Interstitial lung disease in gefitinib-treated Japanese patients with non-small-cell lung cancer: genome-wide analysis of genetic data

Pharmacogenomics. 2011 Jul;12(7):965-75. doi: 10.2217/pgs.11.38.


Aim: 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.

Results: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Case-Control Studies
  • Gefitinib
  • Genome-Wide Association Study
  • Humans
  • Japan
  • Lung Diseases, Interstitial / chemically induced*
  • Lung Diseases, Interstitial / genetics*
  • Lung Neoplasms / drug therapy*
  • Polymorphism, Single Nucleotide
  • Quinazolines / administration & dosage
  • Quinazolines / adverse effects*
  • Retrospective Studies


  • Antineoplastic Agents
  • Quinazolines
  • Gefitinib