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We would like to acknowledge the contributions of Christopher Edlund, the Center for Inherited Disease Research, and the University of Southern California Molecular Genomics Core to the generation and quality control of germline genotype data. We thank CERCA Programme, Generalitat de Catalunya for institutional support.r The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported in part by R01 CA197350, R01 CA081488, P30 CA014089, R01 CA263318, and a generous gift from Daniel and MaryAnn Fong. VM had the support of the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723, the Instituto de Salud Carlos III, co-funded by FEDER funds -a way to build Europe- grants PI17-00092 and the Spanish Association Against Cancer (AECC) Scientific Foundation grant GCTRA18022MORE.

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Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer

Publicated to:Frontiers In Immunology. 14 1268117- - 2023-10-24 14(), DOI: 10.3389/fimmu.2023.1268117

Authors: Tsai, YY; Qu, CX; Bonner, JD; Sanz-Pamplona, R; Lindsey, SS; Melas, M; Mcdonnell, KJ; Idos, GE; Walker, CP; Tsang, KK; Da Silva, DM; Moratalla-Navarro, F; Maoz, A; Rennert, HS; Kast, WM; Greenson, JK; Moreno, V; Rennert, G; Gruber, SB; Schmit, SL

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Abstract

ObjectiveReduced 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).MethodsWe 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).ResultsIndividuals 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.ConclusionOur 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.

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