Abstract 17905: Aetiological Role of Folate Deficiency in Congenital Cardiovascular Malformation: Evidence From “Mendelian Randomisation” and Meta-Analysis
Background: The existence of a causal relationship between lower levels of plasma folate and congenital cardiovascular malformation (CVM) remains contentious. We undertook a genetic approach using the principles of “Mendelian randomization” to determine the causality of folate in CVM risk.
Methods and Findings: We compared genotype frequencies at the methylene tetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism (SNP) in 1186 CVM cases and 4168 controls. The TT genotype at MTHFR C677T is associated with lower plasma folate. Thus, if lower plasma folate had a causal effect on CVM risk, a higher frequency of TT genotype among CVM cases than among healthy controls would be anticipated. We placed our results in the context of a meta-analysis of all previously published studies of this question, which included a further 1883 cases and 3069 controls in 25 studies. We used random-effects models to meta-analyse the data. We conducted sensitivity analyses to examine folate fortification of flour as a potential source of heterogeneity. The primary genotyping data in 1186 cases and 4168 controls revealed a trend towards increased risk with the TT genotype, but this did not reach statistical significance (OR 1.15 [95% CI 0.94-1.40]). Combination of our primary data with previous studies, however, showed association in the complete dataset (OR 1.45 [95% CI 1.12-1.89]; p=0.005) comprising a total of 3069 CVM cases and 7271 controls. Studies conducted in countries without mandatory folate fortification showed an effect of C677T genotype on CVM risk (OR 1.63 [95% CI 1.19 - 2.25]) whereas studies conducted in countries with mandatory fortification did not (OR 0.96 [95% CI 0.64-1.44]). These odds ratios were significantly different from each other (p=0.032).
Conclusions: We demonstrate genetic evidence in favour of a causal relationship between lower levels of plasma folate and CVM. Moreover, our results suggest that folate fortification abrogates the risk of CVM attributable to folate deficiency.
- © 2011 by American Heart Association, Inc.