Skretkowicz K, Skretkowicz J, Gawrońska-Szklarz B, Górnik W, Rychlik-Sych M, Sysa-Jedrzejowska A
Department of Pharmacology and Clinical Pharmacology , Medical University of Lodz, ul. Muszyńskiego 1, 90-151, Lodz, Poland.
Eur J Clin Pharmacol. 2005 Jan;60(11):773-8. doi: 10.1007/s00228-004-0837-x. Epub 2004 Nov 24.
It has been shown that exposure to some environmental toxins may induce scleroderma-like illness in predisposed individuals, but the etiopathogenesis of the idiopathic form of systemic sclerosis (SSc) remains obscure. The genetic background of this illness has been confirmed in multiple studies. We investigated whether patients with SSc differ from healthy subjects with regard to the enzymatic activity of polymorphic N-acetyltransferase 2 (NAT2).
The study was carried out in 39 patients with SSc; 15 fulfilled the criteria of diffuse SSc (dSSc) and 24 of limited SSc (lSSc); an ethnically matched control group consisted of 100 healthy volunteers. Acetylation phenotype was estimated using the isoniazid as a model drug. The most common mutations in the Caucasian population at positions 481T, 803G, 590A and 857A on the NAT2 gene were determined using the polymerase chain reaction-restriction fragment length polymorphism method with deoxyribonucleic acid (DNA) extracted from peripheral blood.
In the group of patients with SSc, the frequency of fast acetylator genotypes was 38.5% (95% CI 23.4-55.4), while that for the genotypes coding slow acetylator status was 51.3% (95% CI 34.8-67.6). There was a strong correlation between NAT2 phenotype and NAT2 genotype with a concordance of 97%. We did not observe a preponderance of slow acetylators among patients with SSc and in two subsets of SSc. With the sample size analyzed in the present study, there is a 90% probability of detecting significant differences in distribution of slow, fast, and intermediate phenotypes between patients with SSc and controls, there is a difference of at least 30.3, 28.7 and 21.9% in the distribution of these phenotypes in the general population, respectively.
Acetylator status does not seem to be the significant factor in the development of SSc in patients with both subsets of this autoimmune disease, but further studies are required to confirm this conclusion.
研究表明，接触某些环境毒素可能会使易感个体患上硬皮病样疾病，但特发性系统性硬化症（SSc）的病因发病机制仍不清楚。多项研究已证实了该疾病的遗传背景。我们调查了SSc患者与健康受试者在多态性N-乙酰转移酶2（NAT2）的酶活性方面是否存在差异。
该研究纳入了39例SSc患者，其中15例符合弥漫性SSc（dSSc）标准，24例符合局限性SSc（lSSc）标准；一个种族匹配的对照组由100名健康志愿者组成。以异烟肼作为模型药物评估乙酰化表型。使用聚合酶链反应-限制性片段长度多态性方法，从外周血中提取脱氧核糖核酸（DNA），确定高加索人群中NAT2基因481T、803G、590A和857A位点最常见的突变。
在SSc患者组中，快速乙酰化基因型的频率为38.5%（95%可信区间23.4-55.4），而编码缓慢乙酰化状态的基因型频率为51.3%（95%可信区间34.8-67.6）。NAT2表型与NAT2基因型之间存在强相关性，一致性为97%。我们在SSc患者以及SSc的两个亚组中均未观察到缓慢乙酰化者占优势。根据本研究分析的样本量，有90%的概率检测到SSc患者与对照组之间缓慢、快速和中间表型分布的显著差异，在一般人群中这些表型的分布差异分别至少为30.3%、28.7%和21.9%。
在这种自身免疫性疾病的两个亚组患者中，乙酰化状态似乎不是SSc发病的重要因素，但需要进一步研究来证实这一结论。
