Is there a causal role for homocysteine concentration in blood pressure? A Mendelian randomization study.
Level 3 - non-randomized controlled study
Mendelian randomization study using observational cohort and GWAS consortium data
PubMed 26675774 · doi:10.3945/ajcn.115.116038
What was done
Mendelian randomization (MR) analysis was used to assess whether blood homocysteine concentration causally influences systolic blood pressure (SBP) and diastolic blood pressure (DBP). Analyses included 4,297 participants from the 1982 Pelotas Birth Cohort in Brazil (evaluated at mean age 22.8 years in 2004-2005) comparing ordinary least-squares (OLS) regression to two-stage least-squares (2SLS) regression using the MTHFR C677T (rs1801133) variant as an instrument. Summary-level MR was also conducted using International Consortium for Blood Pressure (ICBP) genome-wide association study data (>69,000 participants) with rs1801133 and additional homocysteine-associated single nucleotide polymorphisms (SNPs).
What was found
In observational OLS regression, each 1-SD increase in log homocysteine was associated with an increase of 0.9 mm Hg in SBP (95% CI: 0.4, 1.4) and 1.0 mm Hg in DBP (95% CI: 0.6, 1.4). In 2SLS MR regression, the effect estimates were -1.8 mm Hg for SBP (95% CI: -3.9, 0.4; P = 0.01) and 0.1 mm Hg for DBP (95% CI: -1.5, 1.7; P = 0.24). In ICBP consortium MR data, homocysteine was not associated with SBP (beta = 0.6 mm Hg; 95% CI: -0.8, 1.9 mm Hg), while an association with DBP (beta = 1.1 mm Hg; 95% CI: 0.2, 1.9 mm Hg) was not consistent across different genetic instruments.
Why it matters
Observational associations between homocysteine and blood pressure appear to reflect confounding or reverse causation rather than a direct causal effect. Interventions designed to lower homocysteine, such as B-vitamin supplementation, are unlikely to produce meaningful blood pressure reductions.
Limits
The individual-level cohort was restricted to young adults (mean age 22.8 years) from a single birth cohort, where hypertension is relatively rare. In the consortium data, findings for DBP showed heterogeneity and varied depending on the instrument SNPs utilized.
Cited by
- context Elevated homocysteine is a cause of high blood pressure.