IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-50583-8.html
   My bibliography  Save this article

The influence of HLA genetic variation on plasma protein expression

Author

Listed:
  • Chirag Krishna

    (Pfizer Research and Development, Pfizer Inc.)

  • Joshua Chiou

    (Pfizer Research and Development, Pfizer Inc.)

  • Saori Sakaue

    (Harvard Medical School
    Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Joyce B. Kang

    (Harvard Medical School
    Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Stephen M. Christensen

    (Pfizer Research and Development, Pfizer Inc.)

  • Isac Lee

    (Pfizer Research and Development, Pfizer Inc.)

  • Melis Atalar Aksit

    (Pfizer Research and Development, Pfizer Inc.)

  • Hye In Kim

    (Pfizer Research and Development, Pfizer Inc.)

  • David Schack

    (Pfizer Research and Development, Pfizer Inc.)

  • Soumya Raychaudhuri

    (Harvard Medical School
    Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Daniel Ziemek

    (Pfizer Research and Development, Pfizer Inc.)

  • Xinli Hu

    (Pfizer Research and Development, Pfizer Inc.)

Abstract

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.

Suggested Citation

  • Chirag Krishna & Joshua Chiou & Saori Sakaue & Joyce B. Kang & Stephen M. Christensen & Isac Lee & Melis Atalar Aksit & Hye In Kim & David Schack & Soumya Raychaudhuri & Daniel Ziemek & Xinli Hu, 2024. "The influence of HLA genetic variation on plasma protein expression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50583-8
    DOI: 10.1038/s41467-024-50583-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-50583-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-50583-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Grimur Hjorleifsson Eldjarn & Egil Ferkingstad & Sigrun H. Lund & Hannes Helgason & Olafur Th. Magnusson & Kristbjorg Gunnarsdottir & Thorunn A. Olafsdottir & Bjarni V. Halldorsson & Pall I. Olason & , 2023. "Large-scale plasma proteomics comparisons through genetics and disease associations," Nature, Nature, vol. 622(7982), pages 348-358, October.
    2. Chao Tian & Bethann S. Hromatka & Amy K. Kiefer & Nicholas Eriksson & Suzanne M. Noble & Joyce Y. Tung & David A. Hinds, 2017. "Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    3. Kyle J. Travaglini & Ahmad N. Nabhan & Lolita Penland & Rahul Sinha & Astrid Gillich & Rene V. Sit & Stephen Chang & Stephanie D. Conley & Yasuo Mori & Jun Seita & Gerald J. Berry & Joseph B. Shrager , 2020. "A molecular cell atlas of the human lung from single-cell RNA sequencing," Nature, Nature, vol. 587(7835), pages 619-625, November.
    4. Clare Bycroft & Colin Freeman & Desislava Petkova & Gavin Band & Lloyd T. Elliott & Kevin Sharp & Allan Motyer & Damjan Vukcevic & Olivier Delaneau & Jared O’Connell & Adrian Cortes & Samantha Welsh &, 2018. "The UK Biobank resource with deep phenotyping and genomic data," Nature, Nature, vol. 562(7726), pages 203-209, October.
    5. Gao Wang & Abhishek Sarkar & Peter Carbonetto & Matthew Stephens, 2020. "A simple new approach to variable selection in regression, with application to genetic fine mapping," Journal of the Royal Statistical Society Series B, Royal Statistical Society, vol. 82(5), pages 1273-1300, December.
    6. Benjamin B. Sun & Joshua Chiou & Matthew Traylor & Christian Benner & Yi-Hsiang Hsu & Tom G. Richardson & Praveen Surendran & Anubha Mahajan & Chloe Robins & Steven G. Vasquez-Grinnell & Liping Hou & , 2023. "Plasma proteomic associations with genetics and health in the UK Biobank," Nature, Nature, vol. 622(7982), pages 329-338, October.
    7. Flora Castellino & Alex Y. Huang & Grégoire Altan-Bonnet & Sabine Stoll & Clemens Scheinecker & Ronald N. Germain, 2006. "Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell–dendritic cell interaction," Nature, Nature, vol. 440(7086), pages 890-895, April.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Sylvia Hartmann & Summaira Yasmeen & Benjamin M. Jacobs & Spiros Denaxas & Munir Pirmohamed & Eric R. Gamazon & Mark J. Caulfield & Harry Hemingway & Maik Pietzner & Claudia Langenberg, 2023. "ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Isabelle Austin-Zimmerman & Daniel F. Levey & Olga Giannakopoulou & Joseph D. Deak & Marco Galimberti & Keyrun Adhikari & Hang Zhou & Spiros Denaxas & Haritz Irizar & Karoline Kuchenbaecker & Andrew M, 2023. "Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Wenhan Chen & Yang Wu & Zhili Zheng & Ting Qi & Peter M. Visscher & Zhihong Zhu & Jian Yang, 2021. "Improved analyses of GWAS summary statistics by reducing data heterogeneity and errors," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    5. Mary P. LaPierre & Katherine Lawler & Svenja Godbersen & I. Sadaf Farooqi & Markus Stoffel, 2022. "MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Joel T. Rämö & Tuomo Kiiskinen & Richard Seist & Kristi Krebs & Masahiro Kanai & Juha Karjalainen & Mitja Kurki & Eija Hämäläinen & Paavo Häppölä & Aki S. Havulinna & Heidi Hautakangas & Reedik Mägi &, 2023. "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Abolfazl Doostparast Torshizi & Dongnhu T. Truong & Liping Hou & Bart Smets & Christopher D. Whelan & Shuwei Li, 2024. "Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson’s disease," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. Alesha A. Hatton & Fei-Fei Cheng & Tian Lin & Ren-Juan Shen & Jie Chen & Zhili Zheng & Jia Qu & Fan Lyu & Sarah E. Harris & Simon R. Cox & Zi-Bing Jin & Nicholas G. Martin & Dongsheng Fan & Grant W. M, 2024. "Genetic control of DNA methylation is largely shared across European and East Asian populations," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    9. Robert F. Hillary & Danni A. Gadd & Zhana Kuncheva & Tasos Mangelis & Tinchi Lin & Kyle Ferber & Helen McLaughlin & Heiko Runz & Riccardo E. Marioni & Christopher N. Foley & Benjamin B. Sun, 2024. "Systematic discovery of gene-environment interactions underlying the human plasma proteome in UK Biobank," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    10. William R. Reay & Michael P. Geaghan & Murray J. Cairns, 2022. "The genetic architecture of pneumonia susceptibility implicates mucin biology and a relationship with psychiatric illness," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    11. Yanyu Xiao & Jingjing Wang & Jiaqi Li & Peijing Zhang & Jingyu Li & Yincong Zhou & Qing Zhou & Ming Chen & Xin Sheng & Zhihong Liu & Xiaoping Han & Guoji Guo, 2023. "An analytical framework for decoding cell type-specific genetic variation of gene regulation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    12. Javier Botey-Bataller & Hedwig D. Vrijmoeth & Jeanine Ursinus & Bart-Jan Kullberg & Cees C. Wijngaard & Hadewych Hofstede & Ahmed Alaswad & Manoj K. Gupta & Lennart M. Roesner & Jochen Huehn & Thomas , 2024. "A comprehensive genetic map of cytokine responses in Lyme borreliosis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    13. Satu Strausz & Erik Abner & Grace Blacker & Sarah Galloway & Paige Hansen & Qingying Feng & Brandon T. Lee & Samuel E. Jones & Hele Haapaniemi & Sten Raak & George Ronald Nahass & Erin Sanders & Pille, 2024. "SCGB1D2 inhibits growth of Borrelia burgdorferi and affects susceptibility to Lyme disease," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    14. Qingbo S. Wang & Ryuya Edahiro & Ho Namkoong & Takanori Hasegawa & Yuya Shirai & Kyuto Sonehara & Hiromu Tanaka & Ho Lee & Ryunosuke Saiki & Takayoshi Hyugaji & Eigo Shimizu & Kotoe Katayama & Masahir, 2022. "The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    15. Eeva Sliz & Jaakko S. Tyrmi & Nilufer Rahmioglu & Krina T. Zondervan & Christian M. Becker & Outi Uimari & Johannes Kettunen, 2023. "Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    16. Matteo Di Scipio & Mohammad Khan & Shihong Mao & Michael Chong & Conor Judge & Nazia Pathan & Nicolas Perrot & Walter Nelson & Ricky Lali & Shuang Di & Robert Morton & Jeremy Petch & Guillaume Paré, 2023. "A versatile, fast and unbiased method for estimation of gene-by-environment interaction effects on biobank-scale datasets," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    17. Jacob Joseph & Chang Liu & Qin Hui & Krishna Aragam & Zeyuan Wang & Brian Charest & Jennifer E. Huffman & Jacob M. Keaton & Todd L. Edwards & Serkalem Demissie & Luc Djousse & Juan P. Casas & J. Micha, 2022. "Genetic architecture of heart failure with preserved versus reduced ejection fraction," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    18. Vincent Michaud & Eulalie Lasseaux & David J. Green & Dave T. Gerrard & Claudio Plaisant & Tomas Fitzgerald & Ewan Birney & Benoît Arveiler & Graeme C. Black & Panagiotis I. Sergouniotis, 2022. "The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    19. Dick Schijven & Sourena Soheili-Nezhad & Simon E. Fisher & Clyde Francks, 2024. "Exome-wide analysis implicates rare protein-altering variants in human handedness," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    20. Lili Liu & Atlas Khan & Elena Sanchez-Rodriguez & Francesca Zanoni & Yifu Li & Nicholas Steers & Olivia Balderes & Junying Zhang & Priya Krithivasan & Robert A. LeDesma & Clara Fischman & Scott J. Heb, 2022. "Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50583-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.