The influence of HLA genetic variation on plasma protein expression

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 and Xinli Hu ()
Additional contact information
Chirag Krishna: Pfizer Research and Development, Pfizer Inc.
Joshua Chiou: Pfizer Research and Development, Pfizer Inc.
Saori Sakaue: Harvard Medical School
Joyce B. Kang: 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
Daniel Ziemek: Pfizer Research and Development, Pfizer Inc.
Xinli Hu: Pfizer Research and Development, Pfizer Inc.

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50583-8

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