HLA Heterozygosity Influences Colorectal Cancer Risk and Survival Outcome

The diversity of HLAs is critical for effective immune responses against pathogens and cancer. HLA class I molecules present endogenous antigens to eliminate infected or cancerous cells, while HLA class II molecules present exogenous antigens to helper CD4+ T cells, stimulating antibody production. Polymorphisms in HLA genes, particularly in the peptide-binding cleft, create diverse antigen-binding affinities, suggesting evolutionary selection pressure to maintain diversity as a defense against pathogen adaptation.1 One mechanism by which HLA diversity is maintained is through heterozygote advantage,2 where individuals with 2 different alleles at a genetic locus have higher fitness compared with those with 2 identical alleles. Particular attention has been focused on the role of HLA heterozygote advantage in colorectal cancer (CRC).3–5 Our prior study of 5406 patients with CRC and 4635 controls found that HLA class I and/or II alleles may be associated with higher tumor-infiltrating lymphocytes and reduced risk of CRC.4 Here, we expand on this work by analyzing 183,626 participants (84,907 CRC cases and 98,689 controls) from the International Colorectal Cancer GWAS Collaborative, including the United States, Europe, and Australia; United Kingdom and Europe; and Asia (Supplementary Table 1). HLA class I and class II alleles were imputed from germline genotype data, and the number of heterozygous genotypes at HLA class I (A, B, C) and HLA class II (DPB1, DQB1, DRB1) loci were quantified. Logistic regression estimated the risk of CRC, and Cox proportional hazards regression assessed overall survival (OS) and CRC-specific survival (CS) in 20,332 CRC cases (Supplementary Methods). To account for multiple hypothesis testing, we applied a Bonferroni correction, adjusting the statistical significance threshold to P < .0063 (.05/8 independent tests).