Alpha1-Antitrypsin Deficiency-Related Alleles Z and S and the Risk of Wegener's Granulomatosis
Alpha1-Antitrypsin Deficiency-Related Alleles Z and S and the Risk of Wegener's Granulomatosis
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DOI：
10.1002/art.27742
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发表时间：
2010-12-01
影响因子：
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通讯作者：
Merkel, Peter A.
中科院分区：
文献类型：
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作者：
Mahr, Alfred D.;Edberg, Jeffrey C.;Merkel, Peter A.
目标。α(1)-抗胰蛋白酶（α (1)AT）缺乏可能是韦格纳肉芽肿病（WG）易感性的决定因素。先前几项主要是小型病例对照研究表明，5-27%的WG患者携带α (1)AT缺乏症Z等位基因。目前尚不清楚S等位基因（另一个主要的α (1)AT缺陷变体）是否与WG相关。本研究调查了α (1)AT缺乏症Z和S等位基因与发生WG风险的关系。我们研究了α (1)AT缺陷等位基因Z和S在433名无血缘关系的白种人WG患者和421名种族匹配对照中的分布。采用等位基因鉴别法进行基因分型。用精确的统计学方法对病例和对照组的结果进行比较。结果。在WG患者中，Z和S等位基因携带频率分别为7.4%和11.5%。6种可能基因型的频率在病例和对照组之间差异有统计学意义（P = 0.01）。一般遗传2参数共显性模型对数据的拟合效果最好。与正常MM基因型相比，MZ或MS基因型的比值比（OR）为1.47(95%可信区间[95% CI] 0.98-2.22)， ZZ、SS或SZ基因型的比值比（OR）为14.58 （95% CI 2.33-∞）。在排除携带>= 1z或>= 1s等位基因的病例和对照的限制性队列中，观察到类似方向和大小的or。Z和S等位基因均以共显性遗传模式显示与WG风险相关。这些发现加强了α (1)AT缺乏与WG易感性之间因果关系的证据。
Objective. Deficiency of alpha(1)-antitrypsin (alpha(1)AT) may be a determinant of susceptibility to Wegener's granulomatosis (WG). Several previous, mainly small, case-control studies have shown that 5-27% of patients with WG carried the alpha(1)AT deficiency Z allele. It is not clear whether the S allele, the other major alpha(1)AT deficiency variant, is associated with WG. This study investigated the relationship of the alpha(1)AT deficiency Z and S alleles with the risk of developing WG in a large cohort.Methods. We studied the distribution of the alpha(1)AT deficiency alleles Z and S in 433 unrelated Caucasian patients with WG and 421 ethnically matched controls. Genotyping was performed using an allele discrimination assay.Results were compared between cases and controls using exact statistical methods. Results. Among the patients with WG, the allele carriage frequencies of Z and S were 7.4% and 11.5%, respectively. The frequencies of the 6 possible genotypes differed in a statistically significant manner between cases and controls (P = 0.01). The general genetic 2-parameter codominant model provided the best fit to the data. Compared with the normal MM genotype, the odds ratio (OR) for MZ or MS genotypes was 1.47 (95% confidence interval [95% CI] 0.98-2.22), and the OR for ZZ, SS, or SZ genotypes was 14.58 (95% CI 2.33-infinity). ORs of similar direction and magnitude were observed within the restricted cohorts that excluded cases and controls carrying >= 1 Z or >= 1 S allele.Conclusion. Both Z and S alleles display associations with risk of WG in a codominant genetic pattern. These findings strengthen the evidence of a causal link between alpha(1)AT deficiency and susceptibility to WG.