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

Mario Grassi1, Deodato Assanelli, Alessandro Pezzini

  • 1Dipartimento di Scienze Sanitarie Applicate, Sezione di Statistica Medica ed Epidemiologia, Università degli Studi di Pavia, Pavia, Italia.

Thrombosis Research
|August 16, 2006
PubMed

Insights

Mild hyperhomocysteinemia may be a direct risk factor for ischemic heart disease (IHD). This study suggests a causal link between elevated homocysteine levels and IHD, supporting a genotype-phenotype-disease mediation process.

Area of Science:

  • Cardiovascular Genetics
  • Metabolic Disorders
  • Epidemiology

Background:

  • The role of mild hyperhomocysteinemia in ischemic heart disease (IHD) remains unclear, with debate on whether it is a cause or consequence.
  • Investigating the causal relationship between homocysteine (Hcy) and IHD is crucial for understanding cardiovascular disease (CVD) pathogenesis.

Purpose of the Study:

  • To determine if elevated homocysteine levels are a direct cause, a consequence, or reciprocally related to IHD.
  • To elucidate the underlying mechanisms, including potential genotype-phenotype-disease mediation, in the Hcy-IHD association.

Main Methods:

  • Utilized Structural Equation Models (SEMs) to test direct, reversal, and reciprocal causality between total homocysteine (tHcy) and IHD in 94 families.
  • Employed "Pearl's instrumental inequalities" to validate findings and assess the role of MTHFR as an instrumental variable.
  • Analyzed genetic and phenotypic data from 296 family members, including those with premature IHD.

Main Results:

  • A significant association between tHcy and IHD was observed under a direct causality model (OR=1.38, 95% CI: 1.01-1.88 per 10 micromol/l increase in tHcy).
  • Reversal and reciprocal causality models did not show significant associations.
  • MTHFR gene variants indirectly influenced IHD through tHcy, suggesting a mediation effect, despite a non-significant direct MTHFR-IHD relationship.

Conclusions:

  • Findings support a causal relationship between moderately elevated plasma tHcy levels and IHD.
  • Evidence suggests a triangular genotype-phenotype-disease mediation process in the Hcy-IHD association.
  • This implies that homocysteine is a modifiable risk factor for IHD.
Abstract

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