RGD Reference Report - Homocysteine and stroke: evidence on a causal link from mendelian randomisation. - Rat Genome Database

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Homocysteine and stroke: evidence on a causal link from mendelian randomisation.

Authors: Casas, JP  Bautista, LE  Smeeth, L  Sharma, P  Hingorani, AD 
Citation: Casas JP, etal., Lancet. 2005 Jan 15-21;365(9455):224-32.
RGD ID: 6893467
Pubmed: PMID:15652605   (View Abstract at PubMed)
DOI: DOI:10.1016/S0140-6736(05)17742-3   (Journal Full-text)

BACKGROUND: Individuals homozygous for the T allele of the MTHFR C677T polymorphism have higher plasma homocysteine concentrations (the phenotype) than those with the CC genotype, which, if pathogenetic, should put them at increased risk of stroke. Since this polymorphism is distributed randomly during gamete formation, its association with stroke should not be biased or confounded. We investigated consistency between the expected odds ratio for stroke among TT homozygotes, extrapolated from genotype-phenotype and phenotype-disease studies, and the observed odds ratio from a meta-analysis of genotype-disease association studies. METHODS: We searched MEDLINE and EMBASE up to June, 2003, for all relevant studies on the association between homocysteine concentration and the MTHFR polymorphism, and until December, 2003, for those on the association between the polymorphism and the risk of stroke. Pooled odds ratios and 95% CI were calculated by random-effects and fixed-effects models. Consistency between expected and observed odds ratios was assessed by interaction test. FINDINGS: 111 studies met the selection criteria. Among 15635 people without cardiovascular disease, the weighted mean difference in homocysteine concentration between TT and CC homozygotes was 1.93 micromol/L (95% CI 1.38 to 2.47). The expected odds ratio for stroke corresponding to this difference based on previous observational studies was 1.20 (1.10 to 1.31). In our genetic meta-analysis (n=13928) the odds ratio for stroke was 1.26 (1.14 to 1.40) for TT versus CC homozygotes, similar to the expected odds ratio (p=0.29). Consistency between the odds ratios was preserved in analyses by age-group, ethnic background, and geographical location. INTERPRETATION: The observed increase in risk of stroke among individuals homozygous for the MTHFR T allele is close to that predicted from the differences in homocysteine concentration conferred by this variant. This concordance is consistent with a causal relation between homocysteine concentration and stroke.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Stroke  IAGP 6893467DNA:transition:cds:g.677C>T (human)RGD 
Stroke  ISOMTHFR (Homo sapiens)6893467; 6893467DNA:transition:cds:g.677C>T (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Cerebral ischemia  IAGP 6893467DNA:transition:cds:g.677C>TRGD 
Objects Annotated

Genes (Rattus norvegicus)
Mthfr  (methylenetetrahydrofolate reductase)

Genes (Mus musculus)
Mthfr  (methylenetetrahydrofolate reductase)

Genes (Homo sapiens)
MTHFR  (methylenetetrahydrofolate reductase)


Additional Information