Eight-fold increased risk for congenital heart defects in children carrying the nicotinamide N-methyltransferase polymorphism and exposed to medicines and low nicotinamide.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
van Driel
Lydi M J W
LM
Division of Obstetrics and Prenatal Medicine, Department of Obstetrics and Gynaecology, Erasmus University Medical Centre, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Smedts
Huberdina P M
HP
Helbing
Willem A
WA
Isaacs
Aaron
A
Lindemans
Jan
J
Uitterlinden
André G
AG
van Duijn
Cornelia M
CM
de Vries
Jeanne H M
JH
Steegers
Eric A P
EA
Steegers-Theunissen
Régine P M
RP
D000328:Adult; D002648:Child; D064420:Drug-Related Side Effects and Adverse Reactions; D004812:Epidemiologic Methods; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006330:Heart Defects, Congenital / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000235:genetics; D008297:Male; D009536:Niacinamide / Q000008:administration & dosage*; D050903:Nicotinamide N-Methyltransferase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D014803:Vitamin B Complex / Q000008:administration & dosage*
D014803:Vitamin B Complex; D009536:Niacinamide; D050903:Nicotinamide N-Methyltransferase