Direct, reverse or reciprocal causation in the relation between homocysteine and ischemic heart disease.
BACKGROUND
Whether mild hyperhomocysteinemia is a risk factor for ischemic heart disease (IHD) or it is a secondary epiphenomenon remains unknown. We tested the alternative hypotheses that the Hcy-IHD relation is due to direct, reversal or reciprocal causality.


METHODS
Ninety-four families from 32 pedigrees (296 members) including subjects who died for a premature (<50 years) IHD and with at least one family member with also a premature IHD were selected. Three Structural Equation Models were created, in which causal (Model 1), reversal (Model 2), and reciprocal (Model 3) tHcy-IHD relation were tested. Results were confirmed by testing "Pearl's instrumental inequalities".


RESULTS
A significant tHcy-IHD association was found in Model 1 (OR=1.38, 95% CI: 1.01 to 1.88, for any increase of +10 micromol/l in tHcy), as opposed to a non-significant association in the other models (Model 2: MD=+1.63 micromol/l, 95% CI: -1.72 to +4.99 micromol/l; Model 3: OR=0.69, 95% CI: 0.17 to 2.78 for tHcy predictor of IHD; MD=-0.46 micromol/l, 95% CI: -2.41 to 1.48 micromol/l, for IHD predictor of tHcy). "Pearl's instrumental inequalities" qualify MTHFR as an instrument relative to the tHcy-IHD relation. A suppression effect may explain the non-significant total MTHFR-IHD relation (OR=1.275, 95% CI: 1.02 to 1.71 for the indirect MTHFR-tHcy-IHD path; OR=0.52, 95% CI: 0.17 to 1.64 for the direct MTHFR-IHD path).


CONCLUSIONS
Our findings support the assumption of a triangular genotype-phenotype-disease mediation process in the Hcy-IHD relation, and indirectly, of a causal relationship between moderately elevated plasma tHcy levels and IHD.
Grassi
Mario
M
Dipartimento di Scienze Sanitarie Applicate, Sezione di Statistica Medica ed Epidemiologia, Università degli Studi di Pavia, Pavia, Italia.
Assanelli
Deodato
D
Pezzini
Alessandro
A
D000328:Adult; D005260:Female; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000150:complications*; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood* / Q000209:etiology*; D012307:Risk Factors
D006710:Homocysteine