Independent and joint effects of lifestyle, human leukocyte antigen polymorphisms on cancer risk: findings from the UK Biobank

Introduction Immune genetic variation and lifestyle factors jointly influence cancer susceptibility, but their interactions in cancer development remain unclear. We evaluated the independent and joint effects of lifestyle profiles and classical HLA alleles on overall and site-specific cancer risks using sex-stratified analyses. Methods Among 159, 744 men and 175, 037 women of European ancestry in the UK Biobank, 50 common HLA alleles from 11 classical HLA genes were imputed. A healthy lifestyle index incorporating diet, smoking, alcohol intake, physical activity, and adiposity classified participants into favorable, intermediate, or poor lifestyle categories. Independent effects of HLA polymorphisms and lifestyle factors on cancer risk were assessed using logistic regression and Cox proportional hazards models, respectively. Additive and multiplicative interactions were evaluated for cancers associated with both lifestyle and HLA alleles using Cox model. Results During a median follow-up of 13 years, 35, 132 incident cancers occurred. Poor lifestyle increased overall cancer risk by 38% in men and 44% in women. Several HLA alleles were associated with lung, prostate, and non-Hodgkin lymphoma risks in men and kidney and endometrial cancer risks in women. Significant additive interactions were observed between poor lifestyle and a cluster of AH8.1-related HLA alleles (HLA-B*08:01, DQA1*05:01, DQB1*02:01, and DRB1*03:01) for lung cancer in men (relative excess risk due to interaction (RERI)=2.63–3.24), and between poor lifestyle and HLA-A*24:02 for kidney cancer in women (RERI = 3.24, 95%CI=1.20–5.28). Discussion In sex-stratified analyses, unhealthy lifestyles markedly amplified lung cancer risk in men and kidney cancer risk in women among carriers of specific HLA risk alleles. These findings warrant independent replication, particularly in non-European populations and in datasets with directly typed or sequenced HLA alleles.