Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706-1102, USA.
Pharmacogenet Genomics. 2012 Oct;22(10):733-40. doi: 10.1097/FPC.0b013e328357a735.
To determine whether polymorphisms in the sulfonamide detoxification genes, CYB5A (encoding cytochrome b(5)), CYB5R3 (encoding cytochrome b(5) reductase), or NAT2 (encoding N-acetyltransferase 2) were over-represented in patients with delayed sulfonamide drug hypersensitivity, compared with control patients who tolerated a therapeutic course of trimethoprim-sulfamethoxazole without adverse event.
DNA from 99 nonimmunocompromised patients with sulfonamide hypersensitivity who were identified from the Personalized Medicine Research Project at the Marshfield Clinic, and from 99 age-matched, race-matched, and sex-matched drug-tolerant controls, were genotyped for four CYB5A and five CYB5R3 polymorphisms, and for all coding NAT2 SNPs.
CYB5A and CYB5R3 SNPs were found at low allele frequencies (<3-4%), which did not differ between hypersensitive and tolerant patients. NAT2 allele and haplotype frequencies, as well as inferred NAT2 phenotypes, also did not differ between groups (60 vs. 59% slow acetylators). Finally, no difference in NAT2 status was found in a subset of patients with more severe hypersensitivity signs (drug reaction with eosinophilia and systemic symptoms) compared with tolerant patients.
We found no evidence of a substantial involvement of these nine CYB5A or CYB5R3 polymorphisms in sulfonamide hypersensitivity risk, although minor effects cannot be completely ruled out. Despite careful medical record review and full resequencing of the NAT2 coding region, we found no association of NAT2 coding alleles with sulfonamide hypersensitivity (predominantly cutaneous eruptions) in this adult Caucasian population.
确定磺酰胺解毒基因 CYB5A（编码细胞色素 b(5)）、CYB5R3（编码细胞色素 b(5)还原酶）或 NAT2（编码 N-乙酰基转移酶 2）中的多态性是否在发生磺酰胺药物迟发性过敏反应的患者中过度表达，与在 Marshfield 诊所的个性化医学研究项目中确定的 99 例无免疫功能低下且对甲氧苄啶-磺胺甲恶唑治疗方案耐受且无不良事件的对照患者相比。
对 99 例磺酰胺过敏患者和 99 例年龄、种族和性别匹配的药物耐受对照患者的 DNA 进行基因分型，以确定其 CYB5A 和 CYB5R3 四种多态性、五种 CYB5R3 多态性以及所有编码 NAT2 的 SNP。
CYB5A 和 CYB5R3 SNP 的等位基因频率较低（<3-4%），且在过敏和耐受患者之间无差异。NAT2 等位基因和单倍型频率以及推断的 NAT2 表型在两组之间也无差异（60% vs. 59% 为慢乙酰化者）。此外，与耐受患者相比，在具有更严重过敏体征（药物反应伴嗜酸性粒细胞增多和全身症状）的患者亚组中，NAT2 状态无差异。
尽管不能完全排除微小效应，但我们未发现这 9 种 CYB5A 或 CYB5R3 多态性与磺酰胺过敏风险有实质性关联。尽管我们仔细审查了病历并对 NAT2 编码区进行了全测序，但在该成年白种人群中未发现 NAT2 编码等位基因与磺酰胺过敏（主要为皮肤疹）有关。
