Direct, reverse or reciprocal causation in the relation between homocysteine and ischemic heart disease

BackgroundWhether 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.MethodsNinety-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”.ResultsA significant tHcy–IHD association was found in Model 1 (OR = 1.38, 95% CI: 1.01 to 1.88, for any increase of + 10 μmol/l in tHcy), as opposed to a non-significant association in the other models (Model 2: MD = + 1.63 μmol/l, 95% CI: − 1.72 to + 4.99 μmol/l; Model 3: OR = 0.69, 95% CI: 0.17 to 2.78 for tHcy predictor of IHD; MD = − 0.46 μmol/l, 95% CI: − 2.41 to 1.48 μmol/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).ConclusionOur 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.