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European Heart Journal Advance Access originally published online on April 25, 2008
European Heart Journal 2008 29(11):1424-1431; doi:10.1093/eurheartj/ehn170
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

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

Lydi M.J.W. van Driel1,2, Huberdina P.M. Smedts1, Willem A. Helbing2, Aaron Isaacs3, Jan Lindemans4, André G. Uitterlinden4,5,6, Cornelia M. van Duijn6, Jeanne H.M. de Vries7, Eric A.P. Steegers1 and Regine P.M. Steegers-Theunissen1,2,3,6,*

1 Division of Obstetrics and Prenatal Medicine, Department of Obstetrics and Gynaecology, Erasmus University Medical Centre, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
2 Division of Paediatric Cardiology, Department of Paediatrics, Erasmus University Medical Centre, Rotterdam, The Netherlands
3 Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands
4 Department of Clinical Chemistry, Erasmus University Medical Centre, Rotterdam, The Netherlands
5 Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands
6 Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands
7 Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands

Received 29 October 2007; revised 22 February 2008; accepted 4 April 2008; online publish-ahead-of-print 25 April 2008.

* Corresponding author. Tel: +31 10 4636886, Fax: +31 10 4636815, Email: r.steegers{at}erasmusmc.nl

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.

Key Words: Cardiovascular anomalies • Aetiology • NNMT • Nutrition • Medicine • B-vitamin


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