Studies on N-Acetyltransferase (NAT2) Genotype Relationships in Emiratis: Confirmation of the Existence of Phenotype Variation among Slow Acetylators.

Abstract

Individuals with slow N-acetylation phenotype often experience toxicity from drugs such as isoniazid, sulfonamides, procainamide, and hydralazine, whereas rapid acetylators may not respond to these medications. The highly polymorphic N-acetyltransferase 2 enzyme encoded by the NAT2 gene is one of the N-acetylators in humans with a clear impact on the metabolism of a significant number of important drugs. However, there are limited studies on N-acetylation phenotypes and NAT2 genotypes among Emiratis, and thus this study was carried out to fill this gap. Five hundred seventy-six Emirati subjects were asked to consume a soft drink containing caffeine (a nontoxic and reliable probe for predicting the acetylation phenotype) and then provide a buccal swab along with a spot urine sample. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the genotype of each individual. Phenotyping was carried out by analyzing the caffeine metabolites using high-performance liquid chromatography (HPLC) analysis. We found that 78.5%, 19.1%, and 2.4% of the Emirati subjects were slow, intermediate, and rapid acetylators, respectively. In addition, we found that 77.4% of the subjects were homozygous or heterozygous for two nonreference alleles, whereas 18.4% and 4.2% were heterozygous or homozygous for the reference allele (NAT2*4), respectively. The most common genotypes found were NAT2*5B/*7B, NAT2*5B/*6A, NAT2*7B/*14B, and NAT2*4/*5B, with frequencies of 0.255, 0.135, 0.105, and 0.09, respectively. The degree of phenotype/genotype concordance was 96.2%. The NAT2*6A/*6A, NAT2*6A/*7B, NAT2*7B/*7B, and NAT2*5A/*5B genotypes were found to be associated with the lowest 5-acetylamino-6-formylamino-3-methyluracil/1-methylxanthine (AFMU/1X) ratios. There is a high percentage of slow acetylators among Emiratis, which correlates with the presence of nonreference alleles for the NAT2 gene. Individuals who carried NAT2*6A/*6A, NAT2*6A/*7B, NAT2*7B/*7B, or NAT2*5A/*5B genotypes might be at higher risk of toxicity with some drugs and some diseases compared to others, as these genotypes are associated with the slowest acetylation status.