Résumé : Le métabolisme monocarboné ou métabolisme 1-C désigne l’ensemble des voies métaboliques permettant la synthèse et / ou le recyclage de molécules donneur de groupement monocarboné au cours des réactions de méthylation. L’objectif de ce travail était d’évaluer l’implication des métabolismes de la choline, de la phosphatidylcholine (PC) et de la bétaïne dans la physiopathologie des désordres impliquant le métabolisme 1-C en période prénatale et postnatale. Nous avons montré une augmentation progressive de l’expression de la majorité des gènes impliqués dans le métabolisme 1-C au cours de l’ontogénèse hépatique murine, tandis que les leur expression était plus faible avec des profils plus variable au niveau cérébral. Chez l’homme, les valeurs normales des concentrations des intermédiaires du métabolisme 1-C dans le liquide amniotique (LA) en fonction du terme gestationnel ont été déterminées pour tous les paramètres et les concentrations de S-adénosyl-homocystéine et de méthionine étaient augmentées dans les LA du groupe affecté par des défauts de fermeture du tube neural (DFTN) suggérant que certains cas de DFTN pourraient être associés à des déséquilibres du métabolisme 1-C. En post natal, nous avons montré à la fois chez l’homme et l’animal, que les hyperhomocystéinémie d’origine nutritionnelles ou génétiques induisaient une déplétion en bétaïne, épargnant uniquement le rein où elle est un osmolyte majeur. Dans un modèle murin de déficit en cystathionine–beta synthase induisant une hyperhomocystéinémie, une technique de lipidomique ciblée a montré au niveau hépatique des modifications qualitatives des phospholipides (PLs) avec une diminution des PC contenant des acides gras insaturés et des phosphatidyléthanolmines contenant de l’acide arachidonique. Ces modifications des PLs pourraient jouer un rôle dans la constitution de la stéatose hépatique observée dans l’histoire naturelle de cette maladie. En conclusion, ce travail a permis de montrer que la choline, la bétaïne et les PC sont des acteurs indissociables du métabolisme 1-C qui pourraient être impliqués dans la physiopathologie des DFTN et dans les hyperhomocystéinémies. Ils pourraient également être impliqués dans la physiopathologie des stéatoses hépatiques non alcooliques ou des déficits cognitifs, dans lesquels des désordres du métabolisme 1-C ont été observés. / Abstract: One carbon metabolism or 1C metabolism includes all metabolic pathways for the synthesis and / or recycling of molecules involved in methylation reactions. The objective of this study was to evaluate the involvement of choline, phosphatidylcholine (PC) and betaine metabolisms in the pathophysiology of diseases with impaired 1-C metabolism in prenatal and postnatal period. We showed a progressive increase of the expression of the majority of genes involved in 1-C metabolism during the mouse liver ontogeny while their gene expression was at lower levels and with more variable patterns during brain ontogeny. In humans, amniotic fluid concentrations of all intermediates of 1-C metabolism according to gestational term were determined and we observed increased concentrations of S-adenosyl-homocysteine and methionine in pregnancies affected by neural tube defects (NTD) suggesting that some NTDs cases could be associated with an imbalance in 1-C metabolism. In the postnatal period we showed that both in animal and humans and both in nutritional and genetic hyperhomocysteinemia, that betaine pools were decreased, only sparing the kidney betaine concentrations, where betaine acts as an essential osmolyte. In a mouse model of cystathionine-beta synthase deficiency inducing hyperhomocysteinemia, a technic of targeted lipidomic revealed qualitative changes in the liver phospholipids composition, in particular a decrease of PC containing unsaturated fatty acids and of phosphatidylethanolamine containing arachidonic acid and an increase of phosphatidylethanolamine containing docosohaexaenoic acid. This phospholipids remodelage may participate in the development of the steatosis observed in the natural history of this disease. In conclusion, this study has shown that choline, betaine and phosphatidylcholine are essential actors of 1-C metabolism that could be involved in the pathogenesis of NTD and hyperhomocystéinemia. They could also be involved in the pathophgysiology of non alcoholic fatty liver disease or cognitive decline, in which disorders of 1-C metabolism were observed.

Background: Preeclampsia, small for gestational age (SGA), placental abruption, and fetal death are pregnancy complications linked to the utero-placental vasculature with serious consequences for maternal and infant well-being. Elevated homocysteine, a marker of cardiovascular disease risk, is postulated to play a role in placenta-mediated complications, but epidemiologic studies have reported inconsistent findings. The two primary objectives of this thesis were to 1: comprehensively investigate the association of homocysteine with placenta-mediated complications and examine modifying effects of pre-specified factors on this association, and 2: comprehensively investigate determinants of maternal homocysteine during pregnancy. Methods: A systematic review and meta-analysis of prospective studies was conducted to address thesis objective 1. The Ottawa and Kingston (OaK) Birth Cohort, a prospective cohort study that recruited pregnant women between 2002 and 2009, was used to address thesis objectives 1 and 2. Homocysteine concentration was measured between 12 and 20 weeks gestation. Analyses based on the OaK Birth Cohort consisted of multivariable regressions using restricted cubic splines to model associations with continuously distributed variables. Results: Objective 1: In an analysis of 7587 participants, a significant association between homocysteine concentration and a composite outcome of any placenta-mediated complication was observed (odds ratio (OR) for a 5 µmol/L increase: 1.63, 95% Confidence Interval (CI) 1.23-2.16) and SGA (OR 1.76, 95% CI 1.25-2.46), with potential modifying effects of the methylene tetrahydrofolate reductase (MTHFR) 677C>T variant (SGA) and high-risk pregnancy (preeclampsia). In the systematic review identifying 30 prospective cohort or nested case-control studies, a random effects meta-analysis of pooled mean differences in homocysteine between cases and controls in 28 studies revealed significantly higher means for SGA: 0.35 µmol/L (95% CI 0.19 to 0.51, I2=33%); and preeclampsia: 0.87 µmol/L (95% CI 0.52 to 1.21, I2=92%). Significant sources of heterogeneity were study region (SGA and preeclampsia), adjusting for covariates (preeclampsia), folate status (preeclampsia), and severity (preeclampsia). Objective 2: In 7587 OaK participants, factors related to favourable health status were associated with lower maternal homocysteine concentrations. Folic acid supplementation during pregnancy of >1 mg/day did not substantially increase serum folate concentration. Conclusion: This thesis suggests an independent effect of slightly higher homocysteine concentration in the early to mid-second trimester on the risk of any placenta-mediated complication, SGA, and preeclampsia. Modifying effects explain some of the variability in previous studies. Favourable preconception health status was associated with lower maternal homocysteine.

No description available.

M. Tech. (Department of Biotechnology, Faculty of Applied and Computer Sciences), Vaal University of Technology. / Background: Increased serum homocysteine is well known as an independent cardiovascular risk factor. Hyperhomocysteinemia may be due to several factors such as nutritional deficiencies and genetics. The MTHFR C677T polymorphism is associated with increased serum homocysteine. Folate and vitamin B12 play essential roles in lowering homocysteine levels. Limitations have been identified using serum vitamin B12 as a marker for vitamin B12 status due to lack an efficient of test. Holotranscobalamin has been reported as a more accurate marker for vitamin B12 status. Cardiovascular risk due to hyperhomocysteinemia has been confirmed among the elderly in Sharpeville. Knowledge of the prevalence of MTHFR C677T polymorphism among Black elderlies in South Africa is limited. Objectives: The main aim of the study was to evaluate the prevalence of MTHFR C677T polymorphism as a cardiovascular risk in an elderly black population in Sharpeville. Correlations between the presence of MTHFR C677T polymorphism and homocysteine metabolic markers were evaluated. Holotranscobalamin as a diagnostic test for vitamin B12 status was also assessed in this study. Materials and methods: This study was ethically approved by the Vaal University of Technology ethics committee (20140827-1ms). It was an observational, experimental study conducted in 102 elderly (≥60 years) attending the day-care centre in Sharpeville. Real-Time PCR was used to determine MTHFR genotypes. Folate and vitamin B12 were measured with AIA-PACK. Homocysteine levels were determined with an automated Konelab™ 20i and holotranscobalamin by ELISA. STATA 12 software was used for analysis of descriptive and inferential statistics. Results: The prevalence of MTHFR C677T polymorphism in this sample population was 19%. Heterozygous CT single nucleotide polymorphism was 17% and mutant homozygous TT was 2%. The majority (81%) of the subjects had wild type homozygous CC genotypes. No associations were found between MTHFR C677T genotypes and homocysteine and folate levels. Hyperhomocysteinemia was high (54%) and low (5%) folate deficiency found. No vitamin B12 deficiency was found however 7% were on the category of likely to be deficient. Sensitivity and specificity of holotranscobalamin were 100% and 95% respectively. Conclusion: The conclusions drawn from the study is that the prevalence of MTHFR C677T polymorphism is low within elderly in Sharpeville. There is a high risk of cardiovascular disease as a result of high prevalence of hyperhomocysteinemia. An intervention to lower homocysteine concentration of elderlies residing in Sharpeville is needed. Other genetic predisposing factors of increased homocysteine levels should be investigated.