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

Abstract

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 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). Conclusion 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.