Associations between Serum Betaine, Methyl-Metabolizing Genetic Polymorphisms and Risk of Incident Type 2 Diabetes: A Prospective Cohort Study in Community-Dwelling Chinese Adults

Previous studies have explored associations between betaine and diabetes, but few have considered the effects of genes on them. We aimed to examine associations between serum betaine, methyl-metabolizing genetic polymorphisms and the risk of type 2 diabetes in Chinese adults. This prospective study comprised 1565 subjects aged 40–75 without type 2 diabetes at baseline. Serum betaine was measured by high-performance liquid chromatography tandem mass spectrometry. Genotyping of methyl-metabolizing genes was detected by Illumina ASA-750K arrays. Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During a median of 8.9 years of follow-up, 213 participants developed type 2 diabetes. Compared with participants in the lowest quartile of serum betaine, those in the highest quartile had lower risk of type 2 diabetes, adjusted HRs (95%CIs) was 0.46 (0.31, 0.69). For methylenetetrahydrofolate reductase (MTHFR) G1793A (rs2274976) and MTHFR A1298C (rs1801131), participants carrying 1793GA + AA and 1298AC + CC had lower risk of type 2 diabetes. Interactions of serum betaine and genotype of MTHFR G1793A and MTHFR A1298C could be found influencing type 2 diabetes risk. Our findings indicate that higher serum betaine, mutations of MTHFR G1793A and A1298C, as well as the joint effects of them, are associated with lower risk of type 2 diabetes.

ĐẶC ĐIỂM LÂM SÀNG CỦA THAI PHỤ SẨY THAI LIÊN TIẾP KHÔNG RÕ NGUYÊN NHÂN MANG GEN METHYLENETETRAHYDROFOLATE REDUCTASE BỆNH LÝ

Nguyên nhân sẩy thai liên tiếp rất phức tạp và khó xác định, trong đó đa hình đơn gen MTHFR bệnh lý (C677T, A1298C) là một nguyên nhân mới cần tìm hiểu. Nghiên cứu nhằm: Xác định mối liên quan giữa MTHFR và bệnh lý sảy thai liên tiếp; Mô tả đặc điểm lâm sàng của những thai phụ có tiền sử sảy thai liên tiếp mang gen MTHFR (C677T và A1298C) bệnh lý. Đây là 1 nghiên cứu bệnh- chứng, 2 nhóm đều được xác định kiểu gen của gen MTHFR C677T/A1298C bằng phương pháp PCR. Nghiên cứu thu được 43 thai phụ thuộc nhóm bệnh và 30 thai phụ thuộc nhóm chứng. Thời điểm thai sẩy trung bình trong tiền sử của nhóm mang kiểu gen bệnh lý là 8,47 tuần. MTHFR C677T làm tăng nguy cơ xuất hiện triệu chứng doạ sẩy thai trong 3 tháng đầu (p=0,043). Kết luận: Đa hình đơn gen MTHFR C677T tăng xuất hiện triệu chứng doạ sẩy thai trong 3 tháng đầu.

Singleton pregnancy losses before gestational week 22 among patients with autoimmune disorders and Methylenetetrahydrofolate reductase polymorphisms

BACKGROUND: The rates of pregnancy losses (PLs) are increased by maternal risk factors such as autoimmune disorders (AD) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms. OBJECTIVE: To evaluate singleton PLs before gestational week (gw) 22 among patients with AD and MTHFR polymorphisms. METHODS: Totally, 1108 singleton pregnancies in 243 women were categorized as: 1) 148 pregnancies in 33 patients with AD, 2) 316 pregnancies in 66 patients with MTHFR polymorphisms, 3) 644 pregnancies in 144 patients with AD +MTHFR polymorphisms. PLs were classified into subgroups: a) Chemical Pregnancy(CP), b) Blighted Ovum(BO), c) gw ⩽ 10, d) gw11–14 e) gw15–22, f) Ectopic Pregnancy(EP), g) Trophoblastic Disease(TD). Obstetric histories were compared using Beksac Obstetrics Index (BOI): [number of living child + (π/10)]/gravida. RESULTS: PL rates before gw22 were 39.2% (58/148), 33.2% (105/316), and 36.3% (234/644) in AD, MTHFR, and AD +MTHFR groups, respectively (p= 0.421). The rate of Pre-Prenatal Screening Period fetal losses (CP + BO + gw ⩽ 10 fetal losses + EP + TD) were 84.8%, 75.9%, and 77.8% in AD, MTHFR, and AD +MTHFR, respectively (p= 0.264). Gravidity ⩽ 4 versus those with gravidity ⩾ 5 had statistically significant differences in BOI (p< 0.001). CONCLUSIONS: PL rate before gw22 among singleton pregnancies with AD and/or MTHFR polymorphisms was 35.8%. The clinical findings seem to be more complicated in patients with gravidity ⩾ 5.

Individualized Folic Acid Supplementation based on Polymorphisms of Methylenetetrahydrofolate Reductase (MTHFR) and Methionine Synthase Reductase (MTRR), Compared with Traditional Folic Acid Supplementation, Reduces Gestational Diabetes Mellitus

Backgroud: Folic Acid (FA) may contribute to the development of gestational diabetes mellitus (GDM), but existing studies are inconsistent. We examined the genotype distributions and allele frequencies of methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms of pregnant women in China, and compared the effects of individualized folate supplementation and traditional FA supplementation on GDM.Methods: The genotype distributions and allele frequencies of MTHFR C677T, A1298C and MTRR A66G polymorphisms in 968 pregnant women (case group) were tested. FA metabolism was ranked at four levels, and then pregnant women of different levels are supplemented with different doses of FA at different periods. The case group was followed up for pregnancy complications and compared with 1,940 pregnant women traditionally supplemented with FA in the same hospital (control group).Results: The allele frequencies of MTHFR C677T were 63.3% (C) and 36.7% (T), those of MTHFR A1298C were 79.3% (A) and 20.7% (C), and those of MTRR A66G were 75.0% (A) and 25.0% (G). Compared with control group, the incidence of GDM in the case group were significantly lower, especially in high-risk pregnant women after FA supplementation.Conclusion: Traditional FA supplementation based on personal habits is controversial, but the use of polymorphisms of genes to clarify the FA metabolism of pregnant women, appropriate, timely and accurate supplementation of FA can effectively reduce gestational diabetes, especially for high-risk pregnant women.

Hypoventilation and progressive encephalopathy in a neonate with MTHFR deficiency

Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive inherited inborn error of metabolism, which presents with various severity depending on the level of residual enzyme activity. In neonates, it can present with recurrent hypoventilation episodes, persistent encephalopathy with or without microcephaly. MTHFR deficiency also results in hyperhomocysteinemia, homocystinuria and hypomethionemia. We report a male neonate with severe MTHFR deficiency presenting to us on third week of life with progressive encephalopathy, microcephaly, seizures, central hypoventilation. There was similar history in the previous sibling. The patient’s blood lactate, ammonia, tandem mass spectrometry for amino acids and acyl carnitine were normal. He remained encephalopathic with progressive increase in need of respiratory support in spite of supportive treatment and metabolic cocktail consisting of riboflavin, pyridoxine, coenzyme Q and carnitine. This neonate had novel homozygous mutation, which results in MTHFR deficiency. In newborn with hypoventilation or recurrent apnoea with encephalopathy and microcephaly, MTHFR deficiency should be considered as a differential diagnosis. Mutation study helps in confirming diagnosis; however, extended newborn metabolic screening with homocysteine level could help in early diagnosis of these cases.

Relationship between Methylenetetrahydrofolate Reductase C677T Homozygous Mutation and Cerebral Small Vessel Disease Subtypes

Background: Neuroimaging detects cerebral small vessel disease (CSVD) subtypes, including infarction, asymptomatic lacunes, cerebral microbleeds, white matter hyperintensities (WMHs), and enlarged perivascular space. Methylenetetrahydrofolate reductase (MTHFR) plays an essential role in the metabolism of folic acid and homocysteine. The purpose of this study was to investigate the relationship between the MTHFR C677T mutation and CSVD subtypes.Methods: A total of 144 patients with acute ischemic stroke who visited the Korea University Guro Hospital between April 2020 and August 2020 were retrospectively reviewed. After excluding 24 patients, due to missing laboratory, clinical, or imaging information, a total of 120 patients were analyzed.Results: Among the 120 participants, 25% were included in the MTHFR C677T homozygous mutation group, which had significantly lower folic acid levels (6.24±4.21 ng/mL vs. 8.24±4.21 ng/mL, p=0.03) and higher total homocysteine levels (17.09±14.07 μmol/L vs. 9.65±3.19 μmol/L, p<0.01). Using multiple logistic regression analysis, the homozygous mutation (adjusted odds ratio [aOR]=4.29; 95% confidence interval [CI]=1.16–15.90) and age (aOR=1.06; 95% CI=1.01–1.11) were independently associated with moderate to severe WMHs. Additionally, moderate to severe WMHs were more frequent in the homozygous mutation group (86.7% vs. 66.7%, p=0.01). In a detailed analysis, the homozygous mutation group showed a significantly higher rate of moderate to severe periventricular WMH (PWMH) (86.7% vs. 65.6%, p<0.01).Conclusion: The MTHFR C677T homozygous mutation was positively correlated with moderate to severe PWMH subtypes of CSVD.

Polymorphism of methylenetetrahydrofolate reductase (MTHFR) folate metabolism gene and hyperhomocysteinemia in migraine

В обзоре обсуждается роль полиморфизма гена фолатного обмена метилентетрагидрофолат-редуктазы (MTHFR), ответственного за развитие гипергомоцистеинемии в патогенезе мигрени. Изложены общие данные о полиморфизме С677 гена фолатного цикла и метаболизме гомоцистеина. Представлен патогенетический механизм развития мигрени, связанный с провоспалительными, прокоагулянтными свойствами гомоцистеина, активацией процессов окислительного стресса, эндотелиальной дисфункцией и нейрогенным воспалением при повышении концентрации этой аминокислоты. Отражены перспективы и социальная значимость имплементации данных генетических исследований в клиническую практику, их роль в прогнозировании течения мигрени и оценке риска развития осложнений, а также коррекции фармакотерапевтических подходов. Методика. Для поиска данных в базах MEDLINE, SCOPUS и Web of Science использованы поисковые запросы: МТHFR, мигрень, патофизиология, гипергомоцистеинемия, таргетная терапия. The review discusses the role of polymorphism of the methylenetetrahydrofolate reductase (MTHFR) folate metabolism gene responsible for hyperhomocysteinemia in the pathogenesis of migraine. Data on the polymorphism of the folate cycle gene C677 and homocysteine metabolism are presented. The pathogenetic mechanism of migraine associated with proinflammatory, procoagulant properties of homocysteine and with the activation of oxidative stress, endothelial dysfunction, and neurogenic inflammation related with increased concentrations of homocysteine is described. Prospects and social significance of implementing data of genetic research into clinical practice are discussed. Included is the role of genetic research in predicting the course and complications of migraine, in assessment of risk for complications, and in pharmacotherapeutic approaches to migraine treatment. Methods. MEDLINE, SCOPUS and Web of Science databases were used to search for data: MTHFR, migraine, pathophysiology, hyperhomocysteinemia, targeted therapy

Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks

The 5-10-methylenetetrahydrofolate reductase (MTHFR) enzyme is vital for cellular homeostasis due to its key functions in the one-carbon cycle, which include methionine and folate metabolism and protein, DNA, and RNA synthesis. The enzyme is responsible for maintaining methionine and homocysteine (Hcy) balance to prevent cellular dysfunction. Polymorphisms in the MTHFR gene, especially C677T, have been associated with various diseases, including cardiovascular diseases (CVDs), cancer, inflammatory conditions, diabetes, and vascular disorders. The C677T MTHFR polymorphism is thought to be the most common cause of elevated Hcy levels, which is considered an independent risk factor for CVD. This polymorphism results in an amino acid change from alanine to valine, which prevents optimal functioning of the enzyme at temperatures above 37 °C. Many studies have been conducted to determine whether there is an association between the C677T polymorphism and increased risk for CVD. There is much evidence in favour of this association, while several studies have concluded that the polymorphism cannot be used to predict CVD development or progression. This review discusses current research regarding the C677T polymorphism and its relationship with CVD, inflammation, diabetes, and epigenetic regulation and compares the evidence provided for and against the association with CVD.

The 677C>T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice

Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimers disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants in MTHFR, notably 677C>T, are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR677C>T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr677C>T allele on the C57BL/6J background (Mthfr677C>T) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr677C>T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity as well as critical metabolites in the folate and methionine cycles are reduced in the Mthfr677C>T brain. Mice showed reduced tissue perfusion in numerous brain regions by PET/CT as well as significantly reduced vascular density and increased GFAP-expressing astrocytes in frontal cortex . Electron microscopy revealed cerebrovascular damage including endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment. Collectively, these data suggest critical perturbations to cerebrovascular function in Mthfr677C>T mice supporting its use as a model for preclinical studies of VCID.

A Case of Budd-Chiari Syndrome Associated with Erythrocytosis and Homozygous MTHFR C677T Mutation

An erythrocytosis describes an increased erythrocyte, subclassified into relative due to hemoconcentration or absolute by an increase in erythrocyte mass, defined as an increase in hemoglobin concentration and/or hematocrit in the peripheral blood above the sex-specific normal range. Budd-Chiari Syndrome (BCS) is related to an obstruction of the hepatic venous flow leading to occlusion of hepatic veins and their tributaries. Genetic and environmental factors can interact for risk determination of venous thromboembolism. The risk associated with SNP 677C>T and 1298A>C of the methylenetetrahydrofolate reductase (MTHFR), 1691G>A of the Factor V Leiden (FVL) and 20210G>A of the prothrombin (FII) genes were investigated in many studies involving thrombosis. This case report describes the clinical, hematological and biochemistry data about a 48-year-old woman diagnosed with PV and a BCS associated, also carrying 677C>T SNP in homozygosity. The patient started therapy with phlebotomy, hydroxyurea and oral anticoagulant. Currently, she presents a better clinical and laboratory condition with normalized values of hematological and platelet indices. This case report aims to contribute with evidence of related comorbidities and makes it possible to report that genetic factors are involved since the patient's mother had already been diagnosed with absolute erythrocytosis in 2016 at 78 years old. For this main result, we understand that it is clear that a family genetic study can reveal clinical modifying factors in these patients, as there are different clinical severities in the family. Furthermore, we believe in the need for a greater number of randomized clinical trials to add better evidence to complement an ideal therapeutic approach in these patients.