Genetic variants and risk of lung cancer in never smokers: A genome-wide association study

Yafei Li, Chau Chyun Sheu, Yuanqing Ye, Mariza de Andrade, Liang Wang, Shen Chih Chang, Marie C. Aubry, Jeremiah A. Aakre, Mark S. Allen, Feng Chen, Julie M. Cunningham, Claude Deschamps, Ruoxiang Jiang, Jie Lin, Randolph S. Marks, V. Shane Pankratz, Li Su, Yan Li, Zhifu Sun, Hui TangGeorge Vasmatzis, Curtis C. Harris, Margaret R. Spitz, Jin Jen, Renyi Wang, Zuo Feng Zhang, David C. Christiani, Xifeng Wu, Ping Yang

Research output: Contribution to journalArticlepeer-review

178 Scopus citations


Background: Lung cancer in individuals who have never smoked tobacco products is an increasing medical and public-health issue. We aimed to unravel the genetic basis of lung cancer in never smokers. Methods: We did a four-stage investigation. First, a genome-wide association study of single nucleotide polymorphisms (SNPs) was done with 754 never smokers (377 matched case-control pairs at Mayo Clinic, Rochester, MN, USA). Second, the top candidate SNPs from the first study were validated in two independent studies among 735 (MD Anderson Cancer Center, Houston, TX, USA) and 253 (Harvard University, Boston, MA, USA) never smokers. Third, further replication of the top SNP was done in 530 never smokers (UCLA, Los Angeles, CA, USA). Fourth, expression quantitative trait loci (eQTL) and gene-expression differences were analysed to further elucidate the causal relation between the validated SNPs and the risk of lung cancer in never smokers. Findings: 44 top candidate SNPs were identified that might alter the risk of lung cancer in never smokers. rs2352028 at chromosome 13q31.3 was subsequently replicated with an additive genetic model in the four independent studies, with a combined odds ratio of 1·46 (95% CI 1·26-1·70, p=5·94×10-6). A cis eQTL analysis showed there was a strong correlation between genotypes of the replicated SNPs and the transcription level of the gene GPC5 in normal lung tissues (p=1·96×10-4), with the high-risk allele linked with lower expression. Additionally, the transcription level of GPC5 in normal lung tissue was twice that detected in matched lung adenocarcinoma tissue (p=6·75×10-11). Interpretation: Genetic variants at 13q31.3 alter the expression of GPC5, and are associated with susceptibility to lung cancer in never smokers. Downregulation of GPC5 might contribute to the development of lung cancer in never smokers. Funding: US National Institutes of Health; Mayo Foundation.

Original languageEnglish (US)
Pages (from-to)321-330
Number of pages10
JournalThe Lancet Oncology
Issue number4
StatePublished - Apr 2010
Externally publishedYes

ASJC Scopus subject areas

  • Oncology


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