Association of NAT1 and NAT2 genes with nonsyndromic cleft lip and palate

Song,Tao; Wu,Di; Wang,Yongqian; Li,Haidong; Yin,Ningbei; Zhao,Zhenmin

doi:10.3892/mmr.2013.1467

Association of NAT1 and NAT2 genes with nonsyndromic cleft lip and palate

Authors:
- Tao Song
- Di Wu
- Yongqian Wang
- Haidong Li
- Ningbei Yin
- Zhenmin Zhao
View Affiliations

Affiliations: Center of Cleft Lip and Palate, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
Published online on: May 9, 2013 https://doi.org/10.3892/mmr.2013.1467
Pages: 211-216

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Nonsyndromic cleft lip and palate (NSCLP) is a common congenital deformity, often associated with environmental risk factors, including alcohol, smoking, drugs and radiation exposure. N-acetyltransferase (NAT)1 and NAT2 genes are involved in the detoxification and metabolic activation of numerous drugs and chemicals. The aim of the present study was to investigate whether genetic variations in these two genes and gene‑gene interactions are associated with NSCLP. We investigated eight NAT1 tag single nucleotide polymorphisms (SNPs) and five NAT2 tag SNPs, selected from HapMap data. These SNPs were examined for associations with NSCLP in 204 patients and 226 controls. Strong evidence of an association with NSCLP was identified for rs4921580 in the NAT1 gene, and haplotype analysis supported these findings. We also found a significant difference between NSCLP and control groups for rs1041983 in the NAT2 gene. The results of gene‑gene interaction analyses also indicated that the combination of rs4921580 (Cg+gg) x rs1041983 (Ct+tt) increased the risk of NSCLP. Thus, the present study provides evidence for the role of NAT1 and NAT2 variations in NSCLP, and indicates that interactions between the NAT1 and NAT2 genes may be important in susceptibility to NSCLP.

View Figures

View References

1	Stuppia L, Capogreco M, Marzo G, et al: Genetics of syndromic and nonsyndromic cleft lip and palate. J Craniofac Surg. 22:1722–1726. 2011. View Article : Google Scholar : PubMed/NCBI
2	Munger RG, Romitti PA, Daack-Hirsch S, Burns TL, Murray JC and Hanson J: Maternal alcohol use and risk of orofacial cleft birth defects. Teratology. 54:27–33. 1996. View Article : Google Scholar : PubMed/NCBI
3	Little J, Cardy A, Arslan MT, Gilmour M and Mossey PA: Smoking and orofacial clefts: a United Kingdom-based case-control study. Cleft Palate Craniofac J. 41:381–386. 2004. View Article : Google Scholar : PubMed/NCBI
4	Jia ZL, Shi B, Chen CH, Shi JY, Wu J and Xu X: Maternal malnutrition, environmental exposure during pregnancy and the risk of non-syndromic orofacial clefts. Oral Dis. 17:584–589. 2011. View Article : Google Scholar : PubMed/NCBI
5	Hernández-Diaz S, Smith CR, Shen A, et al: Comparative safety of antiepileptic drugs during pregnancy. Neurology. 78:1692–1699. 2012.
6	Cech I, Burau KD and Walston J: Spatial distribution of orofacial cleft defect births in Harris County, Texas, 1990 to 1994, and historical evidence for the presence of low-level radioactivity in tap water. South Med J. 100:560–569. 2007. View Article : Google Scholar : PubMed/NCBI
7	Ramirez D, Lammer EJ, Iovannisci DM, Laurent C, Finnell RH and Shaw GM: Maternal smoking during early pregnancy, GSTP1 and EPHX1 variants, and risk of isolated orofacial clefts. Cleft Palate Craniofac J. 44:366–373. 2007. View Article : Google Scholar : PubMed/NCBI
8	Sim E, Fakis G, Laurieri N and Boukouvala S: Arylamine N-acetyltransferases - from drug metabolism and pharmacogenetics to identification of novel targets for pharmacological intervention. Adv Pharmacol. 63:169–205. 2012. View Article : Google Scholar : PubMed/NCBI
9	Mortensen HM, Froment A, Lema G, et al: Characterization of genetic variation and natural selection at the arylamine N-acetyltransferase genes in global human populations. Pharmacogenomics. 12:1545–1558. 2011. View Article : Google Scholar : PubMed/NCBI
10	Boukouvala S and Fakis G: Arylamine N-acetyltransferases: what we learn from genes and genomes. Drug Metab Rev. 37:511–564. 2005. View Article : Google Scholar : PubMed/NCBI
11	Smelt VA, Mardon HJ and Sim E: Placental expression of arylamine N-acetyltransferases: evidence for linkage disequilibrium between NAT110 and NAT24 alleles of the two human arylamine N-acetyltransferase loci NAT1 and NAT2. Pharmacol Toxicol. 83:149–157. 1998.PubMed/NCBI
12	Ward A, Hickman D, Gordon JW and Sim E: Arylamine N-acetyltransferase in human red blood cells. Biochem Pharmacol. 44:1099–1104. 1992. View Article : Google Scholar : PubMed/NCBI
13	Minchin RF: Acetylation of p-aminobenzoylglutamate, a folic acid catabolite, by recombinant human arylamine N-acetyltransferase and U937 cells. Biochem J. 307(Pt 1): 1–3. 1995.PubMed/NCBI
14	Erickson RP, Cao W, Acuña DK, et al: Confirmation of the role of N-acetyltransferase 2 in teratogen-induced cleft palate using transgenics and knockouts. Mol Reprod Dev. 75:1071–1076. 2008. View Article : Google Scholar : PubMed/NCBI
15	Lammer EJ, Shaw GM, Iovannisci DM, Van Waes J and Finnell RH: Maternal smoking and the risk of orofacial clefts: susceptibility with NAT1 and NAT2 polymorphisms. Epidemiology. 15:150–156. 2004. View Article : Google Scholar : PubMed/NCBI
16	Lammer EJ, Shaw GM, Iovannisci DM and Finnell RH: Periconceptional multivitamin intake during early pregnancy, genetic variation of acetyl-N-transferase 1 (NAT1), and risk for orofacial clefts. Birth Defects Res A Clin Mol Teratol. 70:846–852. 2004. View Article : Google Scholar
17	Lie RT, Wilcox AJ, Taylor J, et al: Maternal smoking and oral clefts: the role of detoxification pathway genes. Epidemiology. 19:606–615. 2008. View Article : Google Scholar : PubMed/NCBI
18	Shi M, Christensen K, Weinberg CR, et al: Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants. Am J Hum Genet. 80:76–90. 2007. View Article : Google Scholar : PubMed/NCBI
19	van Rooij IA, Groenen PM, van Drongelen M, Te Morsche RH, Peters WH and Steegers-Theunissen RP: Orofacial clefts and spina bifida: N-acetyltransferase phenotype, maternal smoking, and medication use. Teratology. 66:260–266. 2002.PubMed/NCBI
20	Komar AA: Silent SNPs: impact on gene function and phenotype. Pharmacogenomics. 8:1075–1080. 2007. View Article : Google Scholar : PubMed/NCBI
21	Cornish VA, Pinter K, Boukouvala S, et al: Generation and analysis of mice with a targeted disruption of the arylamine N-acetyltransferase type 2 gene. Pharmacogenomics J. 3:169–177. 2003. View Article : Google Scholar : PubMed/NCBI
22	Sugamori KS, Wong S, Gaedigk A, et al: Generation and functional characterization of arylamine N-acetyltransferase Nat1/Nat2 double-knockout mice. Mol Pharmacol. 64:170–179. 2003. View Article : Google Scholar : PubMed/NCBI