Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer
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 cance...
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1268117/full |
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| author | Ya-Yu Tsai Chenxu Qu Joseph D. Bonner Rebeca Sanz-Pamplona Rebeca Sanz-Pamplona Rebeca Sanz-Pamplona Rebeca Sanz-Pamplona Sidney S. Lindsey Marilena Melas Kevin J. McDonnell Gregory E. Idos Christopher P. Walker Kevin K. Tsang Diane M. Da Silva Ferran Moratalla-Navarro Ferran Moratalla-Navarro Ferran Moratalla-Navarro Ferran Moratalla-Navarro Asaf Maoz Hedy S. Rennert W. Martin Kast Joel K. Greenson Victor Moreno Victor Moreno Victor Moreno Victor Moreno Gad Rennert Stephen B. Gruber Stephanie L. Schmit Stephanie L. Schmit |
| author_facet | Ya-Yu Tsai Chenxu Qu Joseph D. Bonner Rebeca Sanz-Pamplona Rebeca Sanz-Pamplona Rebeca Sanz-Pamplona Rebeca Sanz-Pamplona Sidney S. Lindsey Marilena Melas Kevin J. McDonnell Gregory E. Idos Christopher P. Walker Kevin K. Tsang Diane M. Da Silva Ferran Moratalla-Navarro Ferran Moratalla-Navarro Ferran Moratalla-Navarro Ferran Moratalla-Navarro Asaf Maoz Hedy S. Rennert W. Martin Kast Joel K. Greenson Victor Moreno Victor Moreno Victor Moreno Victor Moreno Gad Rennert Stephen B. Gruber Stephanie L. Schmit Stephanie L. Schmit |
| author_sort | Ya-Yu Tsai |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T16:24:14Z |
| format | Article |
| id | doaj.art-734420da1acf488eb53b090fc282d13e |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T16:24:14Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-734420da1acf488eb53b090fc282d13e2023-10-24T13:21:13ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-10-011410.3389/fimmu.2023.12681171268117Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancerYa-Yu Tsai0Chenxu Qu1Joseph D. Bonner2Rebeca Sanz-Pamplona3Rebeca Sanz-Pamplona4Rebeca Sanz-Pamplona5Rebeca Sanz-Pamplona6Sidney S. Lindsey7Marilena Melas8Kevin J. McDonnell9Gregory E. Idos10Christopher P. Walker11Kevin K. Tsang12Diane M. Da Silva13Ferran Moratalla-Navarro14Ferran Moratalla-Navarro15Ferran Moratalla-Navarro16Ferran Moratalla-Navarro17Asaf Maoz18Hedy S. Rennert19W. Martin Kast20Joel K. Greenson21Victor Moreno22Victor Moreno23Victor Moreno24Victor Moreno25Gad Rennert26Stephen B. Gruber27Stephanie L. Schmit28Stephanie L. Schmit29Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, United StatesNorris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United StatesCenter for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United StatesCatalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, SpainONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, SpainConsortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, SpainHospital Universitario Lozano Blesa, Aragon Health Research Institute (IISA), ARAID Foundation, Aragon Government, Zaragoza, SpainCenter for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United StatesMolecular Diagnostics, New York Genome Center, New York, NY, United StatesCenter for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United StatesCenter for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United StatesCenter for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United StatesCenter for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United StatesNorris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United StatesCatalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, SpainONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, SpainConsortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, SpainDepartment of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona, Barcelona, Spain0Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States1B. Rappaport Faculty of Medicine, Technion and the Association for Promotion of Research in Precision Medicine (APRPM), Haifa, IsraelNorris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States2Department of Pathology, University of Michigan, Ann Arbor, MI, United StatesCatalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, SpainONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, SpainConsortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, SpainDepartment of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona, Barcelona, Spain1B. Rappaport Faculty of Medicine, Technion and the Association for Promotion of Research in Precision Medicine (APRPM), Haifa, IsraelCenter for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United StatesGenomic Medicine Institute, Cleveland Clinic, Cleveland, OH, United States3Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, United StatesObjectiveReduced 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1268117/fullheterozygote advantagehuman leukocyte antigenheterozygosityHLA diversitycolorectal cancer |
| spellingShingle | Ya-Yu Tsai Chenxu Qu Joseph D. Bonner Rebeca Sanz-Pamplona Rebeca Sanz-Pamplona Rebeca Sanz-Pamplona Rebeca Sanz-Pamplona Sidney S. Lindsey Marilena Melas Kevin J. McDonnell Gregory E. Idos Christopher P. Walker Kevin K. Tsang Diane M. Da Silva Ferran Moratalla-Navarro Ferran Moratalla-Navarro Ferran Moratalla-Navarro Ferran Moratalla-Navarro Asaf Maoz Hedy S. Rennert W. Martin Kast Joel K. Greenson Victor Moreno Victor Moreno Victor Moreno Victor Moreno Gad Rennert Stephen B. Gruber Stephanie L. Schmit Stephanie L. Schmit Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer Frontiers in Immunology heterozygote advantage human leukocyte antigen heterozygosity HLA diversity colorectal cancer |
| title | Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer |
| title_full | Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer |
| title_fullStr | Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer |
| title_full_unstemmed | Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer |
| title_short | Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer |
| title_sort | heterozygote advantage at hla class i and ii loci and reduced risk of colorectal cancer |
| topic | heterozygote advantage human leukocyte antigen heterozygosity HLA diversity colorectal cancer |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1268117/full |
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