The complex etiology of bronchial asthma (BA), one of the most common inflammatory diseases throughout the world, involves a combination of various genetic and environmental factors. A number of investigators have undertaken linkage and association studies to shed light on the genetic background of BA, but the genetic aspects of this disease are still poorly understood. In the course of a project to screen the entire human genome for single nucleotide polymorphisms (SNPs) that might represent useful markers for large-scale association analyses of common diseases and pharmacogenetic traits, we identified six SNPs within the gene encoding I-kappaB-associated protein (IKAP), a regulator of the NF-kappaB signal pathway. Most of these SNPs were in linkage disequilibrium with each other. We observed a strong allelic association between BA in childhood and two of the SNP sites, T3214A (Cys1072Ser) and C3473T (Pro1158Leu); P = 0.000004 for T3214A and P = 0.0009 for C3473T. T3214A was also associated with BA in adult patients (P = 0.000002), but C3473T was not (P = 0.056). To confirm the above results, we compared estimated frequencies of haplotypes of the six SNPs between BA patients and controls. We found a strong association between BA in childhood and a specific haplotype, TGAAAT, that involved two amino-acid substitutions (819T, 2295G, 2446A, 2490A, 3214A, and 3473T; P = 0.00004, odds ratio, 2.94; 95% confidence interval [CI], 2.48-3.4). On the other hand, haplotype TACGTC, which differed from the TGAAAT haplotype in the last five nucleotides, was inversely correlated with the BA phenotype (P = 0.002; odds ratio, 9.83; 95% CI, 8.35-11.31). These results indicated that specific variants of the IKAP gene, or a variant in linkage disequilibrium with the TGAAAT haplotype, might be associated with mechanisms responsible for early-onset BA.

中文翻译：

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IKAP基因产物中的氨基酸取代显着增加了儿童支气管哮喘的风险。

支气管哮喘（BA）是世界上最常见的炎症性疾病之一，其病因复杂，涉及多种遗传和环境因素。许多研究者进行了连锁和关联研究，以了解BA的遗传背景，但对该病的遗传方面仍知之甚少。在筛选整个人类基因组的单核苷酸多态性（SNP）的项目过程中，SNP可能代表了常见疾病和药理学性状的大规模关联分析的有用标记，我们在编码I-kappaB相关的基因中鉴定出六个SNP蛋白（IKAP），NF-κB信号通路的调节剂。这些SNP中的大多数彼此之间处于连锁不平衡。我们观察到儿童期BA与两个SNP位点T3214A（Cys1072Ser）和C3473T（Pro1158Leu）之间存在强烈的等位基因关联。对于T3214A，P = 0.000004，对于C3473T，P = 0.0009。在成人患者中，T3214A也与BA相关（P = 0.000002），而C3473T与T3214A无关（P = 0.056）。为了证实上述结果，我们比较了BA患者和对照组之间六个SNP的单倍型的估计频率。我们发现儿童时期的BA与特定的单倍型TGAAAT之间有很强的联系，TGAAAT涉及两个氨基酸取代（819T，2295G，2446A，2490A，3214A和3473T; P = 0.00004，优势比为2.94; 95％置信区间[CI]，2.48-3.4）。另一方面，单倍型TACGTC与TGAAAT的单倍型在最后五个核苷酸上有所不同，与BA表型呈负相关（P = 0.002；优势比为9.83； 95％CI，8.35-11.31）。这些结果表明，IKAP基因的特定变体，或与TGAAAT单倍型连锁不平衡的变体，可能与导致早发BA的机制有关。