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
Authors: Machiela Mitchell J. , Hsiung Chao Agnes , Shu Xiao‐Ou , Seow Wei Jie , Wang Zhaoming , Matsuo Keitaro , Hong Yun‐Chul , Seow Adeline , Wu Chen , Hosgood H. Dean , Chen Kexin , Wang Jiu‐Cun , Wen Wanqing , Cawthon Richard , Chatterjee Nilanjan , Hu Wei , Caporaso Neil E. , Park Jae Yong , Chen Chien‐Jen , Kim Yeul Hong , Kim Young Tae , Landi Maria Teresa , Shen Hongbing , Lawrence Charles , Burdett Laurie , Yeager Meredith , Chang I‐Shou , Mitsudomi Tetsuya , Kim Hee Nam , Chang Gee‐Chen , Bassig Bryan A. , Tucker Margaret , Wei Fusheng , Yin Zhihua , An She‐Juan , Qian Biyun , Lee Victor Ho Fun , Lu Daru , Liu Jianjun , Jeon Hyo‐Sung , Hsiao Chin‐Fu , Sung Jae Sook , Kim Jin Hee , Gao Yu‐Tang , Tsai Ying‐Huang , Jung Yoo Jin , Guo Huan , Hu Zhibin , Hutchinson Amy , Wang Wen‐Chang , Klein Robert J. , Chung Charles C. , Oh In‐Jae , Chen Kuan‐Yu , Berndt Sonja I. , Wu Wei , Chang Jiang , Zhang Xu‐Chao , Huang Ming‐Shyan , Zheng Hong , Wang Junwen , Zhao Xueying , Li Yuqing , Choi Jin Eun , Su Wu‐Chou , Park Kyong Hwa , Sung Sook Whan , Chen Yuh‐Min , Liu Li , Kang Chang Hyun , Hu Lingmin , Chen Chung‐Hsing , Pao William , Kim Young‐Chul , Yang Tsung‐Ying , Xu Jun , Guan Peng , Tan Wen , Su Jian , Wang Chih‐Liang , Li Haixin , Sihoe Alan Dart Loon , Zhao Zhenhong , Chen Ying , Choi Yi Young , Hung Jen‐Yu , Kim Jun Suk , Yoon Ho‐Il , Cai Qiuyin , Lin Chien‐Chung , Park In Kyu , Xu Ping , Dong Jing , Kim Christopher , He Qincheng , Perng Reury‐Perng , Kohno Takashi , Kweon Sun‐Seog , Chen Chih‐Yi , Vermeulen Roel C.H , Wu Junjie , Lim Wei‐Yen , Chen Kun‐Chieh , Chow Wong‐Ho , Ji Bu‐Tian , Chan John K. C. , Chu Minjie , Li Yao‐Jen , Yokota Jun , Li Jihua , Chen Hongyan , Xiang Yong‐Bing , Yu Chong‐Jen , Kunitoh Hideo , Wu Guoping , Jin Li , Lo Yen‐Li , Shiraishi Kouya , Chen Ying‐Hsiang , Lin Hsien‐Chih , Wu Tangchun , Wong Maria Pik , Wu Yi‐Long , Yang Pan‐Chyr , Zhou Baosen , Shin Min‐Ho , Fraumeni Joseph F. , Zheng Wei , Lin Dongxin , Chanock Stephen J. , Rothman Nathaniel , Lan Qing 
Published: December 2014

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.