title: Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians.
abstract: BACKGROUND
  Hyperhomocysteinemia appears to be an independent risk factor for coronary disease. Elevated levels of plasma total homocysteine (tHCY) can result from genetic or nutrient-related disturbances in the transsulfuration or remethylation pathways for homocysteine metabolism. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate, which serves as a methyl donor for remethylation of homocysteine to methionine. A common mutation in MTHFR recently has been identified.
  
  
  RESULTS
  We assessed the polymorphism in MTHFR, plasma tHCY, and folate using baseline blood levels among 293 Physicians' Health Study participants who developed myocardial infarction (MI) during up to 8 years of follow-up and 290 control subjects. The frequency of the three genotypes was (-/-) (homozygous normal), 47%; (+/-) (heterozygous), 41%; and (+/+) (homozygous mutant), 12%, with a similar distribution among both MI case patients and control subjects. Compared with those with genotype (-/-), the relative risk (RR) of MI among those with (+/-) was 1.1 (95% CI, 0.8 to 1.5), and it was 0.8 (0.5 to 1.4) for the (+/+) genotype; none of these RRs were statistically significant. However, those with genotype (+/+) had an increased mean tHCY level (mean +/- SEM, 12.6 +/- 0.5 nmol/ mL), compared with those with genotype (-/-) (10.6 +/- 0.3) (P < .01). This difference was most marked among men with low folate levels (the lowest quartile distribution of the control subjects): those with genotype (+/+) had tHCY levels of 16.0 +/- 1.1 nmol/mL, compared with 12.3 +/- 0.6 nmol/mL (P < .001) for genotype (-/-).
  
  
  CONCLUSIONS
  In this population, MTHFR polymorphism was associated with higher homocysteine levels but not with risk of MI. A gene-environment interaction might increase the risk by elevating tHCY, especially when folate intake is low.
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA. hpjma@gauss.med.harvard.edu
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.forename: M J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: C H
authors.initials: CH
authors.lastname: Hennekens
authors.forename: P
authors.initials: P
authors.lastname: Frosst
authors.forename: J
authors.initials: J
authors.lastname: Selhub
authors.forename: J
authors.initials: J
authors.lastname: Horsford
authors.forename: M R
authors.initials: MR
authors.lastname: Malinow
authors.forename: W C
authors.initials: WC
authors.lastname: Willett
authors.forename: R
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005492:Folic Acid / Q000097:blood*; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D009203:Myocardial Infarction; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D010820:Physicians; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014481:United States
chemical_list: D006710:Homocysteine; D005492:Folic Acid; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)