Eight-fold increased risk for congenital heart defects in children carrying the nicotinamide N-methyltransferase polymorphism and exposed to medicines and low nicotinamide.
van Driel LMJW., Smedts HPM., Helbing WA., Isaacs A., Lindemans J., Uitterlinden AG., van Duijn CM., de Vries JHM., Steegers EAP., Steegers-Theunissen RPM.
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 (<or=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.