Global Epidemiology, AstraZeneca R&D, Mölndal, Sweden and Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
Pharmacogenomics. 2011 Jul;12(7):965-75. doi: 10.2217/pgs.11.38.
To investigate potential relationships between SNPs and acute interstitial lung disease (ILD) events in Japanese non-small-cell lung cancer patients receiving gefitinib.
MATERIALS & METHODS: Japanese non-small-cell lung cancer patients treated with gefitinib from a prospective pharmacoepidemiological cohort with a nested case-control study component ('CCS'; 52 ILD cases, 139 controls) and a retrospective study (28 ILD cases, 55 controls) were genotyped for nearly 500,000 SNPs. Associations between genotype and ILD were evaluated using Fisher's exact test and logistic regression modeling, and false discovery rate analysis was used to adjust for the large number of statistical tests.
The CCS data provided some false discovery rate evidence that the significance of top-ranking SNPs exceeded levels expected by chance, suggesting some genuine associations. However, replication analyses using retrospective study data were not supportive and there was little evidence of strong genetic associations from a combined analysis. Adjustment of CCS analyses for clinical variables provided little additional convincing evidence. Significant gene-gene interactions between SNP pairs using CCS data were not confirmed in retrospective study replication analyses.
Although it is not possible to exclude genetic influences in ILD etiology, common sequence variation is unlikely to explain a major component of ILD risk. Our top results may provide a useful hypothesis-generating starting point for further research.
研究接受吉非替尼治疗的日本非小细胞肺癌患者中 SNPs 与急性间质性肺病（ILD）事件之间的潜在关系。
使用来自前瞻性药物流行病学队列的嵌套病例对照研究部分（CCS；52 例 ILD 病例，139 例对照）和回顾性研究（28 例 ILD 病例，55 例对照）的吉非替尼治疗的日本非小细胞肺癌患者进行了近 50 万个 SNPs 的基因分型。使用 Fisher 精确检验和逻辑回归模型评估基因型与 ILD 之间的关联，并使用错误发现率分析来调整大量的统计检验。
CCS 数据提供了一些错误发现率证据，表明排名最高的 SNPs 的显著性超过了预期的随机水平，这表明存在一些真正的关联。然而，使用回顾性研究数据的复制分析并不支持，并且从综合分析中几乎没有证据表明存在强烈的遗传关联。对 CCS 分析进行临床变量调整并没有提供更多令人信服的证据。CCS 数据中 SNP 对之间的显著基因-基因相互作用在回顾性研究复制分析中未得到证实。
尽管不能排除遗传因素在 ILD 发病机制中的影响，但常见的序列变异不太可能解释 ILD 风险的主要部分。我们的顶级结果可能为进一步研究提供了一个有用的假说生成起点。
