期刊
INTERNATIONAL JOURNAL OF CANCER
卷 137, 期 2, 页码 311-319出版社
WILEY
DOI: 10.1002/ijc.29393
关键词
association study; genetics; lung cancer; telomere length; genetic risk score
类别
资金
- Ministry of Health [201002007]
- Ministry of Science and Technology [2011BAI09B00]
- National S&T Major Special Project [2011ZX09102-010-01]
- China National High-Tech Research and Development Program [2012AA02A517, 2012AA02A518, 2009AA022705]
- National Science Foundation of China [30890034]
- National Basic Research Program [2012CB944600]
- Scientific and Technological Support Plans from Jiangsu Province [BE2010715]
- Foundation of Guangdong Science and Technology Department [2006B60101010, 2007A032000002, 2011A030400010]
- Guangzhou Science and Information Technology Bureau [2011Y2-00014]
- Chinese Lung Cancer Research Foundation
- National Natural Science Foundation [81101549]
- Natural Science Foundation of Guangdong Province [S2011010000792]
- National Research Program on Genomic Medicine in Taiwan [DOH98-TD-G-111-015]
- National Research Program for Biopharmaceuticals in Taiwan [DOH 100-TD-PB-111-TM013, MOST 103-2325-B-400-011]
- National Science Council, Taiwan [NSC 100-2319-B-400-001]
- National Medical Research Council Singapore [NMRC/0897/2004, NMRC/1075/2006]
- Agency for Science, Technology and Research
- General Research Fund of Research Grant Council, Hong Kong [781511M, 17121414M]
- National Science Foundation, China [91229105]
- Scientific Research on Priority Areas and on Innovative Area from the Ministry of Education, Science, Sports, Culture and Technology of Japan [NCI R01-CA121210]
- National Key Basic Research Program [2011CB503805]
- National Research Foundation of Korea [NRF-2014R1A2A2A05003665]
- Ministry of Health & Welfare, Republic of Korea [0720550-2, A010250]
- National Key Basic Research and Development Program [2011CB503800]
- National Nature Science Foundation of China [81102194]
- Liaoning Provincial Department of Education [LS2010168]
- China Medical Board [00726]
- National Institutes of Health [R37 CA70867]
- National Cancer Institute Intramural Research Program [N02 CP1101066]
Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR=1.51 (95% CI=1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value=4.54 x 10(-14)) even after removing rs2736100 (p value=4.81 x 10(-3)), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk. What's new? The possibility for a relationship between telomere length and cancer is intriguing, but many questions remain, including whether short or long telomeres are involved. Here, a genetic risk score derived from seven telomere-length associated genetic variants revealed a positive association between telomere length and lung cancer risk in Asian women who never smoked. The genetic proxy was unaffected by reverse-causation bias or environmental exposures. The differences in telomere length captured by the variants could aid in the identification of biological mechanisms that underlie the association between longer telomere length and increased lung cancer risk.
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