Prospective study of methylenetetrahydrofolate reductase (MTHFR) variant C677T and risk of all-cause and cardiovascular disease mortality among 6000 US adults.
Level 3 - non-randomized controlled study
Prospective cohort study using Mendelian randomization
PubMed 22492374 · doi:10.3945/ajcn.111.022384
What was done
Researchers conducted a prospective Mendelian randomization study of 5,925 US adults from the NHANES III (1991–1994) Linked Mortality File followed through 2006. They evaluated the association between the MTHFR C677T variant (a proxy for elevated homocysteine) and cardiovascular disease (CVD) and all-cause mortality, adjusting for ethnic group, CVD risk factors, and periods before versus after mandatory folic acid fortification.
What was found
At baseline, individuals with the TT genotype had 2.2-µmol/L higher homocysteine and 1.4-ng/mL lower folate concentrations than those with the CC genotype. TT genotype frequency varied across groups: 1.2% (95% CI: 0.7, 2.0) in non-Hispanic blacks, 11.6% (95% CI: 9.6, 14.0) in non-Hispanic whites, and 19.4% (95% CI: 16.7, 22.3) in Mexican Americans. After adjustment, the TT genotype was associated with significantly lower CVD mortality (HR: 0.69; 95% CI: 0.50, 0.95), with no statistically significant association with all-cause mortality (HR: 0.79; 95% CI: 0.59, 1.05). In stratified analysis, the inverse association with CVD mortality was statistically significant only during the post-fortification follow-up period.
Why it matters
The unexpected finding that a genetic variant raising homocysteine was associated with lower CVD mortality challenges homocysteine's hypothesized causal role in CVD mortality and highlights vulnerabilities of Mendelian randomization analyses.
Limits
Major differences in genotype frequencies across ethnic groups raise potential population stratification concerns. The significant protective effect emerged only after nationwide folic acid fortification, and the authors note the results could reflect chance, residual confounding, or bias rather than true causality.
Cited by
- context Between 25% and 28% of people carry an MTHFR polymorphism.