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

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, 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 & 112 others 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, Wei Zheng, Dongxin Lin, Stephen J. Chanock, Nathaniel Rothman, Qing Lan

Research output: Contribution to journalArticle

48 Citations (Scopus)

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<sup>-14</sup>) even after removing rs2736100 (p value = 4.81 × 10<sup>-3</sup>), 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.

Original languageEnglish
Pages (from-to)311-319
Number of pages9
JournalInternational Journal of Cancer
Volume137
Issue number2
DOIs
Publication statusPublished - 2015 Jul 15

Fingerprint

Telomere
Lung Neoplasms
Smoking
Genome-Wide Association Study
Women's Health
Single Nucleotide Polymorphism
Case-Control Studies
Adenocarcinoma
Leukocytes
Epithelial Cells
Prospective Studies
DNA

Keywords

  • association study
  • genetic risk score
  • genetics
  • lung cancer
  • telomere length

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / 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.

In: International Journal of Cancer, Vol. 137, No. 2, 15.07.2015, p. 311-319.

Research output: Contribution to journalArticle

Machiela, MJ, Hsiung, CA, Shu, XO, Seow, WJ, Wang, Z, Matsuo, K, Hong, YC, Seow, A, Wu, C, Hosgood, HD, Chen, K, Wang, JC, Wen, W, Cawthon, R, Chatterjee, N, Hu, W, Caporaso, NE, Park, JY, Chen, CJ, Kim, YH, Kim, YT, Landi, MT, Shen, H, Lawrence, C, Burdett, L, Yeager, M, Chang, IS, Mitsudomi, T, Kim, HN, Chang, GC, Bassig, BA, Tucker, M, Wei, F, Yin, Z, An, SJ, Qian, B, Lee, VHF, Lu, D, Liu, J, Jeon, HS, Hsiao, CF, Sung, JS, Kim, JH, Gao, YT, Tsai, YH, Jung, YJ, Guo, H, Hu, Z, Hutchinson, A, Wang, WC, Klein, RJ, Chung, CC, Oh, IJ, Chen, KY, Berndt, SI, Wu, W, Chang, J, Zhang, XC, Huang, MS, Zheng, H, Wang, J, Zhao, X, Li, Y, Choi, JE, Su, WC, Park, KH, Sung, SW, Chen, YM, Liu, L, Kang, CH, Hu, L, Chen, CH, Pao, W, Kim, YC, Yang, TY, Xu, J, Guan, P, Tan, W, Su, J, Wang, CL, Li, H, Sihoe, ADL, Zhao, Z, Chen, Y, Choi, YY, Hung, JY, Kim, JS, Yoon, HI, Cai, Q, Lin, CC, Park, IK, Xu, P, Dong, J, Kim, C, He, Q, Perng, RP, Kohno, T, Kweon, SS, Chen, CY, Vermeulen, RCH, Wu, J, Lim, WY, Chen, KC, Chow, WH, Ji, BT, Chan, JKC, Chu, M, Li, YJ, Yokota, J, Li, J, Chen, H, Xiang, YB, Yu, CJ, Kunitoh, H, Wu, G, Jin, L, Lo, YL, Shiraishi, K, Chen, YH, Lin, HC, Wu, T, Wong, MP, Wu, YL, Yang, PC, Zhou, B, Shin, MH, Fraumeni, JF, Zheng, W, Lin, D, Chanock, SJ, Rothman, N & Lan, Q 2015, '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', International Journal of Cancer, vol. 137, no. 2, pp. 311-319. https://doi.org/10.1002/ijc.29393
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. / 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. In: International Journal of Cancer. 2015 ; Vol. 137, No. 2. pp. 311-319.
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title = "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.",
keywords = "association study, genetic risk score, genetics, lung cancer, telomere length",
author = "Machiela, {Mitchell J.} and Hsiung, {Chao Agnes} and Shu, {Xiao Ou} and Seow, {Wei Jie} and Zhaoming Wang and Keitaro Matsuo and Hong, {Yun Chul} and Adeline Seow and Chen Wu and Hosgood, {H. Dean} and Kexin Chen and Wang, {Jiu Cun} and Wanqing Wen and Richard Cawthon and Nilanjan Chatterjee and Wei Hu and Caporaso, {Neil E.} and Park, {Jae Yong} and Chen, {Chien Jen} and Kim, {Yeul Hong} and Kim, {Young Tae} and Landi, {Maria Teresa} and Hongbing Shen and Charles Lawrence and Laurie Burdett and Meredith Yeager and Chang, {I. Shou} and Tetsuya Mitsudomi and Kim, {Hee Nam} and Chang, {Gee Chen} and Bassig, {Bryan A.} and Margaret Tucker and Fusheng Wei and Zhihua Yin and An, {She Juan} and Biyun Qian and Lee, {Victor Ho Fun} and Daru Lu and Jianjun Liu and Jeon, {Hyo Sung} and Hsiao, {Chin Fu} and Sung, {Jae Sook} and Kim, {Jin Hee} and Gao, {Yu Tang} and Tsai, {Ying Huang} and Jung, {Yoo Jin} and Huan Guo and Zhibin Hu and Amy Hutchinson and Wang, {Wen Chang} and Klein, {Robert J.} and Chung, {Charles C.} and Oh, {In Jae} and Chen, {Kuan Yu} and Berndt, {Sonja I.} and Wei Wu and Jiang Chang and Zhang, {Xu Chao} and Huang, {Ming Shyan} and Hong Zheng and Junwen Wang and Xueying Zhao and Yuqing Li and Choi, {Jin Eun} and Su, {Wu Chou} and Park, {Kyong Hwa} and Sung, {Sook Whan} and Chen, {Yuh Min} and Li Liu and Kang, {Chang Hyun} and Lingmin Hu and Chen, {Chung Hsing} and William Pao and Kim, {Young Chul} and Yang, {Tsung Ying} and Jun Xu and Peng Guan and Wen Tan and Jian Su and Wang, {Chih Liang} and Haixin Li and Sihoe, {Alan Dart Loon} and Zhenhong Zhao and Ying Chen and Choi, {Yi Young} and Hung, {Jen Yu} and Kim, {Jun Suk} and Yoon, {Ho Il} and Qiuyin Cai and Lin, {Chien Chung} and Park, {In Kyu} and Ping Xu and Jing Dong and Christopher Kim and Qincheng He and Perng, {Reury Perng} and Takashi Kohno and Kweon, {Sun Seog} and Chen, {Chih Yi} and Vermeulen, {Roel C H} and Junjie Wu and Lim, {Wei Yen} and Chen, {Kun Chieh} and Chow, {Wong Ho} and Ji, {Bu Tian} and Chan, {John K C} and Minjie Chu and Li, {Yao Jen} and Jun Yokota and Jihua Li and Hongyan Chen and Xiang, {Yong Bing} and Yu, {Chong Jen} and Hideo Kunitoh and Guoping Wu and Li Jin and Lo, {Yen Li} and Kouya Shiraishi and Chen, {Ying Hsiang} and Lin, {Hsien Chih} and Tangchun Wu and Wong, {Maria Pik} and Wu, {Yi Long} and Yang, {Pan Chyr} and Baosen Zhou and Shin, {Min Ho} and Fraumeni, {Joseph F.} and Wei Zheng and Dongxin Lin and Chanock, {Stephen J.} and Nathaniel Rothman and Qing Lan",
year = "2015",
month = "7",
day = "15",
doi = "10.1002/ijc.29393",
language = "English",
volume = "137",
pages = "311--319",
journal = "International Journal of Cancer",
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TY - JOUR

T1 - Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia

T2 - A report from the female lung cancer consortium in Asia

AU - Machiela, Mitchell J.

AU - Hsiung, Chao Agnes

AU - Shu, Xiao Ou

AU - Seow, Wei Jie

AU - Wang, Zhaoming

AU - Matsuo, Keitaro

AU - Hong, Yun Chul

AU - Seow, Adeline

AU - Wu, Chen

AU - Hosgood, H. Dean

AU - Chen, Kexin

AU - Wang, Jiu Cun

AU - Wen, Wanqing

AU - Cawthon, Richard

AU - Chatterjee, Nilanjan

AU - Hu, Wei

AU - Caporaso, Neil E.

AU - Park, Jae Yong

AU - Chen, Chien Jen

AU - Kim, Yeul Hong

AU - Kim, Young Tae

AU - Landi, Maria Teresa

AU - Shen, Hongbing

AU - Lawrence, Charles

AU - Burdett, Laurie

AU - Yeager, Meredith

AU - Chang, I. Shou

AU - Mitsudomi, Tetsuya

AU - Kim, Hee Nam

AU - Chang, Gee Chen

AU - Bassig, Bryan A.

AU - Tucker, Margaret

AU - Wei, Fusheng

AU - Yin, Zhihua

AU - An, She Juan

AU - Qian, Biyun

AU - Lee, Victor Ho Fun

AU - Lu, Daru

AU - Liu, Jianjun

AU - Jeon, Hyo Sung

AU - Hsiao, Chin Fu

AU - Sung, Jae Sook

AU - Kim, Jin Hee

AU - Gao, Yu Tang

AU - Tsai, Ying Huang

AU - Jung, Yoo Jin

AU - Guo, Huan

AU - Hu, Zhibin

AU - Hutchinson, Amy

AU - Wang, Wen Chang

AU - Klein, Robert J.

AU - Chung, Charles C.

AU - Oh, In Jae

AU - Chen, Kuan Yu

AU - Berndt, Sonja I.

AU - Wu, Wei

AU - Chang, Jiang

AU - Zhang, Xu Chao

AU - Huang, Ming Shyan

AU - Zheng, Hong

AU - Wang, Junwen

AU - Zhao, Xueying

AU - Li, Yuqing

AU - Choi, Jin Eun

AU - Su, Wu Chou

AU - Park, Kyong Hwa

AU - Sung, Sook Whan

AU - Chen, Yuh Min

AU - Liu, Li

AU - Kang, Chang Hyun

AU - Hu, Lingmin

AU - Chen, Chung Hsing

AU - Pao, William

AU - Kim, Young Chul

AU - Yang, Tsung Ying

AU - Xu, Jun

AU - Guan, Peng

AU - Tan, Wen

AU - Su, Jian

AU - Wang, Chih Liang

AU - Li, Haixin

AU - Sihoe, Alan Dart Loon

AU - Zhao, Zhenhong

AU - Chen, Ying

AU - Choi, Yi Young

AU - Hung, Jen Yu

AU - Kim, Jun Suk

AU - Yoon, Ho Il

AU - Cai, Qiuyin

AU - Lin, Chien Chung

AU - Park, In Kyu

AU - Xu, Ping

AU - Dong, Jing

AU - Kim, Christopher

AU - He, Qincheng

AU - Perng, Reury Perng

AU - Kohno, Takashi

AU - Kweon, Sun Seog

AU - Chen, Chih Yi

AU - Vermeulen, Roel C H

AU - Wu, Junjie

AU - Lim, Wei Yen

AU - Chen, Kun Chieh

AU - Chow, Wong Ho

AU - Ji, Bu Tian

AU - Chan, John K C

AU - Chu, Minjie

AU - Li, Yao Jen

AU - Yokota, Jun

AU - Li, Jihua

AU - Chen, Hongyan

AU - Xiang, Yong Bing

AU - Yu, Chong Jen

AU - Kunitoh, Hideo

AU - Wu, Guoping

AU - Jin, Li

AU - Lo, Yen Li

AU - Shiraishi, Kouya

AU - Chen, Ying Hsiang

AU - Lin, Hsien Chih

AU - Wu, Tangchun

AU - Wong, Maria Pik

AU - Wu, Yi Long

AU - Yang, Pan Chyr

AU - Zhou, Baosen

AU - Shin, Min Ho

AU - Fraumeni, Joseph F.

AU - Zheng, Wei

AU - Lin, Dongxin

AU - Chanock, Stephen J.

AU - Rothman, Nathaniel

AU - Lan, Qing

PY - 2015/7/15

Y1 - 2015/7/15

N2 - 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.

AB - 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.

KW - association study

KW - genetic risk score

KW - genetics

KW - lung cancer

KW - telomere length

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DO - 10.1002/ijc.29393

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EP - 319

JO - International Journal of Cancer

JF - International Journal of Cancer

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