We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.
Bibliographical noteFunding Information:
We would like to thank Eric Engels, Naomi Walsh, Paula L. Hyland, and Rachael Stolzenberg-Solomon for their expert guidance. Additionally, we would like to express our gratitude to all members of the Female Lung Cancer Consortium in Asia. The authors declare no competing interest. This study was supported in part by intramural funding from National Cancer Institute. Further funding was provided by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry Health, Labor and Welfare of Japan, by Health and Labor Sciences Research Grants for Research on Applying Health Technology from the Ministry of Health, Labor and Welfare of Japan, by the National Cancer Center Research and Development Fund, the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (grant No. 2011-0016106), a grant of the National Project for Personalized Genomic Medicine, Ministry for Health & Welfare, Republic of Korea (A111218-11-GM04), the Program for Changjiang Scholars and Innovative Research Team in University in China (IRT_14R40 to K.C.), the National Science & Technology Pillar Program (2011BAI09B00), MOE 111 Project (B13016), the National Natural Science Foundation of China (No. 30772531, and 81272618), Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine (No. 2012A061400006), Special Fund for Research in the Public Interest from the National Health and Family Planning Commission of PRC (No. 201402031), and the Ministry of Science and Technology, Taiwan (MOST 103-2325-B-400-023 & 104-2325-B-400-012). The Japan Lung Cancer Study (JLCS) was supported in part by the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development (15ck0106096h0002) and the Management Expenses Grants from the Government to the National Cancer Center (26-A-1) for Biobank. BioBank Japan was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government. The Japan Public Health Center-based prospective Study (the JPHC Study) was supported by the National Cancer Center Research and Development Fund (23-A31[toku] and 26-A-2) (since 2011) and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010). The Taiwan GELAC Study (Genetic Epidemiological Study for Lung AdenoCarcinoma) was supported by grants from the National Research Program on Genomic Medicine in Taiwan (DOH99-TD-G-111-028), the National Research Program for Biopharmaceuticals in Taiwan (MOHW 103-TDUPB-211-144003, MOST 103-2325-B-400-023) and the Bioinformatics Core Facility for Translational Medicine and Biotechnology Development (MOST 104-2319-B-400-002). This work was also supported by the Jinan Science Research Project Foundation (201102051), the National Key Scientific and Technological Project (2011ZX09307-001-04), the National Natural Science Foundation of China (No.81272293), the State Key Program of National Natural Science of China (81230067), the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIP) (No. NRF2014R1A2A2A05003665), Sookmyung Women's University Research Grants, Korea (1-1603-2048), Agency for Science, Technology and Research (A*STAR), Singapore and the US National Institute of Health Grant (1U19CA148127-01). The overall GWAS project was supported by the intramural program of the US National Institutes of Health/National Cancer Institute. The following is a list of grants by study center: SKLCS (Y.T.K.)—National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2011-0016106). (J.C.) – This work was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health &Welfare, Republic of Korea (grant no. 0720550-2). (J.S·S) – grant number is A010250. WLCS (T.W.)—National Key Basic Research and Development Program (2011CB503800). SLCS (B.Z.)—National Nature Science Foundation of China (81102194). Liaoning Provincial Department of Education (LS2010168). China Medical Board (00726). GDS (Y.L.W.)—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 of China (81101549). Natural Science Foundation of Guangdong Province (S2011010000792). TLCS (K.C. B.Q)—Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT), China (IRT1076). Tianjin Cancer Institute and Hospital. National Foundation for Cancer Research (US). FLCS (J.C.W. D.R. L.J.)—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). National Science Foundation of China (30890034). National Basic Research Program (2012CB944600). Scientific and Technological Support Plans from Jiangsu Province (BE2010715). NLCS (H.S.)—China National High-Tech Research and Development Program Grant (2009AA022705). Priority Academic Program Development of Jiangsu Higher Education Institution. National Key Basic Research Program Grant (2011CB503805). GEL-S (A.S.)—National Medical Research Council Singapore grant (NMRC/0897/2004, NMRC/1075/2006). (J.Liu)—Agency for Science, Technology and Research (A*STAR) of Singapore. GELAC (C.A.H.)—National Research Program on Genomic Medicine in Taiwan (DOH98-TDG-111-015). National Research Program for Biopharmaceuticals in Taiwan (DOH 100TD-PB-111-TM013). National Science Council, Taiwan (NSC 1002319-B-400-001). YLCS (Q.L.)—Supported by the intramural program of U.S. National Institutes of Health, National Cancer Institute. SWHS (W.Z. W-H.C. N.R.)—The work was supported by a grant from the National Institutes of Health (R37 CA70867) and the National Cancer Institute intramural research program, including NCI Intramural Research Program contract (N02 CP1101066). JLCS (K.M. T.K.)—Grants-in-Aid from the Ministry of Health, Labor, and Welfare for Research on Applying Health Technology and for the 3rd-term Comprehensive 10-year Strategy for Cancer Control; by the National Cancer Center Research and Development Fund; by Grant-in-Aid for Scientific Research on Priority Areas and on Innovative Area from the Ministry of Education, Science, Sports, Culture and — Technology of Japan. (W.P.)—NCI R01-CA121210. HKS (J.W.)— General Research Fund of Research Grant Council, Hong Kong (781511M). The Environment and Genetics in Lung Cancer Etiology (EAGLE), Prostate, Lung, Colon, Ovary Screening Trial (PLCO), and Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) studies were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics. ATBC was also supported by U.S. Public Health Service contracts (N01-CN-45165, N01-RC-45035, and N01-RC-37004) from the NCI. PLCO was also supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University (NO1-CN-25522), the Pacific Health Research Institute (NO1-CN-25515), the Henry Ford Health System (NO1-CN-25512), the University of Minnesota, (NO1-CN25513), Washington University (NO1-CN-25516), the University of Pittsburgh (NO1-CN-25511), the University of Utah (NO1-CN25524), the Marshfield Clinic Research Foundation (NO1-CN25518), the University of Alabama at Birmingham (NO1-CN75022), Westat, Inc. (NO1-CN-25476), and the University of California, Los Angeles (NO1-CN-25404). The Cancer Prevention Study-II (CPS-II) Nutrition Cohort was supported by the American Cancer Society. The NIH Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research.
- Lung adenocarcinoma
- Lung cancer
- Mendelian randomization
- Pathway analysis
ASJC Scopus subject areas