Methylenetetrahydrofolate Reductase Research Articles

Evolutionary history and biological adaptation of Han Chinese people on the Mongolian Plateau

Complex demographic processes and natural selection pressures are critical to resolving patterns of the molecular genetic basis of adaptive traits or complex diseases. Recent ancient genome data allow us to trace how key traits evolved in different human populations over time, connecting ancient population history with disease susceptibility in western Eurasians. To fill this gap in eastern Eurasians and provide deep insights into the evolutionary history of the population-specific genetic basis of complex biological traits, we explored the evolutionary basis of adaptive traits in one integrative modern and ancient genomic database, including 225 out of 5583 genomes first reported here. We comprehensively characterized the demographic history and biological adaptation of Han Chinese individuals on the Mongolian Plateau based on the allele frequency spectrum and haplotype-resolved fragments. We found strong genetic homogeneity among geographically different Han populations from Inner Mongolia (IMH). We reconstructed their admixture models and demographic events, revealing that IMH had a close genetic relationship with ancient millet farmers and obtained additional gene flow from Altaic-speaking populations. The enrichment of selected candidate genes suggested that essential metabolism-related genes promoted the rapid adaptation of eastern Eurasians to ancient environmental shifts and dietary changes during agricultural innovations. Evolutionary trajectory reconstruction of metabolism-related genes of methylenetetrahydrofolate reductase (MTHFR) and fatty acid desaturase 1 (FADS1) suggested that ancient dietary shifts during the Neolithic transition period promoted the differentiated metabolic rate of folate and fatty acid. We revealed the polygenicity of biological adaptation traits and the pleiotropy of adaptive genes, indicating that complex recent polygenic adaptations, genetic interactions, and genotype–phenotype correlations have contributed to the genetic architecture of complex traits in eastern Eurasians.

Interactions between folate metabolism-related nutrients and polymorphisms on colorectal cancer risk: a case-control study in the Basque country

Folate-mediated one-carbon metabolism (FOCM) plays an important role in colorectal carcinogenesis. Previous studies have assessed the role of folate-mediated one-carbon metabolism (FOCM)-related gene-diet interaction in the aetiology of colorectal cancer (CRC), however, the results remained inconclusive. Thus, this study aimed to investigate dietary factors and genetic variants related to FOCM, as well as potential nutrient-gene and nutrient-lifestyle interactions, on CRC risk. This observational study included 229 patients diagnosed with CRC and 229 age- and sex-matched subjects as controls from a population-based bowel cancer screening program. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95%CI) for CRC risk. A Bonferroni-corrected threshold of α = 0.005 was considered significant, and P values less than 0.05 were considered to be suggestive of an association. After Bonferroni correction, a high dietary intake of betaine was associated with a decreased risk of CRC in the adjusted model (OR, 95% CI: 0.21, 0.10–0.40, P < 0.001). Two SNPs, rs1476413 and rs17824591, exhibited significant gene-diet interactions with total choline ad vitamin B12 intakes, respectively, in adjusted models (total choline, tertile 3 vs. 1, OR, 95% CI: 0.25, 0.11–0.66, Pinteraction = 0.012; vitamin B12, tertile 2 vs. tertile 1, OR, 95% CI: 2.48, 1.04-5.00, Pinteraction = 0.003). These findings suggest that betaine intake and interactions between some dietary factors and variants in MTHFR and MTHFD1 genes have an influence on CRC risk in the population studied. If these results are confirmed, specific nutritional intervention strategies could be designed.

Navigating thrombotic terrain: unveiling a novel homocystinuria mutation associated with thrombophilia in a 16 year old

BackgroundThrombophilia is characterised by an abnormality of blood coagulation that increases thrombosis. Homocystinuria encompasses a group of disorders marked by increased levels of homocysteine and other amino acids detectable in the bloodstream and urine. Conversely, homocystinuria due to methylenetetrahydrofolatereductase (MTHFR) deficiency, a rarer disorder, stems from impaired folate metabolism due to deficient MTHFR enzyme.Case presentationA 16-year-old boy presented with walking difficulties, headaches, and thrombotic events, thrombophilia workup led to a diagnosis of homocystinuria due to a novel mutation in MTHFR gene. Anticoagulant therapy was initiated which showed clinical improvement, but financial constraints hindered follow-up.ConclusionsThis case highlights the complexities of diagnosing and treating paediatric thrombophilia, particularly in resource-limited settings. Notably, the identified homozygous autosomal recessive (AR) missense variation in the MTHFR gene (Exon 4—c582C>G) represents a novel mutation, suggesting the ongoing significance of genetic research in elucidating the underlying mechanisms of thrombotic disorders.

Impact of Thrombophilic Polymorphisms in Antenatal Women on Perinatal Health: A Single-Center Prospective Study.

Despite pregnancy's hypercoagulable state, the correlation between inherited thrombophilia and thrombotic adverse pregnancy outcomes remains uncertain. The objective of this study was to determine the prevalence of inherited thrombophilic polymorphisms among asymptomatic pregnant individuals and to examine their potential correlation with adverse perinatal outcomes. in this single-center prospective study, 105 healthy pregnant women were included. Genotyping was conducted for factor V Leiden (FVL), prothrombin gene mutation, methylenetetrahydrofolate reductase enzyme (MTHFR) C677T, MTHFR A1298C, and plasminogen activator inhibitor-1 (PAI-1), alongside the assessment of protein C (PC), protein S (PS), and antithrombin (AT) levels. The study analyzed the association between inherited thrombophilic polymorphisms and pregnancy complications linked to placental insufficiency, such as gestational hypertension (GH), preeclampsia (PE), intrauterine death (IUD), fetal growth restriction (FGR), and placental abruption. The prevalence of identifiable thrombophilic polymorphism mutations was 61.9% (95% confidence interval-CI 52.4-70.8%), with the most common single mutation being PAI-1 4G/5G (12/105, 11.4%, 95% CI 6.4-18.5). The most frequent combined mutation was heterozygosity for MTHFR C677T and PAI-1 (12/105, 11.4%, 95% CI 6.4-18.5). Notably, no FVL homozygous carriers or single homozygous and heterozygous carriers for prothrombin polymorphisms were found. Additionally, no deficiencies in PC and AT were detected among participants. Except for homozygosity for PAI-1, none of the studied polymorphisms demonstrated a significant association with pregnancy complications linked to placental insufficiency. The asymptomatic carriers of inherited thrombophilic polymorphisms do not have an increased risk of adverse perinatal outcomes.

COMBINATION OF TWO DIFFERENT C174T AND C235T OF THE ANGIOTENSINOGEN GENE MUTATION AND C677T METHYLENETETRAHYDROFOLATE REDUCTASE GENE MUTATION IN PATIENTS WITH CVD IN THE POPULATION OF AZERBAIJAN

We studied two mutations of C174T (Met174Tre) and C235T (Met235Tre) of the angiotensinogen gene and mutation C677T (Ala677Val) of the methylenetetrahydrofolate reductase gene, as well as their combinations among patients with cardiovascular diseases: coronary heart disease, myocardial infarction and hypertension, using a complex of modern molecular genetic diagnostic methods. A high frequency of these mutations has been established in the group of patients with severe forms of cardiovascular disorders. Homozygous and compound conditions were found in people with severe diseases. In particular, the heterozygous state of the mutation was found in people with moderate hypertension. It was also found that the presence of close blood relationship between the parents of patients with cardiovascular diseases increases the homozygotization of mutations of the genes AGT and MTGFR in probands. Consequently, such persons are susceptible to the disease or in other words, have an increased risk of developing diseases of the cardiovascular system. For the first time, the frequencies of these mutations in the Azerbaijani population have been determined, which are mostly consistent with the frequencies described in other populations of the world. The studied genetic markers are of interest as genes presumably associated with a wide range of cardiovascular diseases and can be used in further population and epidemiological studies. Therefore, the results of molecular genetic studies obtained by us in people with diseases of the cardiovascular system are of great practical importance. Timely prevention by detecting mutations of C174T, C235T of the AGT gene and C677T of the MTGFR gene in patients will allow doctors to carry out qualified treatment of cardiovascular diseases

Discovery of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency in Individuals With Common Psychiatric Comorbidities: A Retrospective Case Review.

A retrospective analysis was conducted of a data set collected in an outpatient behavioral health clinic to assess medication metabolism and methylenetetrahydrofolate reductase (MTHFR) and to see if there was a correlation with certain diagnoses and/or gender. The outpatient routine completed genetic testing on their patients and the test results were later collected through a third-party company, which completed the pharmacogenomic test analyzing genetic variations in DNA, medication metabolism, and an MTHFR deficiency. This study reviewed 186 patients seen in an outpatient setting who were tested for an MTHFR deficiency and compared their psychiatric diagnoses and the number of failed medication attempts. Of those 186 patients, 77 had normal MTHFR enzyme function, 85 were found to have a moderate MTHFR deficiency, and 24 had a severe MTHFR deficiency. Those with a severe MTHFR deficiency had a higher number of medication trials as compared to those without the deficiency and there were overall more patients with a moderate MTHFR deficiency in this data set. Currently, MTHFR deficiency is not commonly tested due to lack of insurance coverage and provider knowledge, and due to the cost of the test itself. Thus, the diagnosis can often be missed.

Exploring the impact of MiR-92a-3p on FOLFOX chemoresistance biomarker genes in colon cancer cell lines.

Introduction: One of the primary obstacles faced by individuals with advanced colorectal cancer (CRC) is the potential development of acquired chemoresistance as the disease advances. Studies have indicated a direct association between elevated levels of miR-92a-3p and the progression, metastasis, and chemoresistance observed in CRC. We proposed that miR-92a-3p impairs FOLFOX (fluorouracil/oxaliplatin) chemotherapy response by upregulating the expression of chemoresistance biomarker genes through the activation of β-catenin and epithelial-mesenchymal transition (EMT). These FOLFOX biomarker genes include the pyrimidine biosynthesis pathway genes dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), and the genes encoding the DNA repair complexes subunits ERCC1 and ERCC2, and XRCC1. Methods: To assess this, we transfected SW480 and SW620 colon cancer cell lines with miR-92a-3p mimics and then quantified the expression of DPYD, TYMS, MTHFR, ERCC1, ERCC2, and XRCC1, the expression of EMT markers and transcription factors, and activation of β-catenin. Results and discussion: Our results reveal that miR-92a-3p does not affect the expression of DPYD, TYMS, MTHFR, and ERCC1. Furthermore, even though miR-92a-3p affects ERCC2, XRCC1, E-cadherin, and β-catenin mRNA levels, it has no influence on their protein expression. Conclusion: We found that miR-92a-3p does not upregulate the expression of proteins of DNA-repair pathways and other genes involved in FOLFOX chemotherapy resistance.

MTHFRC 677T Gene Polymorphism and Homocysteine in North China Patients with Varicocele

To investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, homocysteine, and male infertility with varicocele in North China. One Hundred infertile males with varicocele (VC; grade II-III, VC group) and 100 healthy males with normal semen parameters and no varicocele (NC group) were recruited for PCR microarray, blood and semen testing. Compared with the CC genotype in the NC group, the TT genotype in the NC group and the CC genotype in the VC group showed no significant changes in sperm motility (P=0.191; P=0.130), sperm density (P=0.591, P=0.643), plasma homocysteine level (P=0.511; P=0.677), and seminal plasma MDA (P=0.752; P=0.451). In contrast, VC patients with the TT genotype had higher plasma homocysteine level and seminal plasma MDA levels (P &lt;0.001), lower partial pressure of oxygen in seminal pulse (PO2; P &lt;0.001) and poorer sperm quality (P &lt;0.001), as compared with the CC genotype. This suggests that MTHFR C677C&gt;T may not be a risk factor for male Varicocele in North China. However, this may affect the oxidative stress associated with homocysteine expression, which in turn affects semen parameters in VC patients. Larger studies are needed to validate our findings.

Skin disorders in women with poor obstetric history: MTHFR polymorphisms and importance of preconceptional counseling

Objectives This study focused on the link between skin disorders and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. Methods Study cases were taken from a pre-conceptional care program where patients with poor obstetric history were evaluated in terms of systemic disorders including skin diseases. This retrospective cohort (n = 472) consisted of 110 (23.3%) and 362 (76.7%) women with or without skin disorders, respectively. For ease of analysis, the history of skin diseases was classified into seven categories: (1) acne/rosacea/other acneiform disorders; (2) fungal disease; (3) pruritis/xerosis; (4) psoriasis vulgaris; (5) acrochordons and other benign skin growths; (6) urticaria/dermatitis; and (7) viral diseases. Results In this retrospective cohort of 472 women, we explored the impact of MTHFR A1298C and C677T polymorphisms on skin disorders. Despite similar allelic frequencies, our findings revealed a statistically significant association between the presence of MTHFR polymorphisms and skin disorders (p = .027). Subgroup analysis indicated significantly higher rates of MTHFR polymorphisms in patients with psoriasis vulgaris (p = .033) and acrochordons (p = .030), highlighting their potential relevance in specific skin disorder subtypes. Conclusions The increased prevalence of psoriasis and acrochordons among women with MTHFR deficiency underscores the complex relationship between genetic factors and dermatological health. Our findings emphasized the critical role of MTHFR polymorphisms not only in poor obstetric history but also as significant contributors to skin disorders. This dual association highlights the importance of comprehensive preconception counseling, especially customized for women affected by skin disorders.

Genetic variants of folate metabolism and the risk of multiple sclerosis

ABSTRACT Background and aims Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) of unknown cause. Alterations in one-carbon metabolism have impact in the pathophysiology by genetic susceptibility to MS and increased the risk of MS. The aim of this study was to investigate the contribution of the gene polymorphism on Methylenetetrahydrofolate Reductase (MTHFR), Methionine Synthase Reductase (MTRR), Methionine Synthase (MTR) enzymes and of the essential factors (homocysteine, Hcy; cysteine, Cys; and vitamin B12, VitB12) in folate metabolism. Methods Eligible MS patients (n = 147) and health controls (n = 127) were participated. The gene polymorphisms were analyzed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and the levels of plasma Hcy, Cys and VitB12 were measured by Enzyme Linked Immunuabsorbent Assay (ELISA). Results and conclusion Our results showed that the levels of Hcy and VitB12 were lower and the levels of Cys were higher in MS compared to controls. The observation of high Cys values in all 3 gene polymorphisms suggests that the transsulfiration pathway of Hcy is directed towards Cys formation since the methionine synthesis pathway does not work. We could not find any association with all gene polymorphisms with the risk of MS. The T allele of MTHFR C677T and G allele of MTR A2756G are risk factors for serum Cys level on MS. As for MTR A2756G, serum vitB12 was observed in MS patients with G allele.

Association between polymorphism in the MTHFR gene and encephaloduroarteriosynangiosis-induced collateral circulation formation.

This study aimed to investigate whether high homocysteine (Hcy) levels associated with the MTHFR gene influence the formation of the collateral vascular network in patients with moyamoya disease (MMD) after encephaloduroarteriosynangiosis (EDAS) by influencing the number of endothelial progenitor cells (EPCs) in peripheral blood. A total of 118 Chinese patients with bilateral primary MMD were prospectively included. Blood samples were collected from the anterior cubital vein before surgery, and MTHFR rs9651118 was genotyped using high-throughput mass spectrometry to determine the genotype of the test specimen. Serum Hcy and EPC levels were measured, the latter with flow cytometry. Digital subtraction angiography was performed 6 months after EDAS, and the formation of collateral circulation was evaluated using the Matsushima grade system. The correlations between MTHFR rs9651118 genotype, Hcy and EPC levels, and Matsushima grade were compared. Among the 118 patients, 53 had the TT genotype (wild type) of MTHFR rs9651118, 33 TC genotype (heterozygous mutation), and 32 CC genotype (homozygous mutation). The mean ± SD Hcy level was 13.4 ± 9.5 μmol/L in TT patients, 9.8 ± 3.2 μmol/L in TC patients, and 8.9 ± 2.9 μmol/L in CC patients (p < 0.001). The level of EPCs in the venous blood of TT patients was 0.039% ± 0.016%, that of TC patients 0.088% ± 0.061%, and that of CC patients 0.103% ± 0.062% (p < 0.001). When the rs9651118 gene locus was mutated, Matsushima grade was better (p < 0.001) but there was no difference between heterozygous and homozygous mutations. The results suggest that the MTHFR rs9651118 polymorphism is a good biomarker for collateral vascular network formation after EDAS in MMD patients.

Body mass index, lipid profile, and endothelial dysfunction gene polymorphism in women with early-onset and late-onset preeclampsia

The aim: to investigate and analyze clinical parameters, laboratory biomarkers of lipid metabolism and endothelial dysfunction gene polymorphisms in early-onset and late-onset preeclampsia and to identify potential risk factor(s) for the development of early-onset preeclampsia. Materials and methods: a prospective case-control study included 133 women in the second half of pregnancy, including 46 with early-onset (EOP) and 87 with late-onset preeclampsia (LOP) and 34 conditionally healthy pregnant women with an uncomplicated obstetric history and no risk factors for preeclampsia. Concentrations of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides in blood plasma were determined. Genetic polymorphisms of endothelial dysfunction (192 Q→R PON-1, 677 C→ T MTHFR) were studied using allele-specific polymerase chain reaction. Results: Early-onset preeclampsia is associated with an increased relative risk: preterm delivery by 2.08 times (95 % CI 1.48-2.93), operative delivery by 2.2 times (95 % CI 1.46-3.33), early operative delivery by 2.9 times (95 % CI 1.5-5.5), fetal distress during delivery by 3.78 times (95 % CI 1.2-11.9), a low score on the Apgar scale on the 1st minute, less than 6 points, by 2.59 times (95 % CI 1.84-3.66), on the 5th minute – 5.04 times (95 % CI 1.41-18.11), Grade III prematurity – 13.24 times (95 % CI 3.14-55.78) compared to women with late-onset preeclampsia. The study found that overweight was more often observed in patients with EOP (34.8 %) than in those with normal pregnancy (15.9 %) (p=0.02; OR=2.8; 95 % CI 1.03-7.7), obesity (BMI &gt; 30 kg/m2) was more often recorded in those with LOP (33.33 %) than in the control group (3 (6.8 %)) (p=0.02; OR=6.8; 95 % CI 1.9-23.9). Patients in both groups with preeclampsia showed signs of dyslipidemia, but its significance in the development of early-onset or late-onset preeclampsia has not been separately proven. The study found that the number of carriers of MTHFR 677 TT in the group with EOP prevailed over the indicator of C group where there were no carriers of the pathological homozygote 677TT (p&lt;0.05, OR= 20.73 95 % CI 1.16-371.28), and the T allele in the EOP group occurs 1.78 times more often than in the LOP group (p&lt;0.05, OR=2.22; 95 % CI 1.26-3.88) and 2.43 times more often than in the C group (P&lt;0.05, or= 3.15; 95 % CI 1.54-6.45). Conclusions: Factors of early onset of PE include pre-pregnancy, overweight, first pregnancy, a history of preeclampsia, and carrier of the 677T allele of the MTHFR gene

Genes linked to obesity-related infertility: bridging the knowledge gap

Genetic factors play a pivotal role in the complex relationship between obesity and infertility. This article delves into the genetics of obesity-related infertility, focusing on the essential genes and mechanisms in both sexes. We explored infertility factors in obese females, focusing on polycystic ovary syndrome (PCOS) and the influence of genes like insulin receptor (INSR), androgen receptor (AR), and follicle-stimulating hormone receptor (FSHR). Epigenetic changes are believed to contribute to PCOS-related infertility. The impact of adipokines and inflammation on obesity-related infertility has been discussed, with genes such as fat mass and obesity (FTO) and melanocortin-4-receptor (MC4R) playing significant roles. Genetic factors affecting sperm quality and function, including nuclear receptor subfamily 3 group C member 1 (NR3C1) and methylenetetrahydrofolate reductase (MTHFR), have been investigated in obesity-related infertility in males. Hormonal dysregulation influenced by genetic markers, such as leptin receptor (LEPR), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), was also examined. Genetic factors play a vital role in obesity-related infertility in both sexes. Genes involved in metabolism, hormonal regulation, and inflammation contribute to the complex association between obesity and infertility. Epigenetic changes further complicate the relationship. Understanding these genetic mechanisms is essential to address obesity-related infertility and develop personalized interventions.

The Influence of MTHFR C677T Variants on Neuropathy Risk Among T2dm Patients Receiving Monotherapy Metformin

Neuropathy is the most common microvascular complication among type 2 diabetes mellitus (T2DM). Metformin consumption increases neuropathy risk. The Methylenetetrahydrofolate reductase (MTHFR) enzyme has confirmed its role in neuropathy. Metformin and MTHFR could decrease folate and induce hyperhomoscysteine. One of the common variants of the MTHFR gene is C677T and its located in the exon area. This study aimed to observe the association between variant C677T in the MTHFR gene and the risk of neuropathy among newly diagnosed T2DM patients with naive metformin. This cross-sectional study recruited 103 patients. The neuropathy risk was examined according to medical judgment through Neuropathy Symptom Score (NSS) and Neuropathy Disability Score (NDS) criteria. Genotyping C677T was performed using PCR-RFLP. This study found only one patient has a homozygote mutant, but more than 50% of patients were detected with allele mutants. There were no statistical differences in patient characteristics between CC and CT genotypes (p&gt;0.05). Association between C677T and neuropathy risk was not significant statistically, either in the genotype model (p=0.97), allele model (p=0.82), and dominant model (p=0.91). There was still no significant association after adjusting for several confounding factors. We conclude that C677T in our population did not influence neuropathy risk. More specific criteria and laboratory parameters indicated neuropathy should be examined in the future study.&#x0D; Keywords: MTHFR, neuropathy, metformin, and T2DM

Analysis of 9 patients with adolescence-onset methylenetetrahydrofolate reductase deficiency

Objective: To explore the diagnosis and treatment of adolescence-onset methylenetetrahydrofolate reductase (MTHFR) deficiency. Methods: This was a retrospective case study. Nine patients with adolescence-onset MTHFR deficiency were diagnosed at Peking University First Hospital from January 2016 to December 2022, and followed up for more than 1 year. Their general information, clinical manifestations, laboratory tests, cranial images, MTHFR gene variants, diagnosis, treatment, and outcome were analyzed retrospectively. Results: The 9 patients came from 8 families. They had symptoms at age of 8.0 years to 17.0 years and diagnosed at 9.0 years to 17.5 years. Eight were male and 1 was female. Two patients were brothers, the elder brother developed abnormal gait at 17.0 years; and the younger brother was then diagnosed at 15.0 years of age and treated at the asymptomatic stage, who was 18.0 years old with normal condition during this study. The main manifestations of the 8 symptomatic patients included progressive dyskinesia and spastic paralysis of the lower limbs, with or without intellectual decline, cognitive impairment and behavioral abnormalities. Totally, 15 variants of MTHFR gene were identified in the 9 patients, including 8 novel variants. Five patients had brain image abnormalities. Increased plasma total homocysteine level (65-221 μmol/L) was found in all patients, and decreased to 20-70 μmol/L after treatment with betaine and calcium folinate. Besides, the 8 symptomatic patients had their behavior and cognitive problems significantly improved, with a legacy of lower limb motor disorders. Conclusions: Late-onset MTHFR deficiency can occur in adolescence. The diagnosis is usually delayed because of non-specific clinical symptoms. The test of blood total homocysteine could be used as a selective screening test. Eight novel varients of MTHFR gene were identified. Timely treatment can improve clinical condition significantly, and pre-symptomatic treatment may prevent brain damage.

Prevalence of MTHFR Polymorphisms in Patients With Hypermobile Ehlers-Danlos Syndrome and Hypermobile Spectrum Disorders in a US Hypermobility Clinic.

Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are characterized by joint hypermobility, joint subluxations and dislocations, hyperextensible skin, and chronic and progressive multiorgan comorbidities. Diagnosing hEDS and HSD is difficult because of variable phenotypes and unknown genetic etiology. In our clinic, we observed many patients with hEDS and HSD with a high serum level of unmetabolized folate, which suggests that hypermobility may be linked to methylenetetrahydrofolate reductase (MTHFR)-mediated folate metabolism. The present study aims to examine the prevalence of MTHFR polymorphisms, C677T and A1298C, among patients with hEDS and HSD. Clinical and demographic information of patients visiting our hypermobility clinic from January 2023 to July 2023 were retrospectively reviewed. Continuous variables were reported as mean ± SD and range, whereas categorical variables were reported as total count and percentage. Among 157 patients, 93% of patients were female patients, 52.2% were diagnosed with hEDS, and 47.8% were diagnosed with HSD. Interestingly, 85% of the patients had MTHFR C677T and/or A1298C polymorphisms in heterozygous or homozygous state. MTHFR 677CT/TT genotype was present in 52.9% of cases, and 49.7% of patients had 1298AC/CC genotype. In addition,14% of patients with hypermobility exhibited MTHFR 677TT genotype, 10.2% showed 1298CC genotype, and 17.2% displayed combined heterozygosity, collectively representing 41.4% hypermobile patients with two copies of MTHFR variant alleles. There is a high prevalence of MTHFR polymorphisms among patients with hypermobility, which supports the hypothesis that hypermobility may be dependent on folate status.

Risk Factors of Thrombophilia-Related Mutations for Early and Late Pregnancy Loss.

Background and Objectives: This retrospective cohort study investigates the role of genetic thrombophilia in pregnant women experiencing early pregnancy loss compared to those with late pregnancy loss. Materials and Methods: Participants were categorized into early and late pregnancy loss groups based on gestational age. A total of 156 patients were included, out of which 103 had early-trimester pregnancy losses and 96 had multiple miscarriages. Results: The study revealed a synergistic effect of Factor V Leiden (FVL G1691A) and Methylenetetrahydrofolate Reductase (MTHFR C677T) mutations (coefficient 3.42). Prothrombin (PT) G20210A and β-Fibrinogen 455 G>A mutations exhibited a significant interaction (coefficient 1.98). Additionally, MTHFR A1298C and Plasminogen Activator Inhibitor-1 (PAI-1 4G/5G) mutations showed a significant interaction (coefficient 1.65). FVL G1691A and Endothelial Protein C Receptor (EPCR) allele A1/A2 mutations also demonstrated a significant association (coefficient 2.10). Lastly, MTHFR C677T and Glycoprotein IIb/IIIa T1565C mutations interacted significantly (coefficient 1.77). Risk factor analysis identified several mutations associated with early pregnancy loss, including PAI-1 4G/5G homozygous (OR 3.01), FVL G1691A heterozygous (OR 1.85), and MTHFR A1298C heterozygous (OR 1.55). Both homozygous and heterozygous MTHFR C677T mutations were significant risk factors (OR 2.38; OR 2.06), as was PT G20210A homozygous mutation (OR 1.92). The PAI-1 4G/4G homozygous variant posed a risk (OR 1.36). Late pregnancy loss was associated with MTHFR A1298C homozygous mutation (OR 3.79), β-Fibrinogen 455 G>A heterozygous mutation (OR 2.20), and MTHFR A1298C heterozygous mutation (OR 2.65). Factor XIII G1002T heterozygous mutation (OR 1.18) and PAI-1 4G/5G homozygous mutation (OR 2.85) were also significant risk factors. EPCR allele A1/A2 (OR 1.60) and A2/A3 (OR 1.73) mutations were identified as significant risk factors for late pregnancy loss. Furthermore, FVL G1691A homozygous mutation, PT G20210A homozygous mutation, MTHFR C677T heterozygous mutation, MTHFR A1298C heterozygous mutation, and EPCR allele A1/A2 were identified as significant risk factors for multiple miscarriage. Conclusions: This study highlights significant interactions and risk factors related to genetic thrombophilia mutations in different types of pregnancy loss, contributing valuable insights for miscarriage management guidelines.

Homozygous MTHFR C677T carriers develop idiopathic portal vein thrombosis 20 years earlier than wild type.

The aim of this study was to evaluate the impact of methylene tetrahydrofolate reductase (MTHFR) rs1801133 (C→T667 transition) on age at first idiopathic portal vein thrombosis (PVT) and to identify clinical and/or laboratory variables influencing age at first PVT, including plasma homocysteine and the prothrombin rs1799963 PT (G→A transition at position 20210) (PT) mutation. A retrospective cross-sectional cohort, including 15 MTHFR TT, 32 MTHFR TC and 22 MTHFR CC idiopathic PVT participants contributing demographics, age at PVT, plasma concentrations of homocysteine and of natural anticoagulants. MTHFR TT carriers presented with a lower age at PVT than heterozygous or wild-type genotypes (31 ± 8 vs. 48 ± 15 vs. 52 ± 13 years, P = 0.001) and were more likely to have a plasma HC concentration above the cut-off (73.3 vs. 32 vs. 50%, P = 0.04). MTHFR TT and protein C predicted age at PVT ( P < 0.0001 and P = 0.06); MTHFR TT predicted plasma homocysteine ( P = 0.05). In the MTHFR TT group, plasma homocysteine inversely related to protein C ( P = 0.03). Plasma homocysteine predicted the extent of PVT ( P = 0.03). Compound MTHFR TT + PT GA did not lower age at first PVT compared to MTHFR TT alone (35 ± 9 vs. 30 ± 8 years). MTHFR TT is associated with a 20-year earlier PVT presentation than heterozygous and wild-type MTHFR genotypes. The inverse relation between plasma homocysteine and protein C contributes to the prematurity of PVT in the MTHFR TT group, whereas plasma homocysteine contributes to the extent of PVT. The recent exclusion of MTHFR genotyping from the thrombophilia screen needs revisiting in this setting.

Thrombophilia genetic mutations and their relation to disease severity among patients with COVID-19.

Patients with COVID-19 infection appear to develop virus-induced hypercoagulability resulting in numerous thrombotic events. The aim of the present study was to determine the relationship between the thrombophilia genes mutations (prothrombin G20210A, factor V Leiden, and methyltetrahydrofolate reductase (MTHFR)) and the severity of COVID-19 patients. Prospective cross-sectional study. One hundred and forty patients (80 adults and 60 children) were included in the current study. They were divided into the severe COVID-19 group and the mild COVID-19 group, with each group comprising 40 adults and 30 children. The patients were assessed for FV R506Q, FV R2H1299R, MTHFR A1298C, MTHFR C677T, and prothrombin gene G20210A polymorphisms. CBC, D-dimer, renal and liver function tests, hs-CRP, ferritin, and LDH were also assessed. Thrombotic events were clinically and radiologically documented. Severe COVID-19 cases were significantly more frequent to have a heterozygous mutation for all the studied genes compared to mild COVID-19 cases (p<0.05 for all). Being mutant to gene FV R506Q carried the highest risk of developing a severe disease course (p<0.0001). Patients with abnormally high D-dimer levels were significantly more frequent to be heterozygous for FV R506Q, FV R2H1299R, and prothrombin gene G20210A (p = 0.006, 0.007, and 0.02, respectively). We concluded that there is an evident relationship between severe COVID-19 and inherited thrombophilia. In the current study, FV R506Q gene mutation carried the highest risk of developing a severe COVID-19 disease course.

Effect of L-Methylfolate Supplementation on Sleep for Patients with Reduced Methylenetetrahydrofolate Reductase Activity

Introduction Clinicians have limited options outside controlled substances to address sleep disturbance, which left untreated can negatively affect patient outcomes in cardiovascular health, mental health, immunologic function, and more. For some, genetic factors may influence sleep disturbances. L-methylfolate, the active form of folate, plays a critical role in regulation of monoamine neurotransmitters known to have significant impact on sleep regulation: dopamine, serotonin, norepinephrine. Single nucleotide polymorphisms of the enzyme methylene-tetrahydrofolate-reductase are common and can impact monoamine production. The goal of this study was to evaluate effects of L-methylfolate supplementation on sleep in a cohort with reduced methylene tetrahydrofolate reductase (MTHFR) activity. Methods A retrospective cohort of patients being treated with L-methylfolate in a concierge medical clinic setting was studied. Patients presenting with sleep complaints were evaluated using the Patient-Reported Outcomes Measurement Information System at baseline. Patients with known MTHFR polymorphisms at either C667T and/or A1298C were recommended 5 mg of L-methylfolate daily and were reevaluated at 2 wks, at 4 wks, and at 8 wks of supplementation. Statistical comparisons were made utilizing ANOVA and T-test comparisons. Results Ten were included in the final cohort: six male and four female, average age 43 ± 16 years. Beginning at wk 2, average sleep disturbance improved significantly by −6.94 points (p = 0.005) and by 8 wks, all patients had improvement with a −14.34 change in disturbance from baseline (p = 0.001). Conclusion Improvement in sleep disturbance was seen in both low and intermediate function phenotypes. L-methylfolate may be useful for improving sleep in patients with MTHFR polymorphism.