Genetics of hyperhomocysteinaemia in cardiovascular disease

Abstract

Homocysteine, a sulphur amino acid, is a branch-point intermediate of methionine metabolism. It can be degraded in the transsulphuration pathway to cystathionine, or remethylated to methionine via the remethylation pathway. In both pathways, major genetic defects that cause enzyme de ciencies are associated with very high plasma homocysteine concentrations and excretion of homocystine into the urine. Mildly elevated plasma homocysteine concentrations are thought to be an independent and graded risk factor for both arterial occlusive disease and venous thrombosis. Genetic defects in genes encoding enzymes involved in homocysteine metabolism, or depletion of important cofactors or (co)substrates for those enzymes, including folate, vitamin B 12 and vitamin B 6 , may result in elevated plasma homocysteine concentrations. Plasma homocysteine concentrations are also in uenced by dietary and lifestyle factors. In the last decade, several studies have been conducted to elucidate the genetic determinants of hyperhomocysteinaemia in patients with cardiovascular disease. We report on both environmental and genetic determinants of hyperhomocysteinaemia and give a detailed overview of all the genetic determinants that have been reported to date.

Reconstruction and Validation of Saccharomyces cerevisiae iND750, a Fully Compartmentalized Genome-Scale Metabolic Model

“…Many of the genes in this list are related to a few separate metabolic subsystems with false phenotypic predictions under specific media conditions, indicating that there may be important unidentified biochemical mechanisms present in these systems. An especially interesting example is the high number of false predictions related to methionine and homocysteine biosynthesis, which have been extensively studied both in yeast and in higher eukaryotes because of the role of homocysteine in cardiovascular and neurodegenerative diseases (Lievers et al 2003;Mattson and Haberman 2003). The key gene in this system is MET6, which codes for the methionine synthetase responsible for converting homocysteine into methionine.…”

Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism

“…Subtle alterations in gene expression due to multiple polymorphisms and environmental factors that interact to affect the same metabolic pathway can induce chronic metabolic imbalance and alter nutritional requirements (Gueant et al 2003;Lievers et al 2003;Bailey and Gregory, III 2000). Using the abnormal metabolic phenotype in autistic children as a guide for the selection of functional candidate genes, we evaluated common SNPs in genes encoding methylenetetrahydrofolate (MTHFR 677C>T, MTHFR 1298A>C), methionine synthase reductase (MTRR 66A>G), transcobalamin II (TCN2 776C>G), catechol-Omethyltransferase (COMT 472G>A), glutathione-S-transferase (GST M1 null, GST T1 null), reduced folate carrier (RFC 80 A>G), glutamate-carboxypepsidase (GCPII 1561C>T).…”

Niveles de homocisteína y polimorfismos de los genes de la MTHFR y la CBS en pacientes colombianos con trombosis venosa superficial y profunda

“…Aunque la mayoría de las mutaciones en el gen de la CBS son raras, se ha reportado que la inserción de 68pb en el exón 8 del gen de la CBS es común, encontrándose en estado heterocigoto, aproximadamente, en 12% de la población general (24,25). Al evaluar la frecuencia de los polimorfismos genéticos analizados para trombosis venosa, no se encontraron diferencias estadísticamente significativas y, por ende, incremento en el riesgo, pero cabe destacar una tendencia estadística de un posible efecto protector del polimorfismo CBS 844ins68 en el desarrollo de la enfermedad; se encontró una frecuencia (11%) de este polimorfismo en estado heterocigoto similar a la reportada a nivel mundial en el grupo control y de 3% en los casos.…”

“…El caso del polimorfismo CBS 844ins68 es llamativo, debido a la diversidad de resultados encontrados en la literatura al evaluar su papel en el desarrollo de enfermedad trombótica vascular e hiperhomocisteinemia (24,25 (27), reportaron que el polimorfismo CBS 844ins68 en estado heterocigoto es un factor de riesgo para trombosis venosa profunda en población brasilera, también, se encuentran reportes que indican que la combinación del polimorfismo CBS c.844ins68 con la variante termolábil MTHFR puede incrementar el riesgo de enfermedad oclusiva arterial y venosa (27)(28)(29)(30).…”