Germline HLA heterozygosity is associated with decreased lung cancer risk

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Tan, T, Shaw, VR ORCID: 0000-0002-1172-5686, Byun, J, Lee, HS, Han, Y, Li, Y, Hung, RJ, Christiani, DC, Wang, XA, Johansson, M et al (show 31 more authors) , Xiao, X, Zaridze, D, Bojesen, SE, Shete, S, Albanes, D, Aldrich, MC, Tardon, A, Fernandez-Tardon, G, Le Marchand, L, Rennert, G, Bickeböller, H, Wichmann, HE, Risch, A, Field, JK ORCID: 0000-0003-3951-6365, Davies, M ORCID: 0000-0002-7609-4977, Woll, P, Kiemeney, LA, Haugen, A, Zienolddiny, S, Lam, S, Johansson, M, Grankvist, K, Schabath, MB, Andrew, A, Lazarus, P, Arnold, SM, Zhu, D, Landi, MT, McKay, J, Amos, C and Cheng, C ORCID: 0000-0002-5002-3417 (2026) Germline HLA heterozygosity is associated with decreased lung cancer risk Human Genetics and Genomics Advances, 7 (2). 100567-. ISSN 2666-2477, 2666-2477

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Abstract

Heterozygosity at human leukocyte antigen ( HLA ) loci may improve lung cancer immunosurveillance by increasing recognition of the tumor by the immune system. Previous studies utilizing data from population-level biobanks, such as the United Kingdom Biobank and FinnGen, have identified an association between germline HLA class II ( HLA- II) heterozygosity and reduced lung cancer risk in smokers. In the present study, we evaluate the association between HLA heterozygosity and lung cancer in a large case-control study (15,302 cases and 14,580 controls) with imputed HLA allele-type information, comparing differences in HLA heterozygosity between smokers and non-smokers, among lung cancer subtypes, and at 2- and 4-digit HLA allele resolution. We identify a strong protective association of HLA -II heterozygosity in smokers compared to non-smokers, particularly at the HLA-DPB1 and HLA-DPA1 loci, and provide subtype-specific resolution. Finally, analysis of the additive effects of HLA allele heterozygosity in smokers identified significant associations with several 4-digit HLA alleles, including HLA-B∗08 : 01 , HLA-A∗01 : 01 , HLA-C∗07 : 01 , HLA-DQA1∗05 : 01 , HLA-DRB1∗03 : 01 , and HLA-C∗03 : 04 . Our study provides additional evidence, with added histologic subtype information, that germline HLA -II heterozygosity is inversely associated with lung cancer risk.

Item Type:	Article
Uncontrolled Keywords:	HLA, genetic risk, genetics, lung cancer, smoking, Humans, Lung Neoplasms, Genetic Predisposition to Disease, Heterozygote, Case-Control Studies, Male, HLA Antigens, Female, Alleles, Middle Aged, Aged, Smoking, Risk Factors
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Molecular & Clinical Cancer Medicine
Depositing User:	Symplectic Admin
Date Deposited:	02 Feb 2026 16:56
Last Modified:	11 Apr 2026 19:01
DOI:	10.1016/j.xhgg.2026.100567
Open Access URL:	https://doi.org/10.1016/j.xhgg.2026.100567
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3196839
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