Genetic Modulation of Homocysteinemia

Abstract

With the identification of hyperhomocysteinemia as a risk factor for cardiovascular disease, an understanding of the genetic determinants of plasma homocysteine is important for prevention and treatment. It has been known for some time that homocystinuria, a rare inborn error of metabolism, can be due to genetic mutations that severely disrupt homocysteine metabolism. A more recent development is the finding that milder, but more common, genetic mutations in the same enzymes might also contribute to an elevation in plasma homocysteine. The best example of this concept is a missense mutation (alanine to valine) at base pair (bp) 677 of methylenetetrahydrofolate reductase (MTHFR), the enzyme that provides the folate derivative for conversion of homocysteine to methionine. This mutation results in mild hyperhomocysteinemia, primarily when folate levels are low, providing a rationale (folate supplementation) for overcoming the genetic deficiency. Additional genetic variants in MTHFR and in other enzymes of homocysteine metabolism are being identified as the cDNAs/genes become isolated. These variants include a glutamate to alanine mutation (bp 1298) in MTHFR, an aspartate to glycine mutation (bp 2756) in methionine synthase, and an isoleucine to methionine mutation (bp 66) in methionine synthase reductase. These variants have been identified relatively recently; therefore additional investigations are required to determine their clinical significance with respect to mild hyperhomocysteinemia and vascular disease.

Mutations and Polymorphisms in Genes Affecting Hemostasis Proteins and Homocysteine Metabolism in Children with Arterial Ischemic Stroke

“…The HPA-1a/1b polymorphism of human platelet antigen 1 (HPA-1), localized on platelet glycoprotein GPIIIa, has also been identified as an inherited risk factor for atherothrombosis, enhancing platelet activation [18, 19]. Finally, two common variants (C677T and A1298C) of the gene encoding the thermolabile 5,10-methylenetetrahydrofolate reductase (MTHFR) have been implicated in the development of hyperhomocysteinemia, which has been identified as a risk factor for arterial and venous thrombosis [20, 21]. …”

Does the MTHFR 677C→T variant affect the Recommended Dietary Allowance for folate in the US population?

“…Also, it is unclear whether the effect of the genotype on the folate requirement would be the same for each racial and ethnic group when considering the possible effect of different environmental and genetic backgrounds. The effect of the MTHFR 677C/T variant appears to be more deleterious in a low-folate environment (15) and thus may differ across racial and ethnic groups. Accordingly, data from NHANES 2001-2002 suggest that folic acid intake among nonpregnant women of childbearing age in the United States is inadequate: only 21% of Hispanic women consume 400 lg/d of folic acid from fortified foods and supplements compared with 41% of non-Hispanic white women (34).…”

“…Individuals homozygous for this variant have a mean MTHFR activity that is ,50% of the MTHFR activity of CC individuals, whereas heterozygous individuals have shown intermediate values of activity (13,14). The effect of the variant seems to be more pronounced under low-to normalfolate conditions, which highlights the importance of adequate folate intake to compensate for the lower enzyme activity level (15).…”

Pharmacogenomics and nutrigenomics: synergies and differences

“…Several (but not all) studies have found that this effect occurs only in people who also 554,555,556,557,558,559 have low folate levels. This suggests a gene-diet interaction, which would imply that people with this genetic variation can make more difference to their homocysteine levels by taking folic acid than other people can.…”