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Birth Defects Res A Clin Mol Teratol. 2011 Feb;91(2):77-84. doi: 10.1002/bdra.20763. Epub 2011 Feb 2.

Functional effects of genetic polymorphisms in the N-acetyltransferase 1 coding and 3' untranslated regions.

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Department of Pharmacology and Toxicology, James Graham Brown Cancer Center, Birth Defects Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, KY 40202, USA.



The functional effects of N-acetyltransferase 1 (NAT1) polymorphisms and haplotypes are poorly understood, compromising the validity of associations reported with diseases, including birth defects and numerous cancers.


We investigated the effects of genetic polymorphisms within the NAT1 coding region and the 3'-untranslated region (3'-UTR) and their associated haplotypes on N- and O-acetyltransferase catalytic activities, and NAT1 mRNA and protein levels following recombinant expression in COS-1 cells.


1088T>A (rs1057126; 3'-UTR) and 1095C>A (rs15561; 3'-UTR) each slightly reduced NAT1 catalytic activity and NAT1 mRNA and protein levels. A 9-bp (TAATAATAA) deletion between nucleotides 1065 and 1090 (3'-UTR) reduced NAT1 catalytic activity and NAT1 mRNA and protein levels. In contrast, a 445G>A (rs4987076; V149I), 459G>A (rs4986990; T153T), and 640T>G (rs4986783; S214A) coding region haplotype present in NAT1*11 increased NAT1 catalytic activity and NAT1 protein, but not NAT1 mRNA levels. A combination of the 9-bp (TAATAATAA) deletion and the 445G>A, 459G>A, and 640T>G coding region haplotypes, both present in NAT1*11, appeared to neutralize the opposing effects on NAT1 protein and catalytic activity, resulting in levels of NAT1 protein and catalytic activity that did not differ significantly from the NAT1*4 reference.


Because 1095C>A (3'-UTR) is the sole polymorphism present in NAT1*3, our data suggest that NAT1*3 is not functionally equivalent to the NAT1*4 reference. Furthermore, our findings provide biologic support for reported associations of 1088T>A and 1095C>A polymorphisms with birth defects.

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