Cascorbi I, Drakoulis N, Brockmöller J, Maurer A, Sperling K, Roots I
Institute of Clinical Pharmacology, University Clinic Charité, Humboldt University of Berlin, Germany.
Am J Hum Genet. 1995 Sep;57(3):581-92.
The polymorphic arylamine N-acetyltransferase (NAT2; EC 2.3.1.5) is supposed to be a susceptibility factor for several drug side effects and certain malignancies. A group of 844 unrelated German subjects was genotyped for their acetylation type, and 563 of them were also phenotyped. Seven mutations of the NAT2 gene were evaluated by allele-specific PCR (mutation 341C to T) and PCR-RFLP for mutations at nt positions 191, 282, 481, 590, 803, and 857. From the mutation pattern eight different alleles, including the wild type coding for rapid acetylation and seven alleles coding for slow phenotype, were determined. Four hundred ninety-seven subjects had a genotype of slow acetylation (58.9%; 95% confidence limits 55.5%-62.2%). Phenotypic acetylation capacity was expressed as the ratio of 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine in urine after caffeine intake. Some 6.7% of the cases deviated in genotype and phenotype, but sequencing DNA of these probands revealed no new mutations. Furthermore, linkage pattern of the mutations was always confirmed, as tested in 533 subjects. In vivo acetylation capacity of homozygous wild-type subjects (NAT2*4/*4) was significantly higher than in heterozygous genotypes (P = .001). All mutant alleles showed low in vivo acetylation capacities, including the previously not-yet-defined alleles *5A, *5C, and *13. Moreover, distinct slow genotypes differed significantly among each other, as reflected in lower acetylation capacity of *6A, *7B, and *13 alleles than the group of *5 alleles. The study demonstrated differential phenotypic activity of various NAT2 genes and gives a solid basis for clinical and molecular-epidemiological investigations.
多态性芳胺N - 乙酰基转移酶（NAT2；EC 2.3.1.5）被认为是多种药物副作用和某些恶性肿瘤的易感性因素。对844名无亲缘关系的德国受试者进行了乙酰化类型基因分型，其中563人还进行了表型分析。通过等位基因特异性PCR（341C突变为T）以及针对nt位置191、282、481、590、803和857处突变的PCR - RFLP对NAT2基因的7种突变进行了评估。根据突变模式确定了8种不同的等位基因，包括编码快速乙酰化的野生型以及7种编码慢表型的等位基因。497名受试者的基因型为慢乙酰化（58.9%；95%置信区间55.5% - 62.2%）。表型乙酰化能力通过摄入咖啡因后尿液中5 - 乙酰氨基 - 6 - 甲酰氨基 - 3 - 甲基尿嘧啶与1 - 甲基黄嘌呤的比值来表示。约6.7%的病例在基因型和表型上存在偏差，但对这些先证者的DNA测序未发现新的突变。此外，在533名受试者中进行检测，突变的连锁模式始终得到证实。纯合野生型受试者（NAT24/4）的体内乙酰化能力显著高于杂合基因型（P = .001）。所有突变等位基因的体内乙酰化能力均较低，包括先前未定义的等位基因5A、5C和13。此外，不同的慢基因型彼此之间存在显著差异，表现为6A、7B和13等位基因的乙酰化能力低于*5等位基因组。该研究证明了各种NAT2基因的不同表型活性，为临床和分子流行病学研究提供了坚实的基础。
