Integrative GWAS and Mendelian Randomization Analysis Identifies IREB2 and CD27+ Memory B Cells as Core Drivers of COPD to Lung Cancer Progression

Abstract

Chronic obstructive pulmonary disease (COPD) associates with increased lung cancer incidence and shares genetic susceptibility, yet its independent causal role and driver mechanisms are poorly understood. We integrated data from the National Health and Nutrition Examination Survey (NHANES) cohort with genome-wide association studies (GWAS) summary statistics and Mendelian randomization analyses to map genetic correlations and infer causality between COPD phenotypes and lung cancer. Post-GWAS methods—including transcriptome-wide association study, colocalization, partitioned heritability via heritability estimation from summary statistics (ρ-HESS), and cross-phenotype association (CPASSOC)—identified shared susceptibility loci, highlighting IREB2 and CD27⁺ B cells as potential mediators. Elevated IREB2 expression correlated with accelerated lung-function decline in COPD but predicted improved prognosis in lung cancer B cells, whereas higher CD27⁺ B cell levels in COPD were associated with protumorigenic activity. Single-cell transcriptomic analysis and in vitro knockdown experiments confirmed IREB2's role in modulating B-cell activation and apoptosis pathways within tumors. These results support COPD as an independent lung cancer risk factor and implicate IREB2 and CD27⁺ B cells in COPD-to-cancer progression, laying groundwork for early detection and targeted intervention in high-risk individuals.

Keywords

chronic obstructive pulmonary disease / GWAS / IREB2 / lung cancer / mendelian randomization

References

[1] S. Safiri, K. Carson-Chahhoud, M. Noori, et al., “Burden of chronic obstructive pulmonary disease and its attributable risk factors in 204 countries and territories, 1990-2019: Results From the Global Burden of Disease Study 2019,” Bmj 378 (2022): e069679.

[2] C. Wang, J. Xu, L. Yang, et al., “Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study): A national cross-sectional study,” Lancet 391, no. 10131 (2018): 1706–1717.

[3] A. Leiter, R. R. Veluswamy, and J. P. Wisnivesky, “The global burden of lung cancer: Current status and future trends,” Nature Reviews Clinical Oncology 20, no. 9 (2023): 624–639.

[4] R. S. Zheng, R. Chen, B. F. Han, et al., “Cancer incidence and mortality in China, 2022,” Zhonghua Zhong Liu Za Zhi [Chinese Journal of Oncology] 46, no. 3 (2024): 221–231.

[5] C. Qi, S. W. Sun, and X. Z. Xiong, “From COPD to Lung Cancer: Mechanisms Linking, Diagnosis, Treatment, and Prognosis,” Int J Chron Obstruct Pulmon Dis 17 (2022): 2603–2621.

[6] T. Parimon, J. W. Chien, C. L. Bryson, M. B. McDonell, E. M. Udris, and D. H. Au, “Inhaled corticosteroids and risk of lung cancer Among patients With chronic obstructive pulmonary disease,” American Journal of Respiratory and Critical Care Medicine 175, no. 7 (2007): 712–719.

[7] C. M. Lusk, A. S. Wenzlaff, D. Watza, et al., “Quantitative Imaging Markers of Lung Function in a Smoking Population Distinguish COPD Subgroups With Differential Lung Cancer Risk,” Cancer Epidemiology and Prevention Biomarkers 28, no. 4 (2019): 724–730.

[8] M. Mascalchi and M. Luconi, “Lung Cancer Screening, Emphysema, and COPD,” Chest 159, no. 5 (2021): 1699–1700.

[9] R. Zhang, S. Shen, Y. Wei, et al., “A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians,” Journal of Thoracic Oncology 17, no. 8 (2022): 974–990.

[10] R. P. Young and R. J. Scott, “Gene-Gene Interaction in Ever Smokers With Lung Cancer: Is There Confounding by Chronic Obstructive Pulmonary Disease in Genome-Wide Association Studies?,” Journal of Thoracic Oncology 18, no. 3 (2023): e23–e24.

[11] R. J. Hopkins, F. Duan, G. D. Gamble, et al., “Chr15q25 genetic variant (rs16969968) independently confers risk of lung cancer, COPD and smoking intensity in a prospective study of high-risk smokers,” Thorax 76, no. 3 (2021): 272–280.

[12] S. K. Jha, G. De Rubis, S. R. Devkota, et al., “Cellular senescence in lung cancer: Molecular mechanisms and therapeutic interventions,” Ageing Research Reviews 97 (2024): 102315.

[13] K. H. Prazanowska and S. B. Lim, “An integrated single-cell transcriptomic dataset for non-small cell lung cancer,” Scientific Data 10, no. 1 (2023): 167.

[14] U. Vosa, A. Claringbould, H. J. Westra, et al., “Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression,” Nature Genetics 53, no. 9 (2021): 1300–1310.

[15] K. Piersiala, E. Hjalmarsson, P. F. N. da Silva, et al., “Regulatory B cells producing IL-10 are increased in human tumor draining lymph nodes,” International Journal of Cancer 153, no. 4 (2023): 854–866.

[16] Y. Yang, X. Chen, J. Pan, et al., “Pan-cancer single-cell dissection reveals phenotypically distinct B cell subtypes,” Cell 187, no. 17 (2024): 4790–4811.

[17] G. J. Criner, A. Agusti, H. Borghaei, et al., “Chronic Obstructive Pulmonary Disease and Lung Cancer: A Review for Clinicians,” Chronic Obstr Pulm Dis 9, no. 3 (2022): 454–476.

[18] E. Long, H. Patel, A. Golden, et al., “High-throughput characterization of functional variants highlights heterogeneity and polygenicity underlying lung cancer susceptibility,” American Journal of Human Genetics 111, no. 7 (2024): 1405–1419.

[19] I. Nedeljkovic, E. Carnero-Montoro, L. Lahousse, et al., “Understanding the role of the chromosome 15q25.1 in COPD Through epigenetics and transcriptomics,” European Journal of Human Genetics 26, no. 5 (2018): 709–722.

[20] Y. Zhang, J. Qiu, P. Zhang, J. Zhang, M. Jiang, and Z. Ma, “Genetic variants in FAM13A and IREB2 are associated With the susceptibility to COPD in a Chinese rural population: A case-control study,” Int J Chron Obstruct Pulmon Dis 13 (2018): 1735–1745.

[21] H. Zhou, J. Yang, D. Li, et al., “Association of IREB2 and CHRNA3/5 polymorphisms With COPD and COPD-related phenotypes in a Chinese Han population,” Journal of Human Genetics 57, no. 11 (2012): 738–746.

[22] D. L. DeMeo, T. Mariani, S. Bhattacharya, et al., “Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene,” American Journal of Human Genetics 85, no. 4 (2009): 493–502.

[23] W. J. Kim, A. M. Wood, A. F. Barker, et al., “Association of IREB2 and CHRNA3 polymorphisms With airflow obstruction in severe alpha-1 antitrypsin deficiency,” Respiratory Research 13, no. 1 (2012): 16.

[24] I. Ziolkowska-Suchanek, M. Mosor, P. Gabryel, et al., “Susceptibility loci in lung cancer and COPD: Association of IREB2 and FAM13A With pulmonary diseases,” Scientific Reports 5 (2015): 13502.

[25] H. Khiroya and A. M. Turner, “The role of iron in pulmonary pathology,” Multidiscip Respir Med 10 (2015): 34.

[26] H. Khiroya, J. S. Moore, N. Ahmad, et al., “IRP2 as a potential modulator of cell proliferation, apoptosis and prognosis in nonsmall cell lung cancer,” European Respiratory Journal 49, no. 4 (2017): 1600711.

[27] H. Xia, Y. Wu, J. Zhao, et al., “N6-Methyladenosine-modified circSAV1 triggers ferroptosis in COPD Through recruiting YTHDF1 to facilitate the translation of IREB2,” Cell Death and Differentiation 30, no. 5 (2023): 1293–1304.

[28] C. A. Brandsma, M. N. Hylkema, M. Geerlings, et al., “Increased levels of (class switched) memory B cells in peripheral blood of current smokers,” Respiratory Research 10, no. 1 (2009): 108.

[29] C. A. Brandsma, H. A. Kerstjens, W. H. van Geffen, et al., “Differential switching to IgG and IgA in active smoking COPD patients and healthy controls,” European Respiratory Journal 40, no. 2 (2012): 313–321.

[30] A. Habener, C. Happle, R. Grychtol, et al., “Regulatory B cells control airway hyperreactivity and lung remodeling in a murine asthma model,” Journal of Allergy and Clinical Immunology, 147 no. 6 2021: 2281–2294.e7.

[31] D. Hao, G. Han, A. Sinjab, et al., “The Single-Cell Immunogenomic Landscape of B and Plasma Cells in Early-Stage Lung Adenocarcinoma,” Cancer Discovery 12, no. 11 (2022): 2626–2645.

[32] M. Seifert and R. Kuppers, “Human memory B cells,” Leukemia 30, no. 12 (2016): 2283–2292.

[33] Y. Li, P. Wang, D. Ye, et al., “IGHG1 induces EMT in gastric cancer cells by regulating TGF-beta/SMAD3 signaling pathway,” Journal of Cancer 12, no. 12 (2021): 3458–3467.

[34] B. L. Woolbright, G. Rajendran, E. Abbott, et al., “Role of MIF1/MIF2/CD74 interactions in bladder cancer,” Journal of Pathology 259, no. 1 (2023): 46–55.

[35] L. Garcia-Gerique, M. Garcia, A. Garrido-Garcia, et al., “MIF/CXCR4 signaling axis contributes to survival, invasion, and drug resistance of metastatic neuroblastoma cells in the bone marrow microenvironment,” BMC cancer 22, no. 1 (2022): 669.

[36] B. Pellegrino, K. David, S. Rabani, et al., “CD74 promotes the formation of an immunosuppressive tumor microenvironment in triple-negative breast cancer in mice by inducing the expansion of tolerogenic dendritic cells and regulatory B cells,” Plos Biology 22, no. 11 (2024): e3002905.

[37] C. Zhou, T. Luan, W. Guan, et al., “Oncology-respirology: A discipline in dire need,” (2024): 777–780.

[38] H. J. de Koning, C. M. van der Aalst, P. A. Jong, et al., “Reduced Lung-Cancer Mortality With Volume CT Screening in a Randomized Trial,” New England Journal of Medicine 382, no. 6 (2020): 503–513.

[39] B. R. Stockwell, J. P. Friedmann Angeli, H. Bayir, et al., “Ferroptosis: A ,” Cell 171, no. 2 (2017): 273–285.

[40] G. Gao and X. Zhang, “Broadening horizons: Research on ferroptosis in lung cancer and its potential therapeutic targets,” Frontiers in Immunology 16 (2025): 1542844.

[41] X. Guo, Y. Zhang, L. Zheng, et al., “Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing,” Nature Medicine 24, no. 7 (2018): 978–985.

[42] J. D. McKay, R. J. Hung, Y. Han, et al., “Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility Across histological subtypes,” Nature Genetics 49, no. 7 (2017): 1126–1132.

[43] D. H. Higbee, R. Granell, E. Sanderson, G. Davey Smith, and J. W. Dodd, “Lung function and cardiovascular disease: A two-sample Mendelian randomisation study,” European Respiratory Journal 58, no. 3 (2021).

[44] Z. Zhu, F. Zhang, H. Hu, et al., “Integration of summary data From GWAS and eQTL studies predicts complex trait gene targets,” Nature Genetics 48, no. 5 (2016): 481–487.

[45] H. Shi, N. Mancuso, S. Spendlove, and B. Pasaniuc, “Local Genetic Correlation Gives Insights Into the Shared Genetic Architecture of Complex Traits,” American Journal of Human Genetics 101, no. 5 (2017): 737–751.

[46] T. Berisa and J. K. Pickrell, “Approximately independent linkage disequilibrium blocks in human populations,” Bioinformatics 32, no. 2 (2016): 283–285.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.