Author Affiliations: Division of Human Nutrition and Epidemiology, Wageningen University (Ms Klerk and Drs Verhoef, Kok, and Schouten), and Wageningen Centre for Food Sciences (Ms Klerk and Dr Verhoef), Wageningen, the Netherlands; Clinical Trial Service Unit, Radcliffe Infirmary, Oxford, England (Dr Clarke); and the Laboratory of Pediatrics and Neurology, University Medical Center Nijmegen, Nijmegen, the Netherlands (Dr Blom).
Context In observational studies, individuals with elevated levels of plasma
homocysteine tend to have moderately increased risk of coronary heart disease
(CHD). The MTHFR 677C→T polymorphism is a genetic
alteration in an enzyme involved in folate metabolism that causes elevated
homocysteine concentrations, but its relevance to risk of CHD is uncertain.
Objective To assess the relation of MTHFR 677C→T
polymorphism and risk of CHD by conducting a meta-analysis of individual participant
data from all case-control observational studies with data on this polymorphism
and risk of CHD.
Data Sources Studies were identified by searches of the electronic literature (MEDLINE
and Current Contents) for relevant reports published before June 2001 (using
the search terms MTHFR and coronary
heart disease), hand searches of reference lists of original studies
and review articles (including meta-analyses) on this topic, and contact with
investigators in the field.
Study Selection Studies were included if they had data on the MTHFR 677C→T genotype and a case-control design (retrospective or nested
case-control) and involved CHD as an end point. Data were obtained from 40
(34 published and 6 unpublished) observational studies involving a total of
11 162 cases and 12 758 controls.
Data Extraction Data were collected on MTHFR 677C→T genotype,
case-control status, and plasma levels of homocysteine, folate, and other
cardiovascular risk factors. Data were checked for consistency with the published
article or with information provided by the investigators and converted into
a standard format for incorporation into a central database. Combined odds
ratios (ORs) for the association between the MTHFR 677C→T
polymorphism and CHD were assessed by logistic regression.
Data Synthesis Individuals with the MTHFR 677 TT genotype
had a 16% (OR, 1.16; 95% confidence interval [CI], 1.05-1.28) higher odds
of CHD compared with individuals with the CC genotype. There was significant
heterogeneity between the results obtained in European populations (OR, 1.14;
95% CI, 1.01-1.28) compared with North American populations (OR, 0.87; 95%
CI, 0.73-1.05), which might largely be explained by interaction between the MTHFR 677C→T polymorphism and folate status.
Conclusions Individuals with the MTHFR 677 TT genotype
had a significantly higher risk of CHD, particularly in the setting of low
folate status. These results support the hypothesis that impaired folate metabolism,
resulting in high homocysteine levels, is causally related to increased risk
Klerk M, Verhoef P, Clarke R, et al. MTHFR 677C→T Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis. JAMA. 2002;288(16):2023–2031. doi:10.1001/jama.288.16.2023
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