Abstract
Periconceptional folic acid supplementation reduces the risk of having a child with spina bifida. N-acetyltransferase 1 (NAT1) participates in the catabolism of folates and the acetylation of aromatic and heterocyclic amines. Hence, functional polymorphisms in NAT1, the gene encoding NAT1, could influence the risk of spina bifida via either folate catabolism or acetylation of exogenous agents. Individuals with spina bifida and their parents were genotyped for six NAT1 single nucleotide polymorphisms (SNPs) for which the less common allele is associated with reduced or absent enzyme activity (i.e. 97C>T, 190C>T, 559C>T/560G>A, 640T>G and 752A>T). In addition, a “composite” NAT1 genotype was defined as a function of the genotyped SNPs. Descriptive analyses of the SNPs and of the composite genotype indicated that heterozygous parents were more likely to transmit the common allele than the rare allele to their affected offspring. Furthermore, matings of mothers homozygous for the common allele and heterozygous fathers were more common than the reciprocal matings. Log-linear analyses confirmed that both the maternal (P = 0.008) and offspring (P = 0.003) composite NAT1 genotypes were significantly related to the risk of spina bifida. NAT1 variants that reduce or abolish enzyme activity appear to protect against spina bifida, and to exert their influence via both the maternal and the offspring genotypes. These associations may be attributable to a decrease in either folate catabolism or the conversion of exogenous agents to teratogenic derivatives in women and/or developing embryos with a NAT1 genotype that includes a loss of function allele relative to those who do not.
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Acknowledgments
This study was supported by grants from the National Institutes of Health (HD39195; HD39081), the Ethel Brown Foerderer Fund for Excellence and the General Clinical Research Center (M01-RR00240) of The Childrens Hospital of Philadelphia. The authors are grateful to their colleagues in The Spina Bifida Program (Dr. P. Pasquariello and J. Melchionni) and The Center for Fetal Diagnosis and Therapy (Dr. N.S. Adzick, Dr. M.P. Johnson, Dr. R.D. Wilson, L. Howell, S. Miesnik, M. Oxman and S. Kasperski) at The Children’s Hospital of Philadelphia, and in the Spinal Dysfunction Clinic at The A.I. duPont Hospital for Children (Dr. M. McManus and R. Gleeson), to Gillian Wallace for technical assistance, and to all of the families that have enrolled in this study.
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The sequence reported in this paper has been submitted to GenBank under accession number AY730684.
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Jensen, L.E., Hoess, K., Mitchell, L.E. et al. Loss of function polymorphisms in NAT1 protect against spina bifida. Hum Genet 120, 52–57 (2006). https://doi.org/10.1007/s00439-006-0181-6
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DOI: https://doi.org/10.1007/s00439-006-0181-6