The influence of HLA genetic variation on plasma protein expression.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
31 Jul 2024
31 Jul 2024
Historique:
received:
18
08
2023
accepted:
15
07
2024
medline:
1
8
2024
pubmed:
1
8
2024
entrez:
31
7
2024
Statut:
epublish
Résumé
Genetic variation in the human leukocyte antigen (HLA) loci is associated with risk of immune-mediated diseases, but the molecular effects of HLA polymorphism are unclear. Here we examined the effects of HLA genetic variation on the expression of 2940 plasma proteins across 45,330 Europeans in the UK Biobank, with replication analyses across multiple ancestry groups. We detected 504 proteins affected by HLA variants (HLA-pQTL), including widespread trans effects by autoimmune disease risk alleles. More than 80% of the HLA-pQTL fine-mapped to amino acid positions in the peptide binding groove. HLA-I and II affected proteins expressed in similar cell types but in different pathways of both adaptive and innate immunity. Finally, we investigated potential HLA-pQTL effects on disease by integrating HLA-pQTL with fine-mapped HLA-disease signals in the UK Biobank. Our data reveal the diverse effects of HLA genetic variation and aid the interpretation of associations between HLA alleles and immune-mediated diseases.
Identifiants
pubmed: 39085222
doi: 10.1038/s41467-024-50583-8
pii: 10.1038/s41467-024-50583-8
doi:
Substances chimiques
HLA Antigens
0
Blood Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6469Informations de copyright
© 2024. The Author(s).
Références
Carrington, M. et al. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 283, 1748–1752 (1999).
pubmed: 10073943
doi: 10.1126/science.283.5408.1748
Chowell, D. et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 359, 582–587 (2018).
pubmed: 29217585
doi: 10.1126/science.aao4572
Chowell, D. et al. Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. Nat. Med. 25, 1715–1720 (2019).
pubmed: 31700181
pmcid: 7938381
doi: 10.1038/s41591-019-0639-4
Dendrou, C. A., Petersen, J., Rossjohn, J. & Fugger, L. HLA variation and disease. Nat. Rev. Immunol. 18, 325–339 (2018).
pubmed: 29292391
doi: 10.1038/nri.2017.143
Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).
pubmed: 22286218
pmcid: 3288335
doi: 10.1038/ng.1076
Speed, D., Hemani, G., Johnson, M. R. & Balding, D. J. Improved heritability estimation from genome-wide SNPs. Am. J. Hum. Genet. 91, 1011–1021 (2012).
pubmed: 23217325
pmcid: 3516604
doi: 10.1016/j.ajhg.2012.10.010
Hu, X. et al. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat. Genet. 47, 898–905 (2015).
pubmed: 26168013
pmcid: 4930791
doi: 10.1038/ng.3353
Lenz, T. L. et al. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases. Nat. Genet. 47, 1085–1090 (2015).
pubmed: 26258845
pmcid: 4552599
doi: 10.1038/ng.3379
Sakaue, S. et al. Tutorial: a statistical genetics guide to identifying HLA alleles driving complex disease. Nat. Protoc. 18, 2625–2641 (2023).
pubmed: 37495751
pmcid: 10786448
doi: 10.1038/s41596-023-00853-4
Kang, J. B. et al. Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution. Nat. Genet. https://doi.org/10.1101/2023.03.14.23287257 (2023).
Sakaue, S. et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat. Genet. 53, 1415–1424 (2021).
pubmed: 34594039
doi: 10.1038/s41588-021-00931-x
Luo, Y. et al. A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response. Nat. Genet. 53, 1504–1516 (2021).
pubmed: 34611364
pmcid: 8959399
doi: 10.1038/s41588-021-00935-7
Gutierrez-Arcelus, M. et al. Allele-specific expression changes dynamically during T cell activation in HLA and other autoimmune loci. Nat. Genet. 52, 247–253 (2020).
pubmed: 32066938
pmcid: 7135372
doi: 10.1038/s41588-020-0579-4
Sun, B. B. et al. Genetic regulation of the human plasma proteome in 54,306 UK Biobank participants. Preprint at bioRxiv https://doi.org/10.1101/2022.06.17.496443 (2022).
Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).
pubmed: 30305743
pmcid: 6786975
doi: 10.1038/s41586-018-0579-z
Wik, L. et al. Proximity extension assay in combination with next-generation sequencing for high-throughput proteome-wide analysis. Mol. Cell. Proteom. 20, 100168 (2021).
doi: 10.1016/j.mcpro.2021.100168
Yazar, S. et al. Single-cell eQTL mapping identifies cell type–specific genetic control of autoimmune disease. Science 376, eabf3041 (2024).
doi: 10.1126/science.abf3041
Travaglini, K. J. et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature 587, 619–625 (2020).
pubmed: 33208946
pmcid: 7704697
doi: 10.1038/s41586-020-2922-4
Das, S. et al. Next-generation genotype imputation service and methods. Nat. Genet. 48, 1284–1287 (2016).
pubmed: 27571263
pmcid: 5157836
doi: 10.1038/ng.3656
Tian, C. et al. Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections. Nat. Commun. 8, 599 (2017).
pubmed: 28928442
pmcid: 5605711
doi: 10.1038/s41467-017-00257-5
Patsopoulos, N. A. et al. Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PLoS Genet. 9, e1003926 (2013).
pubmed: 24278027
pmcid: 3836799
doi: 10.1371/journal.pgen.1003926
Mbatchou, J. et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nat. Genet. 53, 1097–1103 (2021).
pubmed: 34017140
doi: 10.1038/s41588-021-00870-7
Sun, B. B. et al. Plasma proteomic associations with genetics and health in the UK Biobank. Nature 622, 329–338 (2023).
pubmed: 37794186
pmcid: 10567551
doi: 10.1038/s41586-023-06592-6
Ishigaki, K. et al. HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors. Nat. Genet. 54, 393–402 (2022).
pubmed: 35332318
pmcid: 9010379
doi: 10.1038/s41588-022-01032-z
Horton, R. et al. Gene map of the extended human MHC. Nat. Rev. Genet. 5, 889–899 (2004).
pubmed: 15573121
doi: 10.1038/nrg1489
Pereyra, F. et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330, 1551–1557 (2010).
pubmed: 21051598
pmcid: 3235490
doi: 10.1126/science.1195271
Raulet, D. H., Gasser, S., Gowen, B. G., Deng, W. & Jung, H. Regulation of ligands for the NKG2D activating receptor. Annu. Rev. Immunol. 31, 413–441 (2013).
pubmed: 23298206
pmcid: 4244079
doi: 10.1146/annurev-immunol-032712-095951
Ferrari de Andrade, L. et al. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 359, 1537–1542 (2018).
pubmed: 29599246
pmcid: 6626532
doi: 10.1126/science.aao0505
Chang, C. C. et al. Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat. Immunol. 3, 237–243 (2002).
pubmed: 11875462
doi: 10.1038/ni760
Harris, J. et al. A vitellogenic-like carboxypeptidase expressed by human macrophages is localized in endoplasmic reticulum and membrane ruffles. Int. J. Exp. Pathol. 87, 29–39 (2006).
pubmed: 16436111
pmcid: 2517344
doi: 10.1111/j.0959-9673.2006.00450.x
Rock, K. L., Reits, E. & Neefjes, J. Present yourself! By MHC class I and MHC class II molecules. Trends Immunol. 37, 724–737 (2016).
pubmed: 27614798
pmcid: 5159193
doi: 10.1016/j.it.2016.08.010
Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).
pubmed: 25613900
doi: 10.1126/science.1260419
Roche, P. A. & Furuta, K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat. Rev. Immunol. 15, 203–216 (2015).
pubmed: 25720354
pmcid: 6314495
doi: 10.1038/nri3818
Li, H. et al. Secreted LRPAP1 binds and triggers IFNAR1 degradation to facilitate virus evasion from cellular innate immunity. Signal Transduct. Target. Ther. 8, 374 (2023).
pubmed: 37743411
pmcid: 10518340
doi: 10.1038/s41392-023-01630-1
Coutelier, M. et al. NPTX1 mutations trigger endoplasmic reticulum stress and cause autosomal dominant cerebellar ataxia. Brain 145, 1519–1534 (2022).
pubmed: 34788392
doi: 10.1093/brain/awab407
Rengarajan, J., Tang, B. & Glimcher, L. H. NFATc2 and NFATc3 regulate T(H)2 differentiation and modulate TCR-responsiveness of naïve T(H)cells. Nat. Immunol. 3, 48–54 (2002).
pubmed: 11740499
doi: 10.1038/ni744
Chen, L. & Tsai, T.-F. HLA-Cw6 and psoriasis. Br. J. Dermatol. 178, 854–862 (2018).
pubmed: 29072309
doi: 10.1111/bjd.16083
Povoleri, G. A. M. et al. Psoriatic and rheumatoid arthritis joints differ in the composition of CD8+ tissue-resident memory T cell subsets. Cell Rep. 42, 112514 (2023).
pubmed: 37195862
pmcid: 10790246
doi: 10.1016/j.celrep.2023.112514
Goyette, P. et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat. Genet. 47, 172–179 (2015).
pubmed: 25559196
pmcid: 4310771
doi: 10.1038/ng.3176
Wang, X., Wong, K., Ouyang, W. & Rutz, S. Targeting IL-10 family cytokines for the treatment of human diseases. Cold Spring Harb. Perspect. Biol. 11, a028548 (2019).
pubmed: 29038121
pmcid: 6360861
doi: 10.1101/cshperspect.a028548
Finan, C. et al. The druggable genome and support for target identification and validation in drug development. Sci. Transl. Med. 9, eaag1166 (2017).
pubmed: 28356508
pmcid: 6321762
doi: 10.1126/scitranslmed.aag1166
Wang, C. et al. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163, 1413–1427 (2015).
pubmed: 26607793
pmcid: 4671820
doi: 10.1016/j.cell.2015.10.068
Ceuppens, J. L. & Baroja, M. L. Monoclonal antibodies to the CD5 antigen can provide the necessary second signal for activation of isolated resting T cells by solid-phase-bound OKT3. J. Immunol. 137, 1816–1821 (1986).
pubmed: 3091691
doi: 10.4049/jimmunol.137.6.1816
Orta-Mascaró, M. et al. CD6 modulates thymocyte selection and peripheral T cell homeostasis. J. Exp. Med. 213, 1387–1397 (2016).
pubmed: 27377588
pmcid: 4986531
doi: 10.1084/jem.20151785
Whitsett, C. F. & Stulting, R. D. The distribution of HLA antigens on human corneal tissue. Investig. Ophthalmol. Vis. Sci. 25, 519–524 (1984).
van Essen, T. H., Roelen, D. L., Williams, K. A. & Jager, M. J. Matching for human leukocyte antigens (HLA) in corneal transplantation – to do or not to do. Prog. Retin. Eye Res. 46, 84–110 (2015).
pubmed: 25601193
doi: 10.1016/j.preteyeres.2015.01.001
Castellino, F. et al. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature 440, 890–895 (2006).
pubmed: 16612374
doi: 10.1038/nature04651
Eldjarn, G. H. et al. Large-scale plasma proteomics comparisons through genetics and disease associations. Nature 622, 348–358 (2023).
pubmed: 37794188
pmcid: 10567571
doi: 10.1038/s41586-023-06563-x
Khan, M., Zhao, Z., Arooj, S., Fu, Y. & Liao, G. Soluble PD-1: predictive, prognostic, and therapeutic value for cancer immunotherapy. Front. Immunol. 11, 587460 (2020).
pubmed: 33329567
pmcid: 7710690
doi: 10.3389/fimmu.2020.587460
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
pubmed: 17701901
pmcid: 1950838
doi: 10.1086/519795
Wang, G., Sarkar, A., Carbonetto, P. & Stephens, M. A simple new approach to variable selection in regression, with application to genetic fine mapping. J. R. Stat. Soc. Ser. B Stat. Methodol. 82, 1273–1300 (2020).
doi: 10.1111/rssb.12388
Bulik-Sullivan, B. K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).
pubmed: 25642630
pmcid: 4495769
doi: 10.1038/ng.3211
Yu, G., Wang, L.-G., Han, Y. & He, Q.-Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS J. Integr. Biol. 16, 284–287 (2012).
doi: 10.1089/omi.2011.0118
Karczewski, K. J. et al. Systematic single-variant and gene-based association testing of thousands of phenotypes in 394,841 UK Biobank exomes. Cell Genom. 2, 100168 (2022).
pubmed: 36778668
pmcid: 9903662
doi: 10.1016/j.xgen.2022.100168