Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: the European Concerted Action Project.
BACKGROUND
Homozygotes for the thermolabile mutation (TT genotype) of the methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) enzyme have elevated plasma concentrations of the cardiovascular disease risk factor homocysteine, particularly if folate depleted.


OBJECTIVE
We examined the relations between thermolabile MTHFR, plasma homocysteine, plasma folate, and vascular disease risk.


METHODS
This was a case-control comparison in 711 vascular disease cases and 747 controls from 9 European countries.


RESULTS
The TT genotype was associated with higher homocysteine and lower plasma folate than the CC and CT genotypes in both cases and controls and a nonsignificant increase in vascular disease risk (1.26; 95% CI: 0.88, 1.81; P = 0.20). The frequency of the TT genotype in cases was not significantly different from that in controls (12.8% compared with 10.8%). After adjustment for traditional risk factors, the TT genotype was associated with an odds ratio of 1.48 (1.0, 2.20) for risk of vascular disease. This risk was attenuated after further adjustment for homocysteine. In subgroups with homocysteine concentrations >or= 9 micro mol/L, risk tended to be higher in CC than in TT subjects. However, CC subjects were characterized by a higher prevalence of the conventional risk factors associated with both elevated plasma homocysteine and serum creatinine. After adjustment, the risk of vascular disease associated with each genotype was not significantly different.


CONCLUSIONS
There was a strong graded association between homocysteine and vascular risk in all genotypes. MTHFR genotype is a key determinant of plasma total homocysteine concentrations. The initially nonsignificant risk estimate associated with the TT genotype was strengthened after adjustment for conventional cardiovascular disease risk factors but was attenuated after adjustment for plasma folate and total homocysteine. The modest risk increase conferred by the TT genotype is mediated mainly by increased total homocysteine and low plasma folate concentrations.
Meleady
Raymond
R
Department of Cardiology, Adelaide-Meath Hospital, Incorporating the National Children's Hospital, Tallaght, Dublin, Ireland. ray.meleady@ghnt.nhs.uk
Ueland
Per M
PM
Blom
Henk
H
Whitehead
Alexander S
AS
Refsum
Helga
H
Daly
Leslie E
LE
Vollset
Stein Emil
SE
Donohue
Cait
C
Giesendorf
Belinda
B
Graham
Ian M
IM
Ulvik
Arve
A
Zhang
Ying
Y
Bjorke Monsen
Anne-Lise
AL
D000328:Adult; D002318:Cardiovascular Diseases / Q000097:blood* / Q000235:genetics; D016022:Case-Control Studies; D005060:Europe; D005260:Female; D005492:Folic Acid / Q000097:blood; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000097:blood / Q000235:genetics*; D012307:Risk Factors
D006710:Homocysteine; D005492:Folic Acid; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)