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Published in final edited form as: Genomics. 2019 Jul 12;112(2):1223–1232. doi: 10.1016/j.ygeno.2019.07.008

Tuberculosis Infection and Lung Adenocarcinoma: Mendelian Randomization and Pathway Analysis of Genome-wide Association Study Data from Never-Smoking Asian Women

Jason YY Wong 1,†, Han Zhang 1,†, Chao A Hsiung 2,†, Kouya Shiraishi 3,†, Kai Yu 1,†, Keitaro Matsuo 4,5,†, Maria Pik Wong 6,†, Yun-Chul Hong 7,†, Jiucun Wang 8,9, Wei Jie Seow 10, Zhaoming Wang 11,12, Minsun Song 1,13, Hee Nam Kim 14, I-Shou Chang 15, Nilanjan Chatterjee 1,16, Wei Hu 1, Chen Wu 17, Tetsuya Mitsudomi 18, Wei Zheng 19, Jin Hee Kim 20, Adeline Seow 10, Neil E Caporaso 1, Min-Ho Shin 14, Lap Ping Chung 6, She-Juan An 21, Ping Wang 22, Yang Yang 23, Hong Zheng 24, Yasushi Yatabe 25, Xu-Chao Zhang 21, Young Tae Kim 26, Qiuyin Cai 19, Zhihua Yin 27, Young-Chul Kim 28,29, Bryan A Bassig 1, Jiang Chang 17, James Chung Man Ho 30, Bu-Tian Ji 1, Yataro Daigo 31,32, Hidemi Ito 33,34, Yukihide Momozawa 35, Kyota Ashikawa 35, Yoichiro Kamatani 36, Takayuki Honda 3, H Dean Hosgood 37, Hiromi Sakamoto 38, Hideo Kunitoh 39, Koji Tsuta 40, Shun-ichi Watanabe 41, Michiaki Kubo 35, Yohei Miyagi 42, Haruhiko Nakayama 43, Shingo Matsumoto 44, Masahiro Tsuboi 45, Koichi Goto 46, Jianxin Shi 1, Lei Song 1, Xing Hua 1, Atsushi Takahashi 36,47, Akiteru Goto 48, Yoshihiro Minamiya 49, Kimihiro Shimizu 50, Kazumi Tanaka 50, Fusheng Wei 51, Fumihiko Matsuda 52, Jian Su 21, Yeul Hong Kim 53, In-Jae Oh 28,29, Fengju Song 24, Wu-Chou Su 54, Yu-Min Chen 55,56, Gee-Chen Chang 57,58, Kuan-Yu Chen 59, Ming-Shyan Huang 60, Li-Hsin Chien 15, Yong-Bing Xiang 61, Jae Yong Park 62, Sun-Seog Kweon 14,63, Chien-Jen Chen 64, Kyoung-Mu Lee 1,65, Batel Blechter 16, Haixin Li 24, Yu-Tang Gao 66, Biyun Qian 24, Daru Lu 8,9, Jianjun Liu 10,67,68, Hyo-Sung Jeon 69, Chin-Fu Hsiao 2, Jae Sook Sung 53, Ying-Huang Tsai 70, Yoo Jin Jung 26, Huan Guo 71, Zhibin Hu 72, Wen-Chang Wang 73, Charles C Chung 1,11, Laurie Burdett 1,11, Meredith Yeager 1,11, Amy Hutchinson 1,11, Sonja I Berndt 1, Wei Wu 27, Herbert Pang 74, Yuqing Li 75, Jin Eun Choi 69, Kyong Hwa Park 53, Sook Whan Sung 76, Li Liu 77, CH Kang 26, Meng Zhu 72, Chung-Hsing Chen 2, Tsung-Ying Yang 58, Jun Xu 78, Peng Guan 27,79, Wen Tan 17, Chih-Liang Wang 80, Michael Hsin 81, Ko-Yung Sit 81, James Ho 82, Ying Chen 10, Yi Young Choi 69, Jen-Yu Hung 60, Jun Suk Kim 83, Ho Il Yoon 84, Chien-Chung Lin 54, In Kyu Park 26, Ping Xu 85, Yuzhuo Wang 72, Qincheng He 27, Reury-Perng Perng 86, Chih-Yi Chen 87,88, Roel Vermeulen 89, Junjie Wu 8,9, Wei-Yen Lim 90, Kun-Chieh Chen 58, Yao-Jen Li 64, Jihua Li 91, Hongyan Chen 8,9, Chong-Jen Yu 92, Li Jin 8,9, Tzu-Yu Chen 2, Shih-Sheng Jiang 15, Jie Liu 93, Taiki Yamaji 94, Belynda Hicks 1,11, Kathleen Wyatt 1,11, Shengchao A Li 1,11, Juncheng Dai 72, Hongxia Ma 72, Guangfu Jin 72, Bao Song 93, Zhehai Wang 93, Sensen Cheng 93, Xuelian Li 27,79, Yangwu Ren 27,79, Ping Cui 24, Motoki Iwasaki 94, Taichi Shimazu 94, Shoichiro Tsugane 94, Junjie Zhu 23, Ying Chen 95, Kaiyun Yang 95, Gening Jiang 23, Ke Fei 23, Guoping Wu 51, Hsien-Chin Lin 2, Hui-Ling Chen 2, Yao-Huei Fang 2, Fang-Yu Tsai 15, Wan-Shan Hsieh 2, Jinming Yu 93, Victoria L Stevens 96, Ite A Laird-Offringa 97, Crystal N Marconett 97, Linda Rieswijk 98, Ann Chao 99, Pan-Chyr Yang 59,‡, Xiao-Ou Shu 19,‡, Tangchun Wu 71,‡, YL Wu 21,‡, Dongxin Lin 17,‡, Kexin Chen 24,‡, Baosen Zhou 27,‡, Yun-Chao Huang 95,‡, Takashi Kohno 3,‡, Hongbing Shen 72,100,‡, Stephen J Chanock 1,‡, Nathaniel Rothman 1,‡, Qing Lan 1,‡
PMCID: PMC6954985  NIHMSID: NIHMS1535770  PMID: 31306748

Abstract

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 5,512 lung adenocarcinoma cases and 6,277 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.

Keywords: Tuberculosis, lung cancer, lung adenocarcinoma, Mendelian Randomization, Pathway Analysis

Introduction

Lung cancer is a substantial health burden worldwide that accounted for nearly 1.76 million deaths in 2018 [1]. Smoking is the most common cause of lung cancer; however, an estimated 25% of lung cancer patients worldwide are never-smokers [2]. Among never-smokers, overall incidence rates of 14.4-20.8 lung cancer cases per 100,000 person-years were estimated for women and 4.8-13.7 cases per 100,000 person-years for men [3, 4]. Asian women have among the highest incidence rates of lung cancer in the world among never-smokers [2, 5]. The complex etiology underlying this malignancy in this population remains unclear; however, various factors including infections [6–9] are suspected to contribute to this excess.

A previous genome-wide association study (GWAS) identified multiple genetic loci, including those on chromosomes 3q28, 5p15.33, 6p21.1, 6p21.32, 6q22.2, 9p21.3, 10q25.2 and 12q13.13 [8–10], that contribute to increased lung adenocarcinoma risk among never-smoking women. Although genomic studies have begun to shed light onto the genetic underpinnings of lung cancer etiology, genetic variants from GWAS in total only explain an estimated 12% of the heritability of lung cancer risk to date [11]. This issue is further compounded by the stringent correction for multiple comparisons that has become convention in GWAS. As a result, many susceptibility genes that potentially contribute to lung cancer development are likely to remain unidentified in GWAS of never-smoking Asian women based on sample sizes used to date. Pathway analysis (also known as gene set analysis) is a powerful method that complements existing GWAS by analyzing pre-defned groups of genes or biological pathways enriched with genetic variants that could potentially be associated with complex diseases [12]. When applied to existing GWAS data, pathway analysis may discover associations that could not be detected by conventional single-marker analyses, in addition to providing the added value of cogent biologic interpretation to GWAS findings.

Pulmonary tuberculosis (TB) is a common respiratory disease found throughout low and middle income countries in Asia that has been reported as a potential risk factor for lung cancer development [6]. Pulmonary TB is a communicable disease that is caused by infection with Mycobacterium tuberculosis (Mtb), a species of pathogenic bacteria that is spread and contracted through contaminated airborne droplets [13]. The symptoms of TB include severe persistent coughing, hemoptysis, chest pain, fever, and weight loss [13]. TB infection may contribute to increased lung cancer risk through biological mechanisms involving prolonged pulmonary inflammation leading to tissue damage, fibrosis, scar formation, and genomic damage [14–16]. Various human studies found a link between pulmonary TB and lung cancer [6, 14, 17–21]; however, several studies did not detect an association [22–26]. As such, the relationship between TB and lung cancer has not been firmly established.

To further investigate the relationship between TB and lung cancer, we analyzed data from previous GWAS of TB within the Female Lung Cancer Consortium in Asia (FLCCA), the largest GWAS of never-smoking women ever conducted to date. A pathway analysis was conducted to determine whether genetic factors related to TB also contribute to lung adenocarcinoma development. We followed-up with Mendelian Randomization (MR) to evaluate the potential association between TB infection and lung adenocarcinoma. Findings from our study may contribute to confirming a link between these respiratory diseases and to the understanding of the biological mechanism underlying lung carcinogenesis independent of cigarette smoking.

Methods

Study sample and GWAS

We evaluated GWAS data from 5,512 lung adenocarcinoma cases and 6,277 cancer-free controls from the Female Lung Cancer Consortium in Asia (FLCCA) [9]. All participating studies provided individual genotype data except for the Nanjing study [27], the Japanese Lung Cancer Collaborative Study (JLCCS) [28], and another Japanese study [29]. These three studies provided summary data instead. Details of the participating studies including the genotyping process, quality control procedures, and statistical methods to generate summary data from the meta-analysis were previously described [8–10, 27–29]. GWAS data are available at dbGAP (https://www.ncbi.nlm.nih.gov/gap, study accession: phs000716.v1.p1). Briefly, the participants were never-smoking adult Asian women who resided in Mainland China, Hong Kong, Singapore, Taiwan, South Korea, and Japan at the time of recruitment (Supplementary Table 1). Nearly all the samples were genotyped using Illumina 660W and 610K SNP microarrays as previously described [9, 27–29]. Unconditional logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the additive trend effects of each SNP (with 1-degree of freedom) on lung adenocarcinoma risk, adjusted for study center, age, and the top three eigenvectors. Summary statistics were generated and used for the subsequent pathway analysis.

Pathway analysis

Pathway analysis was conducted using the summary statistics-based adaptive rank truncated product (sARTP) method, which combines SNP-level association statistics across variants in a gene-set [12]. The sARTP method also used a model selection procedure to identify a subset of genes and SNPs that contributed the most to the overall association. Only genotyped SNPs in the lung adenocarcinoma dataset were analyzed because imputed SNPs in linkage disequilibrium (LD) with genotyped SNPs do not add more information to the pathway analysis. The association signals from up to five SNPs in a gene were adaptively accumulated. The sARTP method adjusts for the number of SNPs in a gene and number of genes in a pathway through a resampling procedure to control for false-positives. The gene- and pathway-level association p-values were estimated from the resampled null distribution using 10 million resampling steps.

A set of 31 TB-related genes was compiled using a lower threshold for known or suggestive single nucleotide polymorphism (SNP) associations with TB from GWAS that were conducted around the world [30–39]. Specifically, genes from each study were chosen if they contained at least one SNP in exons or introns that was associated with TB at a threshold of p<5.0 × 10−6 to maximize sensitivity for data exploration. We mapped SNPs 20 kb upstream and downstream of each gene. We integrated a priori knowledge from previous GWAS conducted around the world when creating the TB gene-set to determine if a trans-ethnic effect exists in the TB-lung cancer association. Using a TB gene-set defined by European and African populations should not result in biased results because the GWAS data used to identify those TB-genes are independent of the data used in our own association analysis.

Pathway analysis based on summary data requires a set of samples with individual genotype data as the reference panel from which the LD between SNPs is estimated. As we only had summary data from the Nanjing study and the two studies from Japan, a reference dataset consisting of 1000 subjects based on individual genotype data in the FLCCA study was created. We performed stratified sampling in cases and controls by oversampling subjects from mainland China and Japan to mimic the genetic pattern in the pooled sample that was comprised of subjects who were scanned across all study centers (Supplementary Table 2, Supplementary Figure 1A/B).

Functional annotation

We used the Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8 (https://david.ncifcrf.gov) and GeneCards – Human Gene Database (https://www.genecards.org/) to explore the biological themes of contributing genes with Pgene<0.05 [40].

Mendelian Randomization

To follow-up on the pathway analysis and generate further evidence for a TB-lung cancer link, we conducted MR as previously described [41] to evaluate a possible causal association between TB and lung adenocarcinoma among never-smoking women. MR is a special form of instrumental variable analysis to determine the causal relationship between an exposure or phenotype and an outcome, even in the presence of unmeasured confounding [41]. Estimation of this potential causal effect is accomplished by mimicking the causal structure of a randomized clinical trial [42–45]. MR uses genetic variants as instrumental variables for modifiable risk factors (i.e. TB infection/susceptibility) that affect a health outcome (i.e., lung adenocarcinoma). Although there are various required conditions [46], the main assumption of MR analysis is that the genetic instrument only affects the outcome through its direct association with the modifiable risk factor. Given that the participants of FLCC A were predominantly of East Asian ancestry, genome-wide significant SNPs that were previously found to be associated with TB in genomic studies of East Asians [35, 47] were used as instruments in our analysis. These SNPs included rs4240897 [35], rs2269497 [35], and rs9272461 [47]. P-values <0.05 for each analysis were considered statistically noteworthy.

This was an observational study and no experiments were conducted on humans. All methods were performed in accordance with relevant guidelines and regulations of the National Institutes of Health and all the participating institutions. Institutional Review Board approval from The Central Institutional Review Board for the National Cancer Institute and all the other study sites, in addition to written informed consent from all research participants were obtained.

Results

Pathway analysis

The overall TB-related gene-set was associated with lung adenocarcinoma (ppathway=0.016) among never-smoking Asian women. Four genes were selected by the sARTP method as having the greatest contribution to the association. These genes included forkhead associated phosphopeptide binding domain 1 (FHAD1, p=0.001), zinc finger protein FOG family member 2 (ZFPM2, p=0.020), major histocompatibility complex class (MHC) II DQ alpha 1 (HLA-DQA1, p=0.009), and discs large MAGUK scaffold protein 2 (DLG2, p=0.017) (Table 1, Supplementary Table 3).

Table 1:

Top genetic variants located in tuberculosis-related genes that contributed to the association with lung adenocarcinoma among never-smoking Asian women

Gene SNP, rs number Chromosome Position, GRCh37-hg19 Reference Allele Effect Allele Estimate, log OR SE PSNP Pgene
FHAD1 rs7539674 1 15597675 A G 1.85 0.40 3.5E-06 0.001
HLA-DQA1 rs3129763 6 32590925 G A −0.58 0.18 1.2E-03 0.009
DLG2 rs 1311159 11 84695711 T C −0.15 0.04 1.3E-05 0.017
ZFPM2 rs2343595 8 106591207 G C 0.09 0.03 5.9E-04 0.020
ZFPM2 - 8 106393057 T C −0.22 0.06 5.9E-04 0.020
ZFPM2 - 8 106546262 C T −0.16 0.05 8.7E-04 0.020
ZFPM2 rs35893068 8 106480315 T C −0.13 0.04 1.2E-03 0.020
ZFPM2 rs2343596 8 106593207 C A −0.09 0.03 2.1E-03 0.020
MEIS2 rs 12909569 15 37217527 A G −0.23 0.06 4.2E-04 0.067
MEIS2 rs3901057 15 37292836 G A 0.13 0.04 0.002 0.067
MEIS2 rs17436991 15 37315283 T C −0.14 0.05 0.003 0.067
MEIS2 rs12708547 15 37227850 G C −0.10 0.03 0.004 0.067
MEIS2 rs4924117 15 37313594 C T 0.09 0.03 0.005 0.067
LRRC69 rs7015316 8 92105675 C T 1.68 0.61 0.006 0.068
LRRC69 rs78041518 8 92189901 A G −0.22 0.08 0.008 0.068
LRRC69 rs147312721 8 92170657 A G −0.41 0.16 0.009 0.068
LRRC69 - 8 92162739 G A −0.44 0.18 0.015 0.068
LRRC69 rs13256627 8 92123208 T C −1.57 0.67 0.019 0.068
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Listed SNPs were selected by the sARTP method as the ones that contributed the most to the overall gene set-association in the pathway analysis. Each SNP was located in or within 20 kb upstream/downstream of each gene.

Mendelian Randomization

There have been a number of large-scale GWAS of pulmonary TB conducted in populations of European ancestry [31, 37]. However, only a few TB GWAS have been conducted in East Asians. From these studies, we identified four independent genome-wide significant variants associated with TB in East Asians, three of which were in our dataset (i.e., rs4240897 [35], rs2269497 [35], and rs9272461 [47]). We conducted MR using the three TB-related SNPs and found that the estimated causal effect of TB on lung adenocarcinoma was statistically noteworthy (ORMR=1.31, 95% CI: 1.03, 1.66, p=0.027). Among these SNPs, the rs4240897G>A variant of the Mitofusin 2 (MFN2) gene was inversely associated with lung adenocarcinoma risk (OR=0.92, 95% CI: 0.86-0.98, p=5.5E-03) and with TB [35].

Discussion

In the largest GWAS of lung cancer among female never-smokers in the world, we applied genomic methods to investigate the relationship between TB infection, TB-related genes, and lung adenocarcinoma. First, we conducted a pathway analysis to evaluate whether genetic factors that refect biologic processes of TB also contribute to lung cancer development. The TB-related gene-set was found to be associated with lung adenocarcinoma, with FHAD1, ZFPM2, DLG2, and HLA-DQA1 contributing to the association. Second, we conducted MR and found evidence for a positive association between TB infection and lung adenocarcinoma. Taken together, our findings further support an etiologic relationship between TB infection and lung cancer pathogenesis that may involve shared genetic factors.

According to the World Health Organization, an estimated 10.4 million people worldwide were afflicted with TB in 2016 [48], while 1.7 million people died from the disease. Over 95% of TB-related deaths occur in low and middle-income countries, with seven nations accounting for 64% of the total (i.e., China, India, Indonesia, Philippines, Pakistan, Nigeria, and South Africa). In 2015, investigators from the Global Burden of Disease Study (GBD) estimated that 15% of the new TB cases (1.56 million) and 4% of TB-related deaths were reported in China [49], the region in which most of our participants resided. Evidence from multiple epidemiological and clinical studies support a link between pulmonary TB and lung cancer [6, 14, 17–21]. However, several studies did not detect an association [22–26], which could be due to the relatively low prevalence of TB in certain populations such as those in more affluent regions of Western countries [6]. As such, the relationship between TB and lung cancer has yet to be firmly established.

TB infection may influence lung cancer risk through biological mechanisms involving prolonged inflammatory/immunologic responses that lead to genetic alterations in proto-oncogenes and/or tumor suppressors [14–16, 50]. HLA-DQA1 was among the notable contributing genes in the pathway analysis and has a central role in regulating adaptive immune response. Previous studies found that variants of the HLA-DQA1 gene were associated with lung adenocarcinoma in a Japanese population [51], while several genomic investigations have found that various HLA variants in the MHC region were associated with lung cancer in Asian and European populations [8, 52].

The MFN2 gene encodes an outer membrane GTPase that contributes to regulating the morphology [53], fission, and fusion [54] of mitochondria, critical organelles that are primarily responsible for aerobic cellular respiration. The role of MFN2 in TB-susceptibility and lung cancer etiology is still unclear. However, a previous study found that MFN2 expression levels were nominally higher in peripheral blood mononuclear cells from TB-infected cases compared to controls [55]. Furthermore, MFN2 is a known hyperplasia suppressor gene [56] and a study of clinical tumor samples found that its expression was significantly higher in lung adenocarcinoma tissues compared to adjacent normal tissues [54]. When MFN2 was knocked down in A549 lung adenocarcinoma cell lines, cellular proliferation, cell cycle and invasion behavior were all deregulated [54]. Given that mitochondria regulates bioenergetics, metabolism, and apoptosis [57], which are key factors in both anti-microbial immunological/inflammatory response [58] and cancer development [59–61], it stands to reason that a regulator of mitochondrial function such as MFN2 may influence both diseases.

In summary, our study expanded upon existing data from the largest genomic study of never-smoking women in the world by identifying genetic factors related to TB susceptibility that may also influence lung adenocarcinoma development. Additionally, results from our MR analysis provide further support for a causal relationship between pulmonary TB and lung adenocarcinoma. Given the high prevalence of TB in low and middle-income countries in East Asia such as China, these findings may partially explain the high lung cancer rates in this susceptible population. Further observational and functional studies are required to replicate our findings and to unravel their biological significance.

Supplementary Material

1

Acknowledgements

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 (At 11218-11-GM04), the Program for Changjiang Scholars and Innovative Research Team in University in China (IRT14R40 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). TECS (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 (HS.)—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-HC., 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 CPI 101066). 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 NO1-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-CN25 524), 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.

Footnotes

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References

  • [1].Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J Clin, 68 (2018) 394–424. [DOI] [PubMed] [Google Scholar]
  • [2].Sun S, Schiller JH, Gazdar AF, Lung cancer in never smokers--a different disease, Nat Rev Cancer, 7 (2007) 778–790. [DOI] [PubMed] [Google Scholar]
  • [3].Wakelee HA, Chang ET, Gomez SL, Keegan TH, Feskanich D, Clarke CA, Holmberg L, Yong LC, Kolonel LN, Gould MK, West DW, Lung cancer incidence in never smokers, J Clin Oncol, 25 (2007) 472–478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Rivera GA, Wakelee H, Lung Cancer in Never Smokers, Adv Exp Med Biol, 893 (2016) 43–57. [DOI] [PubMed] [Google Scholar]
  • [5].Thun MJ, Hannan LM, Adams-Campbell LL, Boffetta P, Buring JE, Feskanich D, Flanders WD, Jee SH, Katanoda K, Kolonel LN, Lee IM, Marugame T, Palmer JR, Riboli E, Sobue T, Avila-Tang E, Wilkens LR, Samet JM, Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies, PLoS Med, 5 (2008) e185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Sisti J, Boffetta P, What proportion of lung cancer in never-smokers can be attributed to known risk factors?, Int J Cancer, 131 (2012) 265–275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Barone-Adesi F, Chapman RS, Silverman DT, He X, Hu W, Vermeulen R, Ning B, Fraumeni JF Jr., Rothman N, Lan Q, Risk of lung cancer associated with domestic use of coal in Xuanwei, China: retrospective cohort study, BMJ, 345 (2012) e5414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Seow WJ, Matsuo K, Hsiung CA, Shiraishi K, Song M, Kim HN, Wong MP, Hong YC, Hosgood HD 3rd, Wang Z, Chang IS, Wang JC, Chatterjee N, Tucker M, Wei H, Mitsudomi T, Zheng W, Kim JH, Zhou B, Caporaso NE, Albanes D, Shin MH, Chung LP, An SJ, Wang P, Zheng H, Yatabe Y, Zhang XC, Kim YT, Shu XO, Kim YC, Bassig BA, Chang J, Ho JC, Ji BT, Kubo M, Daigo Y, Ito H, Momozawa Y, Ashikawa K, Kamatani Y, Honda T, Sakamoto H, Kunitoh H, Tsuta K, Watanabe SI, Nokihara H, Miyagi Y, Nakayama H, Matsumoto S, Tsuboi M, Goto K, Yin Z, Shi J, Takahashi A, Goto A, Minamiya Y, Shimizu K, Tanaka K, Wu T, Wei F, Wong JY, Matsuda F, Su J, Kim YH, Oh IJ, Song F, Lee VH, Su WC, Chen YM, Chang GC, Chen KY, Huang MS, Yang PC, Lin HC, Xiang YB, Seow A, Park JY, Kweon SS, Chen CJ, Li H, Gao YT, Wu C, Qian B, Lu D, Liu J, Jeon HS, Hsiao CF, Sung JS, Tsai YH, Jung YJ, Guo H, Hu Z, Wang WC, Chung CC, Lawrence C, Burdett L, Yeager M, Jacobs KB, Hutchinson A, Berndt SI, He X, Wu W, Wang J, Li Y, Choi JE, Park KH, Sung SW, Liu L, Kang CH, Hu L, Chen CH, Yang TY, Xu J, Guan P, Tan W, Wang CL, Sihoe AD, 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, Chen CY, Vermeulen R, Wu J, Lim WY, Chen KC, Chan JK, Chu M, Li YJ, Li J, Chen H, Yu CJ, Jin L, Lo YL, Chen YH, Fraumeni JF Jr., Liu J, Yamaji T, Yang Y, Hicks B, Wyatt K, Li SA, Dai J,Ma H, Jin G, Song B, Wang Z, Cheng S, Li X, Ren Y, Cui P, Iwasaki M, Shimazu T, Tsugane S, Zhu J, Jiang G, Fei K, Wu G, Chien LH, Chen HL, Su YC, Tsai FY, Chen YS, Yu J, Stevens VL, Laird-Oflringa IA, Marconett CN, Lin D, Chen K, Wu YL, Landi MT, Shen H, Rothman N, Kohno T, Chanock SJ, Lan Q, Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations, Hum Mol Genet, 26 (2017) 454–465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Lan Q, Hsiung CA, Matsuo K, Hong YC, Seow A, Wang Z, Hosgood HD 3rd, Chen K, Wang JC, Chatterjee N, Hu W, Wong MP, Zheng W, Caporaso N, Park JY, Chen CJ, Kim YH, Kim YT, Landi MT, Shen H, Lawrence C, Burdett L, Yeager M, Yuenger J, Jacobs KB, Chang IS, Mitsudomi T, Kim HN, Chang GC, Bassig BA, Tucker M, Wei F, Yin Z, Wu C, An SJ, Qian B, Lee VH, 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 R, Chung CC, Oh IJ, Chen KY, Berndt SI, He X, Wu W, Chang J, Zhang XC, Huang MS, Zheng H, Wang J, Zhao X, Li Y, Choi JE, Su WC, Park KH, Sung SW, Shu XO, 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 AD, 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 R, Wu J, Lim WY, Chen KC, Chow WH, Ji BT, Chan JK, 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, Wu YL, Yang PC, Zhou B, Shin MH, Fraumeni JF Jr., Lin D, Chanock SJ, Rothman N, Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia, Nat Genet, 44 (2012) 1330–1335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Wang Z, Seow WJ, Shiraishi K, Hsiung CA, Matsuo K, Liu J, Chen K, Yamji T, Yang Y, Chang IS, Wu C, Hong YC, Burdett L, Wyatt K, Chung CC, Li SA, Yeager M, Hutchinson A, Hu W, Caporaso N, Landi MT, Chatteijee N, Song M, Fraumeni JF Jr., Kohno T, Yokota J, Kunitoh H, Ashikawa K, Momozawa Y, Daigo Y, Mitsudomi T, Yatabe Y, Hida T, Hu Z, Dai J, Ma H, Jin G, Song B, Wang Z, Cheng S, Yin Z, Li X, Ren Y, Guan P, Chang J, Tan W, Chen CJ, Chang GC, Tsai YH, Su WC, Chen KY, Huang MS, Chen YM, Zheng H, Li H, Cui P, Guo H, Xu P, Liu L, Iwasaki M, Shimazu T, Tsugane S, Zhu J, Jiang G, Fei K, Park JY, Kim YH, Sung JS, Park KH, Kim YT, Jung YJ, Kang CH, Park IK, Kim HN, Jeon HS, Choi JE, Choi YY, Kim JH, Oh IJ, Kim YC, Sung SW, Kim JS, Yoon HI, Kweon SS, Shin MH, Seow A, Chen Y, Lim WY, Liu J, Wong MP, Lee VH, Bassig BA, Tucker M, Berndt SI, Chow WH, Ji BT, Wang J, Xu J, Sihoe AD, Ho JC, Chan JK, Wang JC, Lu D, Zhao X, Zhao Z, Wu J, Chen H, Jin L, Wei F, Wu G, An SJ, Zhang XC, Su J, Wu YL, Gao YT, Xiang YB, He X, Li J, Zheng W, Shu XO, Cai Q, Klein R, Pao W, Lawrence C, Hosgood HD 3rd, Hsiao CF, Chien LH, Chen YH, Chen CH, Wang WC, Chen CY, Wang CL, Yu CJ, Chen HL, Su YC, Tsai FY, Chen YS, Li YJ, Yang TY, Lin CC, Yang PC, Wu T, Lin D, Zhou B, Yu J, Shen H, Kubo M, Chanock SJ, Rothman N, Lan Q, Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women, Hum Mol Genet, 25 (2016) 620–629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Sampson JN, Wheeler WA, Yeager M, Panagiotou O, Wang Z, Berndt SI, Lan Q, Abnet CC, Amundadottir LT, Figueroa JD, Landi MT, Mirabello L, Savage SA, Taylor PR, De Vivo I, McGlynn KA, Purdue MP, Rajaraman P, Adami HO, Ahlbom A, Albanes D, Amary MF, An SJ, Andersson U, Andriole G Jr., Andrulis IL, Angelucci E, Ansell SM, Arici C, Armstrong BK, Arslan AA, Austin MA, Baris D, Barkauskas DA, Bassig BA, Becker N, Benavente Y, Benhamou S, Berg C, Van Den Berg D, Bernstein L, Bertrand KA, Birmann BM, Black A, Boeing H, Boffetta P, Boutron-Ruault MC, Bracci PM, Brinton L, Brooks-Wilson AR, Bueno-de-Mesquita HB, Burdett L, Buring J, Butler MA, Cai Q, Cancel-Tassin G, Canzian F, Carrato A, Carreon T, Carta A, Chan JK, Chang ET, Chang GC, Chang IS, Chang J, Chang-Claude J, Chen CJ, Chen CY, Chen C, Chen CH, Chen C, Chen H, Chen K, Chen KY, Chen KC, Chen Y, Chen YH, Chen YS, Chen YM, Chien LH, Chirlaque MD, Choi JE, Choi YY, Chow WH, Chung CC, Clavel J, Clavel-Chapelon F, Cocco P, Colt JS, Comperat E, Conde L, Connors JM, Conti D, Cortessis VK, Cotterchio M, Cozen W, Crouch S, Crous-Bou M, Cussenot O, Davis FG, Ding T, Diver WR, Dorronsoro M, Dossus L, Duell EJ, Ennas MG, Erickson RL, Feychting M, Flanagan AM, Foretova L, Fraumeni JF Jr., Freedman ND, Beane Freeman LE, Fuchs C, Gago-Dominguez M, Gallinger S, Gao YT, Gapstur SM, Garcia-Closas M, Garcia-Closas R, Gascoyne RD, Gastier-Foster J, Gaudet MM, Gaziano JM, Giffen C, Giles GG, Giovannucci E, Glimelius B, Goggins M, Gokgoz N, Goldstein AM, Gorlick R, Gross M, Grubb R 3rd, Gu J, Guan P, Gunter M, Guo H, Habermann TM, Haiman CA, Halai D, Hallmans G, Hassan M, Hattinger C, He Q, He X, Helzlsouer K, Henderson B, Henriksson R, Hjalgrim H, Hoffman-Bolton J, Hohensee C, Holford TR, Holly EA, Hong YC, Hoover RN, Horn-Ross PL, Hosain GM, Hosgood HD 3rd, Hsiao CF, Hu N, Hu W, Hu Z, Huang MS, Huerta JM, Hung JY, Hutchinson A, Inskip PD, Jackson RD, Jacobs EJ, Jenab M, Jeon HS, Ji BT, Jin G, Jin L, Johansen C, Johnson A, Jung YJ, Kaaks R, Kamineni A, Kane E, Kang CH, Karagas MR, Kelly RS, Khaw KT, Kim C, Kim HN, Kim JH, Kim JS, Kim YH, Kim YT, Kim YC, Kitahara CM, Klein AP, Klein RJ, Kogevinas M, Kohno T, Kolonel LN, Kooperberg C, Kricker A, Krogh V, Kunitoh H, Kurtz RC, Kweon SS, LaCroix A, Lawrence C, Lecanda F, Lee VH, Li D, Li H, Li J, Li YJ, Li Y, Liao LM, Liebow M, Lightfoot T, Lim WY, Lin CC, Lin D, Lindstrom S, Linet MS, Link BK, Liu C, Liu J, Liu L, Ljungberg B, Lloreta J, Di Lollo S, Lu D, Lund E, Malats N, Mannisto S, Le Marchand L, Marina N, Masala G, Mastrangelo G, Matsuo K, Maynadie M, McKay J, McKean-Cowdin R, Melbye M, Melin BS, Michaud DS, Mitsudomi T, Monnereau A, Montalvan R, Moore LE, Mortensen LM, Nieters A, North KE, Novak AJ, Oberg AL, Offit K, Oh IJ, Olson SH, Palli D, Pao W, Park IK, Park JY, Park KH, Patino-Garcia A, Pavanello S, Peeters PH, Perng RP, Peters U, Petersen GM, Picci P, Pike MC, Porru S, Prescott J, Prokunina-Olsson L, Qian B, Qiao YL, Rais M, Riboli E, Riby J, Risch HA, Rizzato C, Rodabough R, Roman E, Roupret M, Ruder AM, Sanjose S, Scelo G, Schned A, Schumacher F, Schwartz K, Schwenn M, Scotlandi K, Seow A, Serra C, Serra M, Sesso HD, Setiawan VW, Severi G, Severson RK, Shanafelt TD, Shen H, Shen W, Shin MH, Shiraishi K, Shu XO, Siddiq A, Sierrasesumaga L, Sihoe AD, Skibola CF, Smith A, Smith MT, Southey MC, Spinelli JJ, Staines A, Stampfer M, Stern MC, Stevens VL, Stolzenberg-Solomon RS, Su J, Su WC, Sund M, Sung JS, Sung SW, Tan W, Tang W, Tardon A, Thomas D, Thompson CA, Tinker LF, Tirabosco R, Tjonneland A, Travis RC, Trichopoulos D, Tsai FY, Tsai YH, Tucker M, Turner J, Vajdic CM, Vermeulen RC, Villano DJ, Vineis P, Virtamo J, Visvanathan K, Wactawski-Wende J, Wang C, Wang CL, Wang JC, Wang J, Wei F, Weiderpass E, Weiner GJ, Weinstein S, Wentzensen N, White E, Witzig TE, Wolpin BM, Wong MP, Wu C, Wu G, Wu J, Wu T, Wu W, Wu X, Wu YL, Wunder JS, Xiang YB, Xu J, Xu P, Yang PC, Yang TY, Ye Y, Yin Z, Yokota J, Yoon HI, Yu CJ, Yu H, Yu K, Yuan JM, Zelenetz A, Zeleniuch-Jacquotte A, Zhang XC, Zhang Y, Zhao X, Zhao Z, Zheng H, Zheng T, Zheng W, Zhou B, Zhu M, Zucca M, Boca SM, Cerhan JR, Ferri GM, Hartge P, Hsiung CA, Magnani C, Miligi L, Morton LM, Smedby KE, Teras LR, Vijai J, Wang SS, Brennan P, Caporaso NE, Hunter DJ, Kraft P, Rothman N, Silverman DT, Slager SL, Chanock SJ, Chatterjee N, Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types, J Natl Cancer Inst, 107 (2015) djv279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Zhang H, Wheeler W, Hyland PL, Yang Y, Shi J, Chatterjee N, Yu K, A Powerful Procedure for Pathway-Based Meta-analysis Using Summary Statistics Identifies 43 Pathways Associated with Type II Diabetes in European Populations, PLoS Genet, 12 (2016) e1006122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Campbell IA, Bah-Sow O, Pulmonary tuberculosis: diagnosis and treatment, BMJ, 332 (2006) 1194–1197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Engels EA, Shen M, Chapman RS, Pfeiffer RM, Yu YY, He X, Lan Q, Tuberculosis and subsequent risk of lung cancer in Xuanwei, China, Int J Cancer, 124 (2009) 1183–1187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Yu YY, Pinsky PF, Caporaso NE, Chatterjee N, Baumgarten M, Langenberg P, Furuno JP, Lan Q, Engels EA, Lung cancer risk following detection of pulmonary scarring by chest radiography in the prostate, lung, colorectal, and ovarian cancer screening trial, Arch Intern Med, 168 (2008) 2326–2332; discussion 2332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Nalbandian A, Yan BS, Pichugin A, Bronson RT, Kramnik I, Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control, Oncogene, 28 (2009) 1928–1938. [DOI] [PubMed] [Google Scholar]
  • [17].Shiels MS, Albanes D, Virtamo J, Engels EA, Increased risk of lung cancer in men with tuberculosis in the alpha-tocopherol, beta-carotene cancer prevention study, Cancer Epidemiol Biomarkers Prev, 20 (2011) 672–678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Bae JM, Li ZM, Shin MH, Kim DH, Lee MS, Ahn YO, Pulmonary tuberculosis and lung cancer risk in current smokers: the Seoul Male Cancer Cohort Study, J Korean Med Sci, 28 (2013) 896–900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Yu YH, Liao CC, Hsu WH, Chen HJ, Liao WC, Muo CH, Sung FC, Chen CY, Increased lung cancer risk among patients with pulmonary tuberculosis: a population cohort study, J Thorac Oncol, 6 (2011) 32–37. [DOI] [PubMed] [Google Scholar]
  • [20].Liang HY, Li XL, Yu XS, Guan P, Yin ZH, He QC, Zhou BS, Facts and fiction of the relationship between preexisting tuberculosis and lung cancer risk: a systematic review, Int J Cancer, 125 (2009) 2936–2944. [DOI] [PubMed] [Google Scholar]
  • [21].Hong S, Mok Y, Jeon C, Jee SH, Samet JM, Tuberculosis, smoking and risk for lung cancer incidence and mortality, Int J Cancer, 139 (2016) 2447–2455. [DOI] [PubMed] [Google Scholar]
  • [22].Denholm R, Schuz J, Straif K, Stucker I, Jockel KH, Brenner DR, De Matteis S, Boffetta P, Guida F, Bruske I, Wichmann HE, Landi MT, Caporaso N, Siemiatycki J, Ahrens W, Pohlabeln H, Zaridze D, Field JK, McLaughlin J, Demers P, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Dumitru RS, Bencko V, Foretova L, Janout V, Kendzia B, Peters S, Behrens T, Vermeulen R, Bruning T, Kromhout H, A CO, Is previous respiratory disease a risk factor for lung cancer?, Am J Respir Crit Care Med, 190 (2014) 549–559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Littman AJ, Thornquist MD, White E, Jackson LA, Goodman GE, Vaughan TL, Prior lung disease and risk of lung cancer in a large prospective study, Cancer Causes Control, 15 (2004) 819–827. [DOI] [PubMed] [Google Scholar]
  • [24].Brownson RC, Alavanja MC, Previous lung disease and lung cancer risk among women (United States), Cancer Causes Control, 11 (2000) 853–858. [DOI] [PubMed] [Google Scholar]
  • [25].Koshiol J, Rotunno M, Consonni D, Pesatori AC, De Matteis S, Goldstein AM, Chaturvedi AK, Wacholder S, Landi MT, Lubin JH, Caporaso NE, Lower risk of lung cancer after multiple pneumonia diagnoses, Cancer Epidemiol Biomarkers Prev, 19 (2010) 716–721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Mayne ST, Buenconsejo J, Janerich DT, Previous lung disease and risk of lung cancer among men and women nonsmokers, Am J Epidemiol, 149 (1999) 13–20. [DOI] [PubMed] [Google Scholar]
  • [27].Hu Z, Wu C, Shi Y, Guo H, Zhao X, Yin Z, Yang L, Dai J, Hu L, Tan W, Li Z, Deng Q, Wang J, Wu W, Jin G, Jiang Y, Yu D, Zhou G, Chen H, Guan P, Chen Y, Shu Y, Xu L, Liu X, Liu L, Xu P, Han B, Bai C, Zhao Y, Zhang H, Yan Y, Ma H, Chen J, Chu M, Lu F, Zhang Z, Chen F, Wang X, Jin L, Lu J, Zhou B, Lu D, Wu T, Lin D, Shen H, A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese, Nat Genet, 43 (2011) 792–796. [DOI] [PubMed] [Google Scholar]
  • [28].Shiraishi K, Okada Y, Takahashi A, Kamatani Y, Momozawa Y, Ashikawa K, Kunitoh H, Matsumoto S, Takano A, Shimizu K, Goto A, Tsuta K, Watanabe S, Ohe Y, Watanabe Y, Goto Y, Nokihara H, Furuta K, Yoshida A, Goto K, Hishida T, Tsuboi M, Tsuchihara K, Miyagi Y, Nakayama H, Yokose T, Tanaka K, Nagashima T, Ohtaki Y, Maeda D, Imai K, Minamiya Y, Sakamoto H, Saito A, Shimada Y, Sunami K, Saito M, Inazawa J, Nakamura Y, Yoshida T, Yokota J, Matsuda F, Matsuo K, Daigo Y, Kubo M, Kohno T, Association of variations in HLA class II and other loci with susceptibility to EGFR-mutated lung adenocarcinoma, Nat Commun, 7 (2016) 12451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Miki D, Kubo M, Takahashi A, Yoon KA, Kim J, Lee GK, Zo JI, Lee JS, Hosono N, Morizono T, Tsunoda T, Kamatani N, Chayama K, Takahashi T, Inazawa J, Nakamura Y, Daigo Y, Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations, Nat Genet, 42 (2010) 893–896. [DOI] [PubMed] [Google Scholar]
  • [30].Chimusa ER, Zaitlen N, Daya M, Moller M, van Helden PD, Mulder NJ, Price AL, Hoal EG, Genome-wide association study of ancestry-specific TB risk in the South African Coloured population, Hum Mol Genet, 23 (2014) 796–809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Curtis J, Luo Y, Zenner HL, Cuchet-Lourenco D, Wu C, Lo K, Maes M, Alisaac A, Stebbings E, Liu JZ, Kopanitsa L, Ignatyeva O, Balabanova Y, Nikolayevskyy V, Baessmann I, Thye T, Meyer CG, Nurnberg P, Horstmann RD, Drobniewski F, Plagnol V, Barrett JC, Nejentsev S, Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration, Nat Genet, 47 (2015) 523–527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Grant AV, Sabri A, Abid A, Abderrahmani Rhorfi I, Benkirane M, Souhi H, Naji Amrani H, Alaoui-Tahiri K, Gharbaoui Y, Lazrak F, Sentissi I, Manessouri M, Belkheiri S, Zaid S, Bouraqadi A, El Amraoui N, Hakam M, Belkadi A, Orlova M, Boland A, Deswarte C, Amar L, Bustamante J, Boisson-Dupuis S, Casanova JL, Schurr E, El Baghdadi J, Abel L, A genome-wide association study of pulmonary tuberculosis in Morocco, Hum Genet, 135 (2016) 299–307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Mahasirimongkol S, Yanai H, Mushiroda T, Promphittayarat W, Wattanapokayakit S, Phromjai J, Yuliwulandari R, Wichukchinda N, Yowang A, Yamada N, Kantipong P, Takahashi A, Kubo M, Sawanpanyalert P, Kamatani N, Nakamura Y, Tokunaga K, Genome-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis, J Hum Genet, 57 (2012) 363–367. [DOI] [PubMed] [Google Scholar]
  • [34].Omae Y, Toyo-Oka L, Yanai H, Nedsuwan S, Wattanapokayakit S, Satproedprai N, Smittipat N, Palittapongarnpim P, Sawanpanyalert P, Inunchot W, Pasomsub E, Wichukchinda N, Mushiroda T, Kubo M, Tokunaga K, Mahasirimongkol S, Pathogen lineage-based genome-wide association study identified CD53 as susceptible locus in tuberculosis, J Hum Genet, 62 (2017) 1015–1022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Qi H, Zhang YB, Sun L, Chen C, Xu B, Xu F, Liu JW, Liu JC, Chen C, Jiao WW, Shen C, Xiao J, Li JQ, Guo YJ, Wang YH, Li QJ, Yin QQ, Li YJ, Wang T, Wang XY, Gu ML, Yu J, Shen AD, Discovery of susceptibility loci associated with tuberculosis in Han Chinese, Hum Mol Genet, 26 (2017) 4752–4763. [DOI] [PubMed] [Google Scholar]
  • [36].Sobota RS, Stein CM, Kodaman N, Scheinfeldt LB, Maro I, Wieland-Alter W, Igo RP Jr., Magohe A, Malone LL, Chervenak K, Hall NB, Modongo C, Zetola N, Matee M, Joloba M, Froment A, Nyambo TB, Moore JH, Scott WK, Lahey T, Boom WH, von Reyn CF, Tishkoff SA, Sirugo G, Williams SM, A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals, Am J Hum Genet, 98 (2016) 514–524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [37].Sveinbjornsson G, Gudbjartsson DF, Halldorsson BV, Kristinsson KG, Gottfredsson M, Barrett JC, Gudmundsson LJ, Blondal K, Gylfason A, Gudjonsson SA, Helgadottir HT, Jonasdottir A, Jonasdottir A, Karason A, Kardum LB, Knezevic J, Kristjansson H, Kristjansson M, Love A, Luo Y, Magnusson OT, Sulem P, Kong A, Masson G, Thorsteinsdottir U, Dembic Z, Nejentsev S, Blondal T, Jonsdottir I, Stefansson K, HLA class II sequence variants influence tuberculosis risk in populations of European ancestry, Nat Genet, 48 (2016) 318–322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [38].Thye T, Vannberg FO, Wong SH, Owusu-Dabo E, Osei I, Gyapong J, Sirugo G, Sisay-Joof A F. Enimil, Chinbuah MA, Floyd S, Warndorff DK, Sichali L, Malema S, Crampin AC, Ngwira B, Teo YY, Small K, Rockett K, Kwiatkowski D, Fine PE, Hill PC, Newport M, Lienhardt C, Adegbola RA, Corrah T, Ziegler A, T.B.G.C. African, C. Wellcome Trust Case Control, Morris AP, Meyer CG, Horstmann RD, Hill AVS, Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2, Nat Genet, 42 (2010) 739–741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Tian C, Hromatka BS, Kiefer AK, Eriksson N, Noble SM, Tung JY, Hinds DA, Genome wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections, Nat Commun, 8 (2017) 599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Huang da W, Sherman BT, Lempicki RA, Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources, Nat Protoc, 4 (2009) 44–57. [DOI] [PubMed] [Google Scholar]
  • [41].Burgess S, Dudbridge F, Thompson SG, Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods, Stat Med, 35 (2016) 1880–1906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Hernan MA, Robins JM, Instruments for causal inference: an epidemiologist’s dream?, Epidemiology, 17 (2006) 360–372. [DOI] [PubMed] [Google Scholar]
  • [43].VanderWeele TJ, Tchetgen Tchetgen EJ, Cornelis M, Kraft P, Methodological challenges in mendelian randomization, Epidemiology, 25 (2014) 427–435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [44].Taylor AE, Davies NM, Ware JJ, VanderWeele T, Smith GD, Munafo MR, Mendelian randomization in health research: using appropriate genetic variants and avoiding biased estimates, Econ Hum Biol, 13 (2014) 99–106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [45].Pierce BL, Ahsan H, Vanderweele TJ, Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants, Int J Epidemiol, 40 (2011) 740–752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [46].Davies NM, Holmes MV, Davey Smith G, Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians, BMJ, 362 (2018) k601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [47].Miao R, Huang S, Li C, Ding S, Wang R, Xu K, Yang C, Xu F, Ge H, An HLA class II locus, previously identified by a genome-wide association study, is also associated with susceptibility to pulmonary tuberculosis in a Chinese population, Infect Genet Evol, 64 (2018) 164–167. [DOI] [PubMed] [Google Scholar]
  • [48].http://www.who.int/mediacentre/factsheets/fs104/en/, World Health Organization, (2018).
  • [49].Zhu S, Xia L, Yu S, Chen S, Zhang J, The burden and challenges of tuberculosis in China: findings from the Global Burden of Disease Study 2015, Sci Rep, 7 (2017) 14601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [50].Knudson AG, Hereditary cancer: two hits revisited, J Cancer Res Clin Oncol, 122 (1996) 135–140. [DOI] [PubMed] [Google Scholar]
  • [51].Kohno T, Kunitoh H, Shimada Y, Shiraishi K, Ishii Y, Goto K, Ohe Y, Nishiwaki Y, Kuchiba A, Yamamoto S, Hirose H, Oka A, Yanagitani N, Saito R, Inoko H, Yokota J, Individuals susceptible to lung adenocarcinoma defined by combined HLA-DQA1 and TERT genotypes, Carcinogenesis, 31 (2010) 834–841. [DOI] [PubMed] [Google Scholar]
  • [52].Ferreiro-Iglesias A, Lesseur C, McKay J, Hung RJ, Han Y, Zong X, Christiani D, Johansson M, Xiao X, Li Y, Qian DC, Ji X, Liu G, Caporaso N, Scelo G, Zaridze D, Mukeriya A, Kontic M, Ognjanovic S, Lissowska J, Szolkowska M, Swiatkowska B, Janout V, Holcatova I, Bolca C, Savic M, Ognjanovic M, Bojesen SE, Wu X, Albanes D, Aldrich MC, Tardon A, Fernandez-Somoano A, Fernandez-Tardon G, Le Marchand L, Rennert G, Chen C, Doherty J, Goodman G, Bickeboller H, Wichmann HE, Risch A, Rosenberger A, Shen H, Dai J, Field JK, Davies M, Woll P, Teare MD, Kiemeney LA, van der Heijden E, Yuan JM, Hong YC, Haugen A, Zienolddiny S, Lam S, Tsao MS, Johansson M, Grankvist K, Schabath MB, Andrew A, Duell E, Melander O, Brunnstrom H, Lazarus P, Arnold S, Slone S, Byun J, Kamal A, Zhu D, Landi MT, Amos CI, Brennan P, Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity, Nat Commun, 9 (2018) 3927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [53].Filadi R, Pendin D, Pizzo P, Mitofusin 2: from functions to disease, Cell Death Dis, 9 (2018) 330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [54].Lou Y, Li R, Liu J, Zhang Y, Zhang X, Jin B, Liu Y, Wang Z, Zhong H, Wen S, Han B, Mitofusin-2 over-expresses and leads to dysregulation of cell cycle and cell invasion in lung adenocarcinoma, Med Oncol, 32 (2015) 132. [DOI] [PubMed] [Google Scholar]
  • [55].Wei YL, Tian Q, Zhao XX, Qiu GZ, Xu Y, Association between MFN2 gene polymorphisms and the risk and prognosis of acute liver failure: a case-control study in a Chinese population, Braz J Med Biol Res, 50 (2017) e5758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [56].Santel A, Fuller MT, Control of mitochondrial morphology by a human mitofusin, J Cell Sci, 114 (2001) 867–874. [DOI] [PubMed] [Google Scholar]
  • [57].Antico Arciuch VG, Elguero ME, Poderoso JJ, Carreras MC, Mitochondrial regulation of cell cycle and proliferation, Antioxid Redox Signal, 16 (2012) 1150–1180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [58].West AP, Mitochondrial dysfunction as a trigger of innate immune responses and inflammation, Toxicology, 391 (2017) 54–63. [DOI] [PubMed] [Google Scholar]
  • [59].Warburg O, On the origin of cancer cells, Science, 123 (1956) 309–314. [DOI] [PubMed] [Google Scholar]
  • [60].Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED, A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth, Cancer Cell, 11 (2007) 37–51. [DOI] [PubMed] [Google Scholar]
  • [61].Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I, Dichloroacetate induces apoptosis in endometrial cancer cells, Gynecol Oncol, 109 (2008) 394–402. [DOI] [PMC free article] [PubMed] [Google Scholar]

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