TY - JOUR
T1 - Genetic variants and risk of lung cancer in never smokers
T2 - A genome-wide association study
AU - Li, Yafei
AU - Sheu, Chau Chyun
AU - Ye, Yuanqing
AU - de Andrade, Mariza
AU - Wang, Liang
AU - Chang, Shen Chih
AU - Aubry, Marie C.
AU - Aakre, Jeremiah A.
AU - Allen, Mark S.
AU - Chen, Feng
AU - Cunningham, Julie M.
AU - Deschamps, Claude
AU - Jiang, Ruoxiang
AU - Lin, Jie
AU - Marks, Randolph S.
AU - Pankratz, V. Shane
AU - Su, Li
AU - Li, Yan
AU - Sun, Zhifu
AU - Tang, Hui
AU - Vasmatzis, George
AU - Harris, Curtis C.
AU - Spitz, Margaret R.
AU - Jen, Jin
AU - Wang, Renyi
AU - Zhang, Zuo Feng
AU - Christiani, David C.
AU - Wu, Xifeng
AU - Yang, Ping
N1 - Funding Information:
We thank Susan Ernst for her technical assistance with the manuscript. The Microarray Shared Resource and the Genotyping Shared Resource of the Mayo Clinic Advanced Genomic Technology Center, respectively, did all the genome-wide association and gene-expression analyses described in this study. This study was supported by US National Institutes of Health research grants R01-CA80127 (to PY), R01-CA84354 (to PY), CA111646 (to XW), CA127615 (to XW), CA055769 (to MRS), CA092824 (to DCC), CA074386 (to DCC), CA090578 (to DCC), P50 CA90833 (to ZFZ), T32 CA09142 (to ZFZ), and Mayo Foundation funds (to PY and JJ).
PY - 2010/4
Y1 - 2010/4
N2 - 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.
AB - 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.
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U2 - 10.1016/S1470-2045(10)70042-5
DO - 10.1016/S1470-2045(10)70042-5
M3 - Article
C2 - 20304703
AN - SCOPUS:77950341944
SN - 1470-2045
VL - 11
SP - 321
EP - 330
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 4
ER -