Homocysteine, folate, methylene tetrahydrofolate reductase genotype and vascular morbidity in diabetic subjects

2002 ◽  
Vol 102 (6) ◽  
pp. 631-637 ◽  
Author(s):  
Joey M. KAYE ◽  
Kim G. STANTON ◽  
Vincent J. MCCANN ◽  
Samuel D. VASIKARAN ◽  
Valerie BURKE ◽  
...  
Keyword(s):  
Vascular Disease ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr Gene ◽  
Plasma Homocysteine ◽  
Serum Folate ◽  
Type I ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Mthfr Genotype ◽  
Erythrocyte Folate

In the present study, the determinants of fasting plasma homocysteine in diabetic subjects were examined; whether plasma homocysteine and vascular disease are related and the influence of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene on serum and erythrocyte folate, plasma homocysteine and vascular disease. Diabetic clinic subjects (Type I, n = 354; Type II, n = 392) were recalled for a cross-sectional survey. Standard methods were used to measure biochemical variables and to characterize vascular disease and MTHFR genotype. Plasma homocysteine was significantly and directly related to age, male sex and serum urea, and inversely related to serum folate and vitamin B12, independently in stepwise regression. When corrected for age and sex, homocysteine was significantly related to hard end points of coronary artery disease and stroke (each P<0.01), remaining significant when additionally adjusted for serum folate (P = 0.043 and P = 0.019 respectively). Serum folate was not clearly related to these events, although there was a trend to associate with the lower quintile of serum folate. The MTHFR genotype was not a determinant of plasma homocysteine, even in those in the lowest quintile of serum folate, nor of vascular disease. TT homozygosity at residue 677 was associated with elevation of total erythrocyte folate compared with both other genotypes (P<0.0001), almost certainly due to the diversion of 5,10-methylenetetrahydrofolate into derivates subsequent to the partial metabolic block that results from the MTHFR enzyme defect. In conclusion, in this clinic cohort of people with diabetes, vascular disease is related to plasma homocysteine, which is correlated with serum folate. The MTHFR genotype does not significantly influence either plasma homocysteine or vascular disease, despite it being a determinant of erythrocyte folate, which reflects its effect on folate metabolism.

scholarly journals Folate status of Ghanaian populations in London and Accra

2009 ◽  
Vol 103 (3) ◽  
pp. 437-444 ◽  
Author(s):  
Matilda Owusu ◽  
Jane Thomas ◽  
Edwin Wiredu ◽  
Maria Pufulete
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Plasma Homocysteine ◽  
Folate Intake ◽  
Serum Folate ◽  
Cross Sectional ◽  
Folate Status ◽  
Supplement Use ◽  
Increased Risk ◽  
Erythrocyte Folate ◽  
The Uk

Migration to the UK is associated with higher incidence of stroke in African populations. A low folate status has been associated with increased risk of stroke, likely to be mediated through raised plasma homocysteine concentrations. We conducted a cross-sectional study to compare blood folate and homocysteine concentrations in eighty healthy Ghanaian migrants living in London matched by sex, age and occupation to 160 individuals from an urban population in Accra, Ghana. Folate intake was determined using three 24 h recalls. Fasting blood samples were collected for the determination of serum and erythrocyte folate and plasma homocysteine concentrations and the methylenetetrahydrofolate reductase (MTHFR) 677C → T polymorphism. Reported mean folate intake was 20 % lower in London compared with Accra (P < 0·001). However, serum folate was 44 % higher, erythrocyte folate 30 % higher and plasma homocysteine was 26 % lower in subjects from London compared with those from Accra (P < 0·001). These differences persisted after adjusting for confounders including the MTHFR 677C → T mutation, which was rare in both populations. Although there were no associations between dietary folate intake and blood folates (P>0·05), folic acid supplement use, which was more prevalent in London than Accra (25 and 10 %, respectively,P = 0·004) was associated with erythrocyte folate in both populations (P < 0·01). The main predictors of plasma homocysteine concentrations were erythrocyte folate and male sex (P < 0·001). Findings from the present study suggest that migration from Ghana to the UK results in improvement of biomarkers of folate status despite the fact that reported dietary intake of folate was apparently lower in subjects from London.

scholarly journals Riboflavin as a Determinant of Plasma Total Homocysteine: Effect Modification by the Methylenetetrahydrofolate Reductase C677T Polymorphism

2000 ◽  
Vol 46 (8) ◽  
pp. 1065-1071 ◽  
Author(s):  
Steinar Hustad ◽  
Per Magne Ueland ◽  
Stein Emil Vollset ◽  
Ying Zhang ◽  
Anne Lise Bjørke-Monsen ◽  
...  
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Multiple Linear Regression Model ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Serum Folate ◽  
Flavin Mononucleotide ◽  
Cross Sectional ◽  
Plasma Thcy ◽  
Total Homocysteine ◽  
Plasma Total Homocysteine

Abstract Background: Plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease. tHcy concentrations are partly determined by folate, cobalamin, and vitamin B6 status, and methylenetetrahydrofolate reductase (MTHFR) and other flavoenzymes are important for the biotransformation of these vitamins. This motivates the investigation of the possible relationship between riboflavin status and tHcy. Methods: The study had a cross-sectional design and included 423 healthy blood donors, ages 19–69 years. We determined plasma tHcy, serum folate, serum cobalamin, serum creatinine, and MTHFR C677T genotype. In addition, we measured riboflavin and its two coenzyme forms, flavin mononucleotide and flavin adenine dinucleotide, in EDTA plasma by capillary electrophoresis and laser-induced fluorescence detection. Results: Riboflavin determined tHcy independently in a multiple linear regression model with adjustment for sex, age, folate, cobalamin, creatinine, and MTHFR genotype (P = 0.008). tHcy was 1.4 μmol/L higher in the lowest compared with the highest riboflavin quartile. The riboflavin-tHcy relationship was modified by genotype (P = 0.004) and was essentially confined to subjects with the C677T transition of the MTHFR gene. Conclusions: Plasma riboflavin is an independent determinant of plasma tHcy. Studies on deficient populations are needed to evaluate the utility of riboflavin supplementation in hyperhomocysteinemia.

scholarly journals Effects of Periconceptional Multivitamin Supplementation on Folate and Homocysteine Levels Depending on Genetic Variants of Methyltetrahydrofolate Reductase in Infertile Japanese Women

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1381
Author(s):  
Keiji Kuroda ◽  
Takashi Horikawa ◽  
Yoko Gekka ◽  
Azusa Moriyama ◽  
Kazuki Nakao ◽  
...  
Keyword(s):  
Folic Acid ◽  
Methylenetetrahydrofolate Reductase ◽  
Homocysteine Level ◽  
Folic Acid Supplementation ◽  
Serum Folate ◽  
Folate Level ◽  
Multivitamin Supplementation ◽  
Mthfr Polymorphisms ◽  
Mthfr Genotype ◽  
Multivitamin Supplements

Methylenetetrahydrofolate reductase (MTHFR) has various polymorphisms, and the effects of periconceptional folic acid supplementation for decreasing neural tube defects (NTDs) risk differ depending on the genotypes. This study analyzed the effectiveness of multivitamin supplementation on folate insufficiency and hyperhomocysteinemia, depending on MTHFR polymorphisms. Of 205 women, 72 (35.1%), 100 (48.8%) and 33 (16.1%) had MTHFR CC, CT and TT, respectively. Serum folate and homocysteine levels in women with homozygous mutant TT were significantly lower and higher, respectively, than those in women with CC and CT. In 54 women (26.3% of all women) with a risk of NTDs, multivitamin supplementation containing folic acid and vitamin D for one month increased folate level (5.8 ± 0.9 to 19.2 ± 4.0 ng/mL, p < 0.0001) and decreased the homocysteine level (8.2 ± 3.1 to 5.8 ± 0.8 nmol/mL, p < 0.0001) to minimize the risk of NTDs in all women, regardless of MTHFR genotype. Regardless of MTHFR genotype, multivitamin supplements could control folate and homocysteine levels. Tests for folate and homocysteine levels and optimal multivitamin supplementation in women with risk of NTDs one month or more before pregnancy should be recommended to women who are planning a pregnancy.

scholarly journals 2020 Update to Spinal Muscular Atrophy Management in Saudi Arabia

2021 ◽  
Vol 9 ◽  
Author(s):  
Fahad A. Bashiri ◽  
Mohamad-Hani Temsah ◽  
Khalid Hundallah ◽  
Fahad Alsohime ◽  
Yazed AlRuthia
Keyword(s):  
Gene Therapy ◽  
Saudi Arabia ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Management Strategies ◽  
Annual Conference ◽  
Type I ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Society Annual

Novel therapeutic strategies have shown some promise in treating spinal muscular atrophy (SMA). However, the outcomes and acceptance of these new strategies are yet to be explored. We aimed to investigate physicians' opinions and perceptions toward management strategies of SMA across Saudi Arabia. This is a cross-sectional survey using a self-administered, structured questionnaire sent to physicians who care for SMA patients during the Saudi Pediatric Neurology Society annual conference. A total of 72 clinicians of different neurological subspecialties were included. 48.6% prescribed nusinersen to their patients, with 39% of them having patients started on nusinersen. Though, 8.3% prescribed onasemnogene abeparvovec for 1–3 patients, while none of their patients started on the treatment. 64.3% stated that the only treatment available for SMA in their settings is supportive care. Around 69.4% described having a moderate to high knowledge on SMA gene therapy, and 79.2% would recommend it. 48.6% confirmed they would prescribe gene therapy at the age of 6 months, and 78.3% would prescribe it for type-I SMA. Pediatric neurologists are receptive to novel and innovative therapies for SMA in Saudi Arabia. However, the high treatment acquisition cost, strict regulations, logistical issues, and budget constraints delay their adoption and implementation.

Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1

2019 ◽  
Vol 32 (9) ◽  
pp. 959-967 ◽  
Author(s):  
Jaya Sujatha Gopal-Kothandapani ◽  
Arpan B. Doshi ◽  
Kath Smith ◽  
Martin Christian ◽  
Talat Mushtaq ◽  
...  
Keyword(s):  
Clinical Presentation ◽  
Phenotypic Diversity ◽  
Novel Mutation ◽  
British Society ◽  
Type I ◽  
Missense Mutations ◽  
Cross Sectional Survey ◽  
Marked Rise ◽  
Cross Sectional ◽  
Serum Aldosterone

Abstract Background Type I pseudohypoaldosteronism (PHA1) is a rare condition characterised by profound salt wasting, hyperkalaemia and metabolic acidosis due to renal tubular resistance to aldosterone (PHA1a) or defective sodium epithelial channels (PHA1b or systemic PHA). Our aim was to review the clinical presentation related to the genotype in patients with PHA1. Methods A questionnaire-based cross-sectional survey was undertaken through the British Society of Paediatric Endocrinology and Diabetes (BSPED) examining the clinical presentation and management of patients with genetically confirmed PHA1. We also reviewed previously reported patients where genotypic and phenotypic information were reported. Results Genetic confirmation was made in 12 patients with PHA1; four had PHA1a, including one novel mutation in NR3C2; eight had PHA1b, including three with novel mutations in SCNN1A and one novel mutation in SCNN1B. It was impossible to differentiate between types of PHA1 from early clinical presentation or the biochemical and hormonal profile. Patients presenting with missense mutations of SCNN1A and SCNN1B had a less marked rise in serum aldosterone suggesting preservation in sodium epithelial channel function. Conclusions We advocate early genetic testing in patients with presumed PHA1, given the challenges in differentiating between patients with PHA1a and PHA1b. Clinical course differs between patients with NR3C2 and SCNN1A mutations with a poorer prognosis in those with multisystem PHA. There were no obvious genotype-phenotype correlations between mutations on the same gene in our cohort and others, although a lower serum aldosterone may suggest a missense mutation in SCNN1 in patients with PHA1b.

scholarly journals C677T and A1298C Polymorphisms of the Methylenetetrahydrofolate Reductase Gene: Incidence and Effect of Combined Genotypes on Plasma Fasting and Post-Methionine Load Homocysteine in Vascular Disease

2001 ◽  
Vol 47 (4) ◽  
pp. 661-666 ◽  
Author(s):  
Naomi Q Hanson ◽  
Ömer Aras ◽  
Feng Yang ◽  
Michael Y Tsai
Keyword(s):  
Vascular Disease ◽  
Methylenetetrahydrofolate Reductase ◽  
Statistical Significance ◽  
Plasma Concentrations ◽  
Serum Folate ◽  
Fluorometric Detection ◽  
Polymorphism Analysis ◽  
Wild Type ◽  
Methionine Load ◽  
A1298c Polymorphism

Abstract Background: Moderately increased plasma concentrations of total homocysteine (tHcy) have been shown to be an important risk factor for vascular diseases. Two common polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene, the thermolabile C677T and a more recently reported A1298C polymorphism, may contribute to hyperhomocysteinemia. Methods: Using PCR and restriction fragment length polymorphism analysis, we studied the prevalence of the C677T and A1298C MTHFR genotypes and the combined effect of these polymorphisms on plasma tHcy concentrations, as measured by HPLC with fluorometric detection, both fasting and post-methionine load (PML), in 1238 individuals. Results: The prevalences of the C677T and A1298C genotypes did not differ significantly in 772 individuals with documented coronary artery disease (CAD), 137 individuals with deep-vein thrombosis (DVT), and 329 individuals without documented vascular disease. Individuals homozygous for the 677T allele had significantly increased fasting tHcy, particularly in the presence of low folate, compared with individuals homozygous for the wild-type allele. Neither the 1298AC nor the 1298CC genotype was associated with significantly increased fasting or PML tHcy concentrations irrespective of serum folate. Of the nine combined MTHFR genotypes, six were present in &gt;10% of the population. Of these, the difference in mean fasting tHcy reached statistical significance (P &lt;0.005) only in individuals with the 677TT/1298AA genotype compared with individuals with the wild-type 677CC/1298AA genotype. Differences in mean fasting tHcy did not reach statistical significance in individuals heterozygous for both MTHFR variants. We detected two 677CT/1298CC and three 677TT/1298AC individuals; only one, an 677TT/1298AC individual, had increased tHcy (both fasting and PML). No individuals had the 677TT/1298CC genotype. Conclusions: The prevalences of the C677T and A1298C polymorphisms did not differ among individuals with CAD, DVT, or those without documented vascular disease. In contrast to the C677T polymorphism, the A1298C polymorphism is not associated with increased fasting tHcy. Although the two polymorphisms usually exist in trans configuration, crossover may occur rarely to form recombinant chromosomes.

scholarly journals Female genital mutilation in children presenting to Australian paediatricians

2017 ◽  
Vol 102 (6) ◽  
pp. 509-515 ◽  
Author(s):  
Yvonne Zurynski ◽  
Amy Phu ◽  
Premala Sureshkumar ◽  
Sarah Cherian ◽  
Marie Deverell ◽  
...  
Keyword(s):  
Child Health ◽  
Child Protection ◽  
Female Genital Mutilation ◽  
Cultural Awareness ◽  
Cultural Practice ◽  
Type I ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Genital Mutilation ◽  
Female Genital

ObjectiveThe WHO reports that female genital mutilation/cutting (FGM/C) is an ancient cultural practice prevalent in many countries. FGM/C has been reported among women resident in Australia. Our paper provides the first description of FGM/C in Australian children.DesignCross-sectional survey conducted in April–June 2014.SettingPaediatricians and other child health specialists recruited through the Australian Paediatric Surveillance Unit were asked to report children aged <18 years with FGM/C seen in the last 5 years, and to provide data for demographics, FGM/C type, complications and referral for each case.ParticipantsOf 1311 eligible paediatricians/child health specialists, 1003 (76.5%) responded.ResultsTwenty-three (2.3%) respondents had seen 59 children with FGM/C and provided detailed data for 31. Most (89.7%) were identified during refugee screening and were born in Africa. Three (10.3%) were born in Australia: two had FGM/C in Australia and one in Indonesia. All parents were born overseas, mainly Africa (98.1%). Ten children had WHO FGM/C type I, five type II, five type III and six type IV. Complications in eight children included recurrent genitourinary infections, menstrual, sexual, fertility and psychological problems. Nineteen children (82.6%) were referred to obstetrics/gynaecology: 16 (69.9%) to social work and 13 (56.5%) to child protection.ConclusionsThis study confirms that FGM/C is seen in paediatric clinical practice within Australia. Paediatricians need cultural awareness, education and resources to help them identify children with FGM/C and/or at risk of FGM/C, to enable appropriate referral and counselling of children, families and communities to assist in the prevention of this practice.

scholarly journals B-vitamins, homocysteine metabolism and CVD

2004 ◽  
Vol 63 (4) ◽  
pp. 597-603 ◽  
Author(s):  
J. J. Strain ◽  
L. Dowey ◽  
M. Ward ◽  
K. Pentieva ◽  
H. McNulty
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Independent Predictor ◽  
Systemic Disease ◽  
Plasma Concentrations ◽  
Nutrient Status ◽  
Mthfr Gene ◽  
Plasma Homocysteine ◽  
B Vitamins ◽  
Vitamin B ◽  
Pathophysiological Mechanism

The present review focuses on the B-vitamins, i.e. folate, vitamin B12, vitamin B6and riboflavin, that are involved in homocysteine metabolism. Homocysteine is a S-containing amino acid and its plasma concentrations can be raised by various constitutive, genetic and lifestyle factors, by inadequate nutrient status and as a result of systemic disease and various drugs. Hyperhomocysteinaemia is a modest independent predictor of CVD and stroke, but causality and the precise pathophysiological mechanism(s) of homocysteine action remain unproven. The predominant nutritional cause of raised plasma homocysteine in most healthy populations is folate insufficiency. Vitamin B12and, to a lesser extent, vitamin B6are also effective at lowering plasma homocysteine, especially after homocysteine lowering by folic acid in those individuals presenting with raised plasma homocysteine. However, riboflavin supplementation appears to be effective at lowering plasma homocysteine only in those individuals homozygous for the T allele of the C677 T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. This gene codes for the MTHFR enzyme that produces methyltetrahydrofolate, which, in turn, is a substrate for the remethylation of homocysteine by the vitamin B12-dependent enzyme methionine synthase. Individuals with the MTHFR 677 TT genotype are genetically predisposed to elevated plasma homocysteine, and in most populations have a markedly higher risk of CVD.

Phase I Clinical and Pharmacogenetic Trial of Irinotecan and Raltitrexed Administered Every 21 Days to Patients With Cancer

2001 ◽  
Vol 19 (20) ◽  
pp. 4081-4087 ◽  
Author(s):  
James P. Stevenson ◽  
Maryann Redlinger ◽  
Leo A.J. Kluijtmans ◽  
Weijing Sun ◽  
Kenneth Algazy ◽  
...  
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Clinical Investigation ◽  
Performance Status ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Plasma Homocysteine ◽  
Gastrointestinal Malignancies ◽  
Patients With Cancer ◽  
Functional Polymorphisms

PURPOSE: Irinotecan and raltitrexed display schedule-dependent synergy in vitro, which supports the clinical investigation of the combination. Functional polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene result in intracellular redistribution of folate derivatives, which may affect raltitrexed-associated cytotoxicity.PATIENTS AND METHODS: Patients with a range of solid cancers and good performance status received irinotecan as a 90-minute infusion on day 1 and raltitrexed as a 15-minute infusion on day 2, repeated every 21 days. Samples were collected for MTHFR C677T genotyping and fasting plasma homocysteine during the first cycle.RESULTS: Thirty-nine assessable patients received 127 cycles of therapy. Irinotecan doses ranged from 100 to 350 mg/m2, and raltitrexed, 1.0 to 4.0 mg/m2. Raltitrexed doses of more than 3.0 mg/m2were not tolerated and were associated with dose-limiting asthenia, diarrhea, and AST/ALT elevation. Irinotecan/raltitrexed doses of 350/3.0 mg/m2were well-tolerated; principal toxicities included neutropenia, diarrhea, and fatigue. Two partial responses were observed in patients with pretreated gastroesophageal cancers. Homozygotes with the MTHFR 677 TT polymorphism incurred significantly less raltitrexed-associated toxicity than those with either wild-type or heterozygous genotypes (P = .05). No significant differences were noted in plasma homocysteine values between the genotypic subtypes, and plasma homocysteine levels did not predict the risk of toxicity.CONCLUSION: Irinotecan and raltitrexed doses of 350 and 3.0 mg/m2are recommended for further study on a day 1, 2 schedule every 21 days. Efficacy results suggest that trials in upper and lower gastrointestinal malignancies are warranted. MTHFR C677T genotypes may be predictive of clinical raltitrexed toxicity.

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