Arylamine N-acetyltransferase gene polymorphisms: markers for atopic asthma, serum IgE and blood eosinophil counts

Abstract

Introduction: Polymorphisms in N-acetyltransferase 2 (NAT2), present on chromosome 8p22, are responsible for the N-acetylation variants, which segregate human populations into rapid, intermediate and slow acetylators and influence the susceptibility towards atopic disorders. We have undertaken a study of the North Indian population to screen for various NAT2 polymorphisms and to investigate their association with atopic asthma and related phenotypes. Methods: First, to establish linkage of the 8p22 region with asthma, 158 families were recruited from North India. Next, a total of 219 unrelated atopic asthmatics and 210 unrelated healthy controls were recruited for case-control disease association studies. Results: A suggestive linkage was observed with microsatellite marker D8S549, 2.6 MB upstream of NAT2. By sequencing the DNA of 40 individuals, the T111C, G191A, A434C and C759T single nucleotide polymorphisms (SNPs) in NAT2 were found to be nonpolymorphic in our population and a pattern of strong linkage disequilibrium was observed among the T341C, C481T and A803G polymorphisms. Thus, a total of 429 individuals were genotyped for the C481T and unlinked C282T polymorphisms. The C481T polymorphism was found to be significantly associated with asthma in our case-control studies at the genotype level (Armitage p = 0.00027). C481T also showed a marginal association with serum total IgE (TsIgE) (p = 0.022). Furthermore, percent blood eosinophil counts were found to be significantly higher in patients carrying the 481T allele (p = 0.0037). Significant association was also detected with respect to the C282T polymorphism and TsIgE (p = 0.008). Moreover, C_T was found to be an important risk (p = 0.001), while C_C was a major protective haplotype (p = 0.0005). The associations remained significant after Bonferroni correction for multiple testing. Conclusion: In summary, the genetic variants of the NAT2 gene do not seem to affect asthma alone, but act as modulators of asthma-related traits, such as serum IgE and blood eosinophil counts, and therefore could serve as genetic markers.