studies are needed to confirm whether research on this mutation should be considered unnecessary in women with infertility.

The effect of the MTHFR C677T mutation on athletic performance and the homocysteine level of soccer players and sedentary individuals

This study investigated athletic performance and homocysteine (Hcy) levels in relation to the methylenetetrahydrofolate reductase (MTHFR) C677T mutation and explored the relationship between this mutation and other cardiac risk factors in soccer players and sedentary individuals. The study groups consisted of randomly selected soccer players (n=48) from the Turkish Super and Major League and sedentary male students (n=48) aged 18-27. Anthropometric variables, aerobic and anaerobic thresholds were measured, furthermore, biochemical assays were performed. The level of HDL cholesterol, LDL cholesterol, triglyceride, Hcy, folate, vitamin B12, hemogram and MTHFR C677T was investigated. The results showed that there was a statistical difference between the two groups in terms of body mass, body fat, the BMI, the aerobic threshold heart rate (ATHR), aerobic threshold velocity (ATVL) and anaerobic threshold velocity (ANTVL). The soccer players were found to have lower levels of triglyceride, total cholesterol and LDL cholesterol, and higher levels of folate than the sedentary participants. The analysis of the alleles of the MTHFR C677T polymorphism showed that the participants that carried TT genotypes had a lower level of vitamin B12 and folate, and a higher level of Hcy than the participants carrying CC and CT genotypes. In conclusion, the baseline homocysteine and cardiovascular fitness levels of healthy young males with the TT genotypes of the MTHFR C677T genotype were found to strongly correlate with their levels of Hcy.