Abstract 5874: Heterozygote advantage at HLA class I and II loci and colorectal cancer risk
Authors: Tsai Ya-Yu , Qu Chenxu , Bonner Joseph D. , Sanz-Pamplona Rebeca , Lindsey Sidney , Melas Marilena , McDonnell Kevin J. , Idos Gregory E. , Walker Christopher P. , Tsang Kevin K. , Da Silva Diane M. , Moratalla Ferran , Maoz Asaf , Rennert Hedy S. , Kast W. Martin , Greenson Joel K. , Moreno Victor , Rennert Gad , Gruber Stephen B. , Schmit Stephanie L. 
Published: June 2022

Abstract
Diversity in Human Leukocyte Antigen (HLA) genes has been associated with risk of several diseases, including Non-Hodgkin’s lymphoma and ulcerative colitis. Reduced diversity at HLA loci may adversely affect the host’s ability to recognize foreign antigens and tumor neoantigens, and subsequently, increase disease burden. To better understand the role of inherited HLA diversity in colorectal cancer (CRC) risk, we utilized data from a population-based study of 10,347 participants (5,574 CRC cases and 4,773 healthy controls) from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Germline DNA samples were genotyped using genome-wide arrays, and HLA Class I and II four-digit resolution alleles were imputed using SNP2HLA and a reference panel of 5,225 individuals from the Type 1 Diabetes Genetics Consortium. Heterozygosity and homozygosity at each HLA locus and the number of homozygous genotypes at class I loci (A, B, C) and class II loci (DQB1, DRB1, DPB1) were quantified. To examine the joint effect of Class I and Class II loci, we combined the total number of homozygotes for all loci and categorized into 3 groups: heterozygotes at all loci, 1 to 4 homozygotes, or 5 or more homozygotes. Logistic regression was used to estimate the risk of CRC associated with HLA locus homozygosity. Individuals with heterozygous genotypes for all loci served as the reference category, and analyses were adjusted for sex, age, genotyping platform, and global ancestry. Individuals with homozygous genotypes at all 3 Class I genes had an increased risk of CRC when compared to those with heterozygous genotypes at all Class I loci (OR: 1.34; 95% CI: 1.02-1.76, P = 0.033; Ptrend = 0.039). A similar association was observed for Class II loci, with an OR of 1.32 (95% CI: 1.05-1.65, P = 0.015; Ptrend = 0.157). For HLA Class I and II combined, individuals with five or more homozygous genotypes at HLA class I or II loci were at higher risk for developing CRC (OR: 1.84, 95% CI: 1.24-2.73, P = 0.0023; Ptrend = 0.015), when compared to those with all heterozygous genotypes. Our findings support a heterozygote advantage at HLA class I and II loci as a protective factor for CRC. This indicates an important role for HLA genetic variability in the etiology of CRC potentially operating through a mechanism of decreased diversity of tumor neoantigens that can be displayed to the adaptive immune system.
Citation Format: Ya-Yu Tsai, Chenxu Qu, Joseph D. Bonner, Rebeca Sanz-Pamplona, Sidney Lindsey, Marilena Melas, Kevin J. McDonnell, Gregory E. Idos, Christopher P. Walker, Kevin K. Tsang, Diane M. Da Silva, Ferran Moratalla, Asaf Maoz, Hedy S. Rennert, W. Martin Kast, Joel K. Greenson, Victor Moreno, Gad Rennert, Stephen B. Gruber, Stephanie L. Schmit. Heterozygote advantage at HLA class I and II loci and colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5874.