Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia.

Abstract

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 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 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.

• Authors: Mitchell J Machiela, Chao Agnes Hsiung, Xiao-Ou Shu, Wei Jie Seow, Zhaoming Wang, Keitaro Matsuo, Yun-Chul Hong, Adeline Seow, Chen Wu, H Dean Hosgood 3rd, Kexin Chen, Jiu-Cun Wang, Wanqing Wen, Richard Cawthon, Nilanjan Chatterjee, Wei Hu, Neil E Caporaso, Jae Yong Park, Chien-Jen Chen, Yeul Hong Kim, Young Tae Kim, Maria Teresa Landi, Hongbing Shen, Charles Lawrence, Laurie Burdett, Meredith Yeager, I-Shou Chang, Tetsuya Mitsudomi, Hee Nam Kim, Gee-Chen Chang, Bryan A Bassig, Margaret Tucker, Fusheng Wei, Zhihua Yin, She-Juan An, Biyun Qian, Victor Ho Fun Lee, Daru Lu, Jianjun Liu, Hyo-Sung Jeon, Chin-Fu Hsiao, Jae Sook Sung, Jin Hee Kim, Yu-Tang Gao, Ying-Huang Tsai, Yoo Jin Jung, Huan Guo, Zhibin Hu, Amy Hutchinson, Wen-Chang Wang, Robert J Klein, Charles C Chung, In-Jae Oh, Kuan-Yu Chen, Sonja I Berndt, Wei Wu, Jiang Chang, Xu-Chao Zhang, Ming-Shyan Huang, Hong Zheng, Junwen Wang, Xueying Zhao, Yuqing Li, Jin Eun Choi, Wu-Chou Su, Kyong Hwa Park, Sook Whan Sung, Yuh-Min Chen, Li Liu, Chang Hyun Kang, Lingmin Hu, Chung-Hsing Chen, William Pao, Young-Chul Kim, Tsung-Ying Yang, Jun Xu, Peng Guan, Wen Tan, Jian Su, Chih-Liang Wang, Haixin Li, Alan Dart Loon Sihoe, Zhenhong Zhao, Ying Chen, Yi Young Choi, Jen-Yu Hung, Jun Suk Kim, Ho-Il Yoon, Qiuyin Cai, Chien-Chung Lin, In Kyu Park, Ping Xu, Jing Dong, Christopher Kim, Qincheng He, Reury-Perng Perng, Takashi Kohno, Sun-Seog Kweon, Chih-Yi Chen, Roel C H Vermeulen, Junjie Wu, Wei-Yen Lim, Kun-Chieh Chen, Wong-Ho Chow, Bu-Tian Ji, John K C Chan, Minjie Chu, Yao-Jen Li, Jun Yokota, Jihua Li, Hongyan Chen, Yong-Bing Xiang, Chong-Jen Yu, Hideo Kunitoh, Guoping Wu, Li Jin, Yen-Li Lo, Kouya Shiraishi, Ying-Hsiang Chen, Hsien-Chih Lin, Tangchun Wu, Maria Pik Wong, Yi-Long Wu, Pan-Chyr Yang, Baosen Zhou, Min-Ho Shin, Joseph F Fraumeni Jr, Wei Zheng, Dongxin Lin, Stephen J Chanock, Nathaniel Rothman, Qing Lan
• Journal: International journal of cancer (Int J Cancer) Vol. 137 Issue 2 Pg. 311-9 (Jul 15 2015) ISSN: 1097-0215 [Electronic] United States
• PMID: 25516442 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Published 2014. This article is a US Government work and, as such, is in the public domain of the United States of America.

Topics

• Adult
• Aged
• Asian People (genetics)
• China
• Female
• Genetic Predisposition to Disease (ethnology, genetics)
• Genome-Wide Association Study (statistics & numerical data)
• Hong Kong
• Humans
• Japan
• Lung Neoplasms (ethnology, genetics)
• Middle Aged
• Odds Ratio
• Polymorphism, Single Nucleotide
• Prospective Studies
• Republic of Korea
• Risk Factors
• Singapore
• Smoking
• Taiwan
• Telomere (genetics)
• Telomere Homeostasis (genetics)