Aims: Congenital heart defects (CHDs) have a multifactorial origin, in which subtle genetic factors and peri-conception exposures interact. We hypothesize that derangements in the homocysteine and detoxification pathways, due to a polymorphism in the nicotinamide N-methyltransferase (NNMT) gene, low maternal dietary nicotinamide intake, and medicine use in the peri-conception period, affect CHD risk. Methods and results: In 292 case and 316 control families, maternal peri-conception medicine use and low dietary intake of nicotinamide (13.8 mg/day) were independently associated with CHD risk [odds ratio (95% confidence interval) 1.6 (1.1¿2.3) and 1.5 (1.03¿2.3), respectively]. No significant association was found for the NNMT AG/AA genotype in mothers [0.9 (0.7¿1.3)], fathers [1.1 (0.8¿1.6)], or children [1.1 (0.8¿1.6)]. However, the combination of peri-conception medicine use, low dietary nicotinamide intake, and the NNMT AG/AA genotype in mothers or children showed risk of 2.7 (1.02¿8.1) and 8.8 (2.4¿32.5), respectively. Conclusion: Children carrying the NNMT A allele face additional CHD risk in combination with peri-conception exposure to medicines and/or a low dietary nicotinamide intake. These findings provide a first set of data against which future studies with larger sample sizes can be compared with.
- plasma homocysteine