A common polymorphism in methionine synthase reductase increases risk of premature coronary artery disease.
BACKGROUND
Methionine synthase reductase (MTRR) catalyzes the regeneration of methylcobalamin, a cofactor of methionine synthase, an enzyme essential for maintaining adequate intracellular pools of methionine and tetrahydrofolate, as well as for maintaining homocysteine concentrations at nontoxic levels. We recently identified a common A-->G polymorphism at position 66 of the cDNA sequence of MTRR; this variant was associated with a greater than normal risk for spina bifida in the presence of low levels of cobalamin.


OBJECTIVE
To investigate whether the polymorphism was associated with alterations in levels of homocysteine, folate, and vitamin B12, and with risk of developing premature coronary artery disease (CAD), in a population of individuals presenting for cardiac catheterization procedures.


METHODS
We screened 180 individuals aged < 58 years with angiographically documented coronary-artery occlusions or occlusion-free major arteries for the presence of the 66A-->G MTRR polymorphism using a polymerase-chain-reaction-based assay.


RESULTS
We identified a trend in risk of premature CAD across the genotype groups (P = 0.03) with a sex-adjusted relative risk of premature CAD equal to 1.49 (95% confidence interval 1.10-2.03) for the GG versus AA genotype groups. There was no difference in fasting levels of plasma total homocysteine, serum folate, and vitamin B12 among the three MTRR genotypes.


CONCLUSIONS
Our findings suggest that the GG genotype of MTRR is a significant risk factor for the development of premature CAD, by a mechanism independent of the detrimental vascular effects of hyperhomocysteinemia. This association needs to be confirmed in other studies.
Brown
C A
CA
Department of Pediatrics, Carolinas Medical Center, Charlotte, North Carolina, USA. cbrown@carolinas.org
McKinney
K Q
KQ
Kaufman
J S
JS
Gravel
R A
RA
Rozen
R
R
D000367:Age Factors; D001483:Base Sequence; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D003627:Data Interpretation, Statistical; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005420:Flavoproteins / Q000235:genetics*; D005492:Folic Acid / Q000097:blood; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D012306:Risk; D012737:Sex Factors; D014805:Vitamin B 12 / Q000097:blood
D005420:Flavoproteins; D006710:Homocysteine; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D014805:Vitamin B 12