title: Interstitial lung disease in gefitinib-treated Japanese patients with non-small-cell lung cancer: genome-wide analysis of genetic data.
abstract: OBJECTIVE
  To investigate potential relationships between SNPs and acute interstitial lung disease (ILD) events in Japanese non-small-cell lung cancer patients receiving gefitinib.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Global Epidemiology, AstraZeneca R&D, Mölndal, Sweden and Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden. fredrik.nyberg@astrazeneca.com
authors.forename: Fredrik
authors.initials: F
authors.lastname: Nyberg
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Barratt
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Ansar
authors.initials: A
authors.lastname: Jawaid
authors.forename: Shuji
authors.initials: S
authors.lastname: Hada
authors.forename: Takaaki
authors.initials: T
authors.lastname: Umemura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Koichiro
authors.initials: K
authors.lastname: Nakata
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.forename: Harubumi
authors.initials: H
authors.lastname: Kato
authors.forename: Shoji
authors.initials: S
authors.lastname: Kudoh
authors.forename: Ruth
authors.initials: R
authors.lastname: March
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D016022:Case-Control Studies; D000077156:Gefitinib; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan; D017563:Lung Diseases, Interstitial / Q000139:chemically induced* / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy*; D020641:Polymorphism, Single Nucleotide; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects*; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077156:Gefitinib