Aetiological role of folate deficiency in congenital cardiovascular malformation: Evidence from 'mendelian randomisation' and meta-analysis


The existence of a causal relationship between lower levels of plasma folate and congenital cardiovascular malformation (CVM) remains contentious. We present a genetic approach using “Mendelian randomization” to determine the causality of folate in CVM risk. We compared genotype frequencies at the (MTHFR) C677T SNP in 1186 CVM cases and 4168 controls. The TT genotype at MTHFR C677T is known to be associated with lower activity of MTHFR and plasma folate, and higher levels of plasma homocysteine. We placed our results in the context of a metaanalysis including 3069 CHD cases and 7271 controls. 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, revealed association in the complete dataset (OR 1.45 [95% CI 1.12-1.89]; p=0.005). Studies conducted in countries with mandatory folate fortification showed no effect of C677T genotype on CHD risk, whereas studies conducted in countries without mandatory fortification showed a significant effect of genotype. The absence of a genetic association in studies performed in countries practicing folate fortification suggests that fortification largely abrogates the risk of CHD attributable to folate deficiency.

Genetic Epidemiology 2012; 36(2):118-171