Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants

Karnes, Jason H.; Bastarache, Lisa; Shaffer, Christian M.; Gaudieri, Silvana; Xu, Yaomin; Glazer, Andrew M.; Mosley, Jonathan D.; Zhao, Shilin; Raychaudhuri, Soumya; Mallal, S.; Ye, Zhan; Mayer, John; Brilliant, Murray H.; Hebbring, Scott J.; Roden, Dan M.; Phillips, Elizabeth; Denny, Joshua C.

doi:10.1126/scitranslmed.aai8708

Cited by 105 publications

(98 citation statements)

References 64 publications

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“…Of all PRS evaluated, the oral cavity/pharyngeal and lung cancer PRS were most commonly implicated in associations with cross-cancer and non-cancer phenotypes. These results support existing evidence of cancer pleiotropy, given that the PRS for both cancers included variants in two well-known pleiotropic cancer regions -TERT-CLPTM1L (2) and HLA (3,4). Notwithstanding shared susceptibility regions, the relationship between oral cavity/pharyngeal and lung cancers was inconsistent.…”

Section: Discussionsupporting

confidence: 77%

“…Indeed, genome-wide association studies (GWAS) of individual cancer types have identified loci associated with other cancer types, including 5p15 (TERT-CLPTM1L) (2), 6p21 (HLA complex) (3,4), and 8q24 (5). Non-GWAS approaches have yielded further pleiotropic cancer risk variants, and genetic correlation studies have identified cancer pairs with shared heritability (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

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Cross-Cancer Evaluation of Polygenic Risk Scores for 17 Cancer Types in Two Large Cohorts

Graff

Cavazos

Thai

et al. 2020

Preprint

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Genetic factors that influence etiologic mechanisms shared across cancers could affect the risk of multiple cancer types. We investigated polygenic risk score (PRS)-specific pleiotropy across 17 cancers in two large population-based cohorts. The study population included European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and the UK Biobank (48,969 cases, 359,802 controls). We selected known independent risk variants from published GWAS to construct a PRS for each cancer type. Within cohorts, each PRS was evaluated in multivariable logistic regression models with respect to the cancer for which it was developed and each other cancer type. Results were then meta-analyzed across cohorts. In the UK Biobank, each PRS was additionally evaluated relative to 20 cancer risk factors or biomarkers. All PRS replicated associations with their corresponding cancers (p<0.05). Eleven cross-cancer associations -ten positive and one inverse -were found after correction for multiple testing (p<0.05/17=0.0029). Two cancer pairs showed bidirectional associations; the melanoma PRS was positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS was positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS was inversely associated with lung cancer. We identified 65 associations between a cancer PRS and non-cancer phenotype. In this study examining cross-cancer PRS associations in two cohorts unselected for phenotype, we validated known and uncovered novel patterns of pleiotropy. Our results have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies. 5 STATEMENT OF SIGNIFICANCEBy examining cross-cancer polygenic risk score associations, we validated known and uncovered novel patterns of pleiotropy. Our results may inform investigations of risk prediction, shared etiology, and precision prevention strategies.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Cross-Cancer Evaluation of Polygenic Risk Scores for 17 Cancer Types in Two Large Cohorts

Graff

Cavazos

Thai

et al. 2020

Preprint

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“…Finally, prior works indicate that genetic variations within particular MHC genes are known to influence vaccine efficacy (42), rejection rates of transplanted organs (43), susceptibility to autoimmune diseases (44) and antitumor immunity (45,46). Our work raises the possibility that, by altering the maturation and functionality of the immune system, the size of the epitope binding repertoire of MHC variants itself could have an impact on these processes.…”

Section: Discussionmentioning

confidence: 67%

Pathogen diversity drives the evolution of promiscuous peptide binding of human MHC-II alleles

Manczinger

Boross

Kemény

et al. 2018

Preprint

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Major histocompatibility complex (MHC) molecules mediate the adaptive immune response against pathogens. Certain MHC alleles are generalists: they present an exceptionally large variety of antigenic peptides. However, the functional implications of such elevated epitope binding promiscuity in the MHC molecules are largely unknown. According to what we term the pathogen-driven promiscuity hypothesis, exposure to a broad range of pathogens favors the evolution of highly promiscuous MHC variants. Consistent with this hypothesis, we found that in pathogen-rich geographical regions, humans are more likely to carry promiscuous MHC class II DRB1 alleles, and the switch between high and low promiscuity levels has occurred repeatedly and in a rapid manner during human evolution. We also show that selection for promiscuous peptide binding shapes MHC genetic diversity. In sum, our study offers a conceptually novel mechanism to explain the global distribution of allelic variants of a key human immune gene by demonstrating that pathogen pressure maintains promiscuous MHC class II alleles. More generally, our work highlights the hitherto neglected role of epitope binding promiscuity in immune defense, with implications for medical genetics and epidemiology.

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“…2 ). Three of the 11 independent amino acid variations, HLA-DRB1 residue 67 and 71, HLA-DQB1 residue 55 are associated with type 1 diabetes, multiple sclerosis, hypothyroidism, rheumatoid arthritis, and other inflammatory polyarthritis according to PheWAS database 12, 13 . We then estimated to what extent these MHC variants can influence each TRBV gene usage variation using multiple linear regression.…”

Section: Resultsmentioning

confidence: 99%

Germline-encoded TCR-MHC contacts promote TCR V gene bias in umbilical cord blood T cell repertoire

Gao

Chen

Zhang

et al. 2019

Preprint

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T cells recognize antigens as peptides bound to major histocompatibility complex (MHC) proteins through T cell receptors (TCRs) on their surface. To recognize a wide range of pathogens, each individual possesses a substantial number of TCRs with an extremely high degree of variability. It remains controversial whether germline-encoded TCR repertoire is shaped by MHC polymorphism and, if so, what is the preference between MHC genetic variants and TCR V gene compatibility. To investigate the “net” genetic association between MHC variations and TRBV genes, we applied quantitative trait locus (QTL) mapping to test the associations between MHC polymorphism and TCR β chain V (TRBV) genes usage using umbilical cord blood (UCB) samples of 201 Chinese newborns. We found TRBV gene and MHC loci that are predisposed to interact with one another differ from previous conclusions. The majority of MHC amino acid residues associated with the TRBV gene usage show spatial proximities in known structures of TCR-pMHC complexes. These results show for the first time that MHC variants bias TRBV gene usage in UCB of Chinese ancestry and indicate that germline-encoded contacts influence TCR-MHC interactions in intact T cell repertoires.

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Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants

Cited by 105 publications

References 64 publications

Cross-Cancer Evaluation of Polygenic Risk Scores for 17 Cancer Types in Two Large Cohorts

Cross-Cancer Evaluation of Polygenic Risk Scores for 17 Cancer Types in Two Large Cohorts

Pathogen diversity drives the evolution of promiscuous peptide binding of human MHC-II alleles

Germline-encoded TCR-MHC contacts promote TCR V gene bias in umbilical cord blood T cell repertoire

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