Germline HLA heterozygosity is associated with decreased lung cancer risk

Taotao Tan; Vikram R Shaw; Jinyoung Byun; Hyun-Sung Lee; Younghun Han; Yafang Li; Rayjean J Hung; David C Christiani; Xin-An Wang; Mattias Johansson; Xiangjun Xiao; David Zaridze; Stig Egil Bojesen; Sanjay Shete; Demetrios Albanes; Melinda C Aldrich; Adonina Tardon; Guillermo Fernandez-Tardon; Loïc Le Marchand; Gad Rennert; Heike Bickeböller; H-Erich Wichmann; Angela Risch; John K Field; Michael Davies; Penella Woll; Lambertus A Kiemeney; Aage Haugen; Shanbeh Zienolddiny; Stephen Lam; Mikael Johansson; Kjell Grankvist; Matthew B Schabath; Angeline Andrew; Philip Lazarus; Susanne M Arnold; Dakai Zhu; Maria Teresa Landi; James McKay; Christopher Amos; Chao Cheng

doi:10.1016/j.xhgg.2026.100567

Germline HLA heterozygosity is associated with decreased lung cancer risk

Taotao Tan, Vikram R Shaw, Jinyoung Byun, Hyun-Sung Lee, Younghun Han, Yafang Li, Rayjean J Hung, David C Christiani, Xin-An Wang, Mattias Johansson, Xiangjun Xiao, David Zaridze, Stig Egil Bojesen, Sanjay Shete, Demetrios Albanes, Melinda C Aldrich, Adonina Tardon, Guillermo Fernandez-Tardon, Loïc Le Marchand, Gad RennertHeike Bickeböller, H-Erich Wichmann, Angela Risch, John K Field, Michael Davies, Penella Woll, Lambertus A Kiemeney, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Mikael Johansson, Kjell Grankvist, Matthew B Schabath, Angeline Andrew, Philip Lazarus, Susanne M Arnold, Dakai Zhu, Maria Teresa Landi, James McKay, Christopher Amos, Chao Cheng

Department of Clinical Biochemistry

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.

Original language	English
Article number	100567
Journal	HGG advances
Volume	7
Issue number	2
ISSN	2666-2477
DOIs	https://doi.org/10.1016/j.xhgg.2026.100567
Publication status	Published - 2026

Keywords

genetic risk
genetics
HLA
lung cancer
smoking

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Tan, T., Shaw, V. R., Byun, J., Lee, H.-S., Han, Y., Li, Y., Hung, R. J., Christiani, D. C., Wang, X.-A., Johansson, M., Xiao, X., Zaridze, D., Bojesen, S. E., Shete, S., Albanes, D., Aldrich, M. C., Tardon, A., Fernandez-Tardon, G., Le Marchand, L., ... Cheng, C. (2026). Germline HLA heterozygosity is associated with decreased lung cancer risk. HGG advances, 7(2), Article 100567. https://doi.org/10.1016/j.xhgg.2026.100567

Tan, T, Shaw, VR, Byun, J, Lee, H-S, Han, Y, Li, Y, Hung, RJ, Christiani, DC, Wang, X-A, Johansson, M, 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, H-E, Risch, A, Field, JK, Davies, M, 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 & Cheng, C 2026, 'Germline HLA heterozygosity is associated with decreased lung cancer risk', HGG advances, vol. 7, no. 2, 100567. https://doi.org/10.1016/j.xhgg.2026.100567

@article{d7eb5614699849048af2f1f0e3714f46,

title = "Germline HLA heterozygosity is associated with decreased lung cancer risk",

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.",

keywords = "genetic risk, genetics, HLA, lung cancer, smoking",

author = "Taotao Tan and Shaw, \{Vikram R\} and Jinyoung Byun and Hyun-Sung Lee and Younghun Han and Yafang Li and Hung, \{Rayjean J\} and Christiani, \{David C\} and Xin-An Wang and Mattias Johansson and Xiangjun Xiao and David Zaridze and Bojesen, \{Stig Egil\} and Sanjay Shete and Demetrios Albanes and Aldrich, \{Melinda C\} and Adonina Tardon and Guillermo Fernandez-Tardon and \{Le Marchand\}, Lo{\"i}c and Gad Rennert and Heike Bickeb{\"o}ller and H-Erich Wichmann and Angela Risch and Field, \{John K\} and Michael Davies and Penella Woll and Kiemeney, \{Lambertus A\} and Aage Haugen and Shanbeh Zienolddiny and Stephen Lam and Mikael Johansson and Kjell Grankvist and Schabath, \{Matthew B\} and Angeline Andrew and Philip Lazarus and Arnold, \{Susanne M\} and Dakai Zhu and Landi, \{Maria Teresa\} and James McKay and Christopher Amos and Chao Cheng",

year = "2026",

doi = "10.1016/j.xhgg.2026.100567",

language = "English",

volume = "7",

journal = "HGG advances",

issn = "2666-2477",

publisher = "Elsevier Inc.",

number = "2",

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TY - JOUR

T1 - Germline HLA heterozygosity is associated with decreased lung cancer risk

AU - Tan, Taotao

AU - Shaw, Vikram R

AU - Byun, Jinyoung

AU - Lee, Hyun-Sung

AU - Han, Younghun

AU - Li, Yafang

AU - Hung, Rayjean J

AU - Christiani, David C

AU - Wang, Xin-An

AU - Johansson, Mattias

AU - Xiao, Xiangjun

AU - Zaridze, David

AU - Bojesen, Stig Egil

AU - Shete, Sanjay

AU - Albanes, Demetrios

AU - Aldrich, Melinda C

AU - Tardon, Adonina

AU - Fernandez-Tardon, Guillermo

AU - Le Marchand, Loïc

AU - Rennert, Gad

AU - Bickeböller, Heike

AU - Wichmann, H-Erich

AU - Risch, Angela

AU - Field, John K

AU - Davies, Michael

AU - Woll, Penella

AU - Kiemeney, Lambertus A

AU - Haugen, Aage

AU - Zienolddiny, Shanbeh

AU - Lam, Stephen

AU - Johansson, Mikael

AU - Grankvist, Kjell

AU - Schabath, Matthew B

AU - Andrew, Angeline

AU - Lazarus, Philip

AU - Arnold, Susanne M

AU - Zhu, Dakai

AU - Landi, Maria Teresa

AU - McKay, James

AU - Amos, Christopher

AU - Cheng, Chao

PY - 2026

Y1 - 2026

N2 - 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.

AB - 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.

KW - genetic risk

KW - genetics

KW - HLA

KW - lung cancer

KW - smoking

UR - https://www.scopus.com/pages/publications/105028336526

U2 - 10.1016/j.xhgg.2026.100567

DO - 10.1016/j.xhgg.2026.100567

M3 - Journal article

C2 - 41530975

SN - 2666-2477

VL - 7

JO - HGG advances

JF - HGG advances

IS - 2

M1 - 100567

ER -

Germline HLA heterozygosity is associated with decreased lung cancer risk

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