The Department of Otolaryngology, Hôpital Hôtel-Dieu de Montréal, Université de Montréal, Montreal, Quebec, Canada.
Am J Rhinol Allergy. 2010 Jan-Feb;24(1):e4-9. doi: 10.2500/ajra.2010.24.3429.
Alpha-1-antitrypsin (AAT) is a serine protease inhibitor that blocks the protease, neutrophil elastase. Previous population studies have suggested that heterozygote status for the AAT gene (SERPINA1) is a risk factor for chronic rhinosinusitis with nasal polyposis (CRSwNP). This implies a potential genetic predisposition to CRS tied to AAT deficiency. The purpose of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in the SERPINA1 gene and CRS.
DNA extracted from a population of 206 patients diagnosed with CRSwNPs and 196 postal code-matched controls was used. A maximally informative set of tagging SNPs from SERPINA1 on chromosome 14q were selected from the HapMap data set (International HapMap Consortium, Nature 437:1299-1320, 2005) and genotyped on the Sequenom platform (Sequenom, San Diego, CA).
Successful genotyping was performed for 32 of 33 SNPs. Two SNPs (rs1243168 and rs4900229) located upstream of the SERPINA1gene, were associated with CRS. Individuals homozygous (TT) for these SNPs had an increased probability of having CRS with an odds ratio of 5.95 and 1.49, respectively. Subgroup analysis according to severity of disease identified each SNP to be increasingly common in individuals as disease severity increased (p < 0.001). These individuals were also less likely to be responsive to medical therapy (p < 0.001).
Polymorphisms of the SERPINA1 gene are associated with clinically severe CRS. These results, from a small subset of individuals with CRS, suggest that defects in AAT may be implicated in a subset of individuals unresponsive to conventional therapy and suggests that alternate therapies may be required for their management.
α-1-抗胰蛋白酶（AAT）是一种丝氨酸蛋白酶抑制剂，可阻断蛋白酶，中性粒细胞弹性蛋白酶。先前的人群研究表明，AAT 基因（SERPINA1）的杂合状态是慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）的危险因素。这意味着 AAT 缺乏与 CRS 相关的潜在遗传易感性。本研究旨在探讨 SERPINA1 基因中的单核苷酸多态性（SNP）与 CRS 的关系。
从诊断为 CRSwNP 的 206 例患者和 196 例邮政编码匹配的对照者的人群中提取 DNA。从 HapMap 数据集（国际 HapMap 联盟，Nature 437:1299-1320，2005）中选择染色体 14q 上 SERPINA1 的一组信息量最大的标记 SNP，并在 Sequenom 平台（Sequenom，圣地亚哥，CA）上进行基因分型。
成功对 33 个 SNP 中的 32 个进行了基因分型。位于 SERPINA1 基因上游的两个 SNP（rs1243168 和 rs4900229）与 CRS 相关。这些 SNP 纯合（TT）的个体发生 CRS 的可能性增加，比值比分别为 5.95 和 1.49。根据疾病严重程度进行的亚组分析表明，随着疾病严重程度的增加，每个 SNP 在个体中变得越来越常见（p<0.001）。这些个体对药物治疗的反应也较低（p<0.001）。
SERPINA1 基因的多态性与临床上严重的 CRS 相关。这些来自一小部分 CRS 患者的结果表明，AAT 的缺陷可能与一部分对常规治疗无反应的个体有关，并表明需要替代疗法来治疗他们。
