AUTHOR=Tsai Ya-Yu , Qu Chenxu , Bonner Joseph D. , Sanz-Pamplona Rebeca , Lindsey Sidney S. , Melas Marilena , McDonnell Kevin J. , Idos Gregory E. , Walker Christopher P. , Tsang Kevin K. , Da Silva Diane M. , Moratalla-Navarro Ferran , Maoz Asaf , Rennert Hedy S. , Kast W. Martin , Greenson Joel K. , Moreno Victor , Rennert Gad , Gruber Stephen B. , Schmit Stephanie L. TITLE=Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1268117 DOI=10.3389/fimmu.2023.1268117 ISSN=1664-3224 ABSTRACT=Objective

Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host’s ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC).

Methods

We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Heterozygosity at each HLA locus and the number of heterozygous genotypes at HLA class -I (A, B, and C) and HLA class -II loci (DQB1, DRB1, and DPB1) were quantified. Logistic regression analysis was used to estimate the risk of CRC associated with HLA heterozygosity. Individuals with homozygous genotypes for all loci served as the reference category, and the analyses were adjusted for sex, age, genotyping platform, and ancestry. Further, we investigated associations between HLA diversity and tumor-associated T cell repertoire features, as measured by tumor infiltrating lymphocytes (TILs; N=2,839) and immunosequencing (N=2,357).

Results

Individuals with all heterozygous genotypes at all three class I genes had a reduced odds of CRC (OR: 0.74; 95% CI: 0.56-0.97, p= 0.031). A similar association was observed for class II loci, with an OR of 0.75 (95% CI: 0.60-0.95, p= 0.016). For class-I and class-II combined, individuals with all heterozygous genotypes had significantly lower odds of developing CRC (OR: 0.66, 95% CI: 0.49-0.87, p= 0.004) than those with 0 or one heterozygous genotype. HLA class I and/or II diversity was associated with higher T cell receptor (TCR) abundance and lower TCR clonality, but results were not statistically significant.

Conclusion

Our findings support a heterozygote advantage for the HLA class-I and -II loci, indicating an important role for HLA genetic variability in the etiology of CRC.