Association Between Plasma Homocysteine Level and Mortality: A Mendelian Randomization Study.

Area of Science:

• Cardiovascular Epidemiology
• Genetic Epidemiology
• Metabolic Health

Background:

• Elevated homocysteine levels have been inconsistently associated with cardiovascular mortality in observational studies.
• Randomized controlled trials have yielded conflicting results regarding homocysteine's impact on mortality.

Purpose of the Study:

• To investigate the causal relationship between plasma homocysteine concentrations and all-cause and cardiovascular mortality.
• To utilize Mendelian randomization (MR) analysis to overcome limitations of observational studies.

Main Methods:

• The Namwon Study cohort (10,005 participants) was analyzed.
• Observational analysis employed multivariate Cox proportional regression.
• Mendelian randomization analysis used 2-stage least squares regression with the methylenetetrahydrofolate reductase (MTHFR) polymorphism as an instrumental variable.

Main Results:

• Observational analysis showed a positive association between higher homocysteine levels and increased all-cause and cardiovascular mortality.
• Mendelian randomization analysis revealed no significant causal association between genetically predicted homocysteine levels and all-cause or cardiovascular mortality.

Conclusions:

• Mendelian randomization analysis does not support a causal role for elevated plasma homocysteine in premature mortality.
• The findings suggest that the observed association in observational studies may be confounded or non-causal.