biostudies-literatureUnknown7(2)Tan TFoundation for the National Institutes of HealthCancer Prevention and Research Institute of TexasHeterozygosity 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 hHGG advances100567https://www.ebi.ac.uk/biostudies/studies/S-EPMC12860938biostudies-literatureGermline HLA heterozygosity is associated with decreased lung cancer risk.PMC12860938Zienolddiny SByun JWichmann HEWang XAMcKay JHan YChristiani DCAmos CLe Marchand LAldrich MCLee HSBojesen SEShete SHung RJGrankvist KAndrew ALazarus PCheng CKiemeney LATardon ABickeboller HHaugen AXiao XRisch AWoll PArnold SMZhu DLi YRennert GAlbanes DDavies MLandi MTLam STan TJohansson MShaw VRZaridze DField JKFernandez-Tardon GSchabath MBfalseGermline HLA heterozygosity is associated with decreased lung cancer risk.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 h2026-01-01T00:00:00Z2026 Jan2026-06-20T03:12:33.317Z2026-06-20T03:10:10.212ZS-EPMC128609384153097510.1016/j.xhgg.2026.100567