Functional polymorphisms in NFκB1/IκBα predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese
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Lung inflammation is the major pathogenetic feature for both chronic obstructive pulmonary disease (COPD) and lung cancer. The nuclear factor-kappa B (NFκB) and its inhibitor (IκB) play crucial roles in inflammatory. Here, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in NFκB/IκB confer consistent risks for COPD and lung cancer. Four putative functional SNPs (NFκB1: −94del>insATTG; NFκB2: −2966G>A; IκBα: −826C>T, 2758G>A) were analyzed in southern and validated in eastern Chineses to test their associations with COPD risk in 1,511 COPD patients and 1,677 normal lung function controls, as well as lung cancer risk in 1,559 lung cancer cases and 1,679 cancer-free controls. We found that the −94ins ATTG variants (ins/del + ins/ins) in NFκB1 conferred an increased risk of COPD (OR 1.27, 95 % CI 1.06–1.52) and promoted COPD progression by accelerating annual FEV1 decline (P = 0.015). The 2758AA variant in IκBα had an increased risk of lung cancer (OR 1.53, 95 % CI 1.30–1.80) by decreasing IκBα expression due to the modulation of microRNA hsa-miR-449a but not hsa-miR-34b. Furthermore, both adverse genotypes exerted effect on increasing lung cancer risk in individuals with pre-existing COPD, while the −94del>insATTG did not in those without pre-existing COPD. However, no significant association with COPD or lung cancer was observed for −2966G>A and −826C>T. Our data suggested a common susceptible mechanism of inflammation in lung induced by genetic variants in NFκB1 (−94del>ins ATTG) or IκBα (2758G>A) to predict risk of COPD or lung cancer.
This study was supported by the National Natural Scientific Foundation of China grants 30671813, 30872178, 81072366, 81273149 (Dr. J. Lu), and partly by 81170043 (Dr. P.Ran), 30872142 (Dr. W. Ji) and 81001278, 81171895 (Dr. Y. Zhou); Guangdong Provincial High Level Experts Grants 2010-79 (Dr. J. Lu); Guangdong Provincial Science and Technology Planning Project Grant 2011B031800378 (Dr. D. Huang), Guangdong Provincial Medical Scientific Research Grants A2012520 (Dr. D. Huang); Guangzhou civic Science and Technology grant 2012-Y2-00029 (Dr. B. Liu); Changjiang Scholars and Innovative Research Team in University grant IRT0961 (Dr. J. Wang), Guangdong natural science foundation team grant 10351012003000000 (Dr. W. Lu). We thank Dr. Bohang Zeng, Dr. Yunnan Wang, Dr. Zhanhong Xie and Ms. Wanmin Zeng for their assistance in recruiting the subjects; Hongjun Zhao, Xiaoxuan Ling and Lin Liu for their laboratory assistance.
Conflict of interest
The authors have declared no conflicts of interest.
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