Modeling of clinical phenotypes in systemic lupus erythematosus based on the platelet transcriptome and FCGR2a genotype.
FCGR2a
Lupus
Lupus Nephritis
Platelet
RNA-seq
Systemic lupus erythematosus
Transcriptomics
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
07 04 2023
07 04 2023
Historique:
received:
28
11
2022
accepted:
12
03
2023
medline:
11
4
2023
entrez:
7
4
2023
pubmed:
8
4
2023
Statut:
epublish
Résumé
The clinical heterogeneity of SLE with its complex pathogenesis remains challenging as we strive to provide optimal management. The contribution of platelets to endovascular homeostasis, inflammation and immune regulation highlights their potential importance in SLE. Prior work from our group showed that the Fcγ receptor type IIa (FcγRIIa)-R/H131 biallelic polymorphism is associated with increased platelet activity and cardiovascular risk in SLE. The study was initiated to investigate the platelet transcriptome in patients with SLE and evaluate its association across FcγRIIa genotypes and distinct clinical features. Fifty-one patients fulfilling established criteria for SLE (mean age = 41.1 ± 12.3, 100% female, 45% Hispanic, 24% black, 22% Asian, 51% white, mean SLEDAI = 4.4 ± 4.2 at baseline) were enrolled and compared with 18 demographically matched control samples. The FCGR2a receptor was genotyped for each sample, and RNA-seq was performed on isolated, leukocyte-depleted platelets. Transcriptomic data were used to create a modular landscape to explore the differences between SLE patients and controls and various clinical parameters in the context of FCGR2a genotypes. There were 2290 differentially expressed genes enriched for pathways involved in interferon signaling, immune activation, and coagulation when comparing SLE samples vs controls. When analyzing patients with proteinuria, modules associated with oxidative phosphorylation and platelet activity were unexpectedly decreased. Furthermore, genes that were increased in SLE and in patients with proteinuria were enriched for immune effector processes, while genes increased in SLE but decreased in proteinuria were enriched for coagulation and cell adhesion. A low-binding FCG2Ra allele (R131) was associated with decreases in FCR activation, which further correlated with increases in platelet and immune activation pathways. Finally, we were able to create a transcriptomic signature of clinically active disease that performed significantly well in discerning SLE patients with active clinical disease form those with inactive clinical disease. In aggregate, these data demonstrate the platelet transcriptome provides insight into lupus pathogenesis and disease activity, and shows potential use as means of assessing this complex disease using a liquid biopsy.
Sections du résumé
BACKGROUND
The clinical heterogeneity of SLE with its complex pathogenesis remains challenging as we strive to provide optimal management. The contribution of platelets to endovascular homeostasis, inflammation and immune regulation highlights their potential importance in SLE. Prior work from our group showed that the Fcγ receptor type IIa (FcγRIIa)-R/H131 biallelic polymorphism is associated with increased platelet activity and cardiovascular risk in SLE. The study was initiated to investigate the platelet transcriptome in patients with SLE and evaluate its association across FcγRIIa genotypes and distinct clinical features.
METHODS
Fifty-one patients fulfilling established criteria for SLE (mean age = 41.1 ± 12.3, 100% female, 45% Hispanic, 24% black, 22% Asian, 51% white, mean SLEDAI = 4.4 ± 4.2 at baseline) were enrolled and compared with 18 demographically matched control samples. The FCGR2a receptor was genotyped for each sample, and RNA-seq was performed on isolated, leukocyte-depleted platelets. Transcriptomic data were used to create a modular landscape to explore the differences between SLE patients and controls and various clinical parameters in the context of FCGR2a genotypes.
RESULTS
There were 2290 differentially expressed genes enriched for pathways involved in interferon signaling, immune activation, and coagulation when comparing SLE samples vs controls. When analyzing patients with proteinuria, modules associated with oxidative phosphorylation and platelet activity were unexpectedly decreased. Furthermore, genes that were increased in SLE and in patients with proteinuria were enriched for immune effector processes, while genes increased in SLE but decreased in proteinuria were enriched for coagulation and cell adhesion. A low-binding FCG2Ra allele (R131) was associated with decreases in FCR activation, which further correlated with increases in platelet and immune activation pathways. Finally, we were able to create a transcriptomic signature of clinically active disease that performed significantly well in discerning SLE patients with active clinical disease form those with inactive clinical disease.
CONCLUSIONS
In aggregate, these data demonstrate the platelet transcriptome provides insight into lupus pathogenesis and disease activity, and shows potential use as means of assessing this complex disease using a liquid biopsy.
Identifiants
pubmed: 37029410
doi: 10.1186/s12967-023-04059-w
pii: 10.1186/s12967-023-04059-w
pmc: PMC10082503
doi:
Substances chimiques
Receptors, IgG
0
FCGR2A protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
247Subventions
Organisme : NIH HHS
ID : R35HL144993
Pays : United States
Organisme : NIH HHS
ID : R01HL139909
Pays : United States
Organisme : NIH HHS
ID : GM136573
Pays : United States
Informations de copyright
© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
Références
J Thromb Haemost. 2015 Jun;13(6):893-908
pubmed: 25900780
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
BMC Bioinformatics. 2018 Nov 6;19(1):404
pubmed: 30400809
Blood. 2000 Dec 15;96(13):4246-53
pubmed: 11110698
N Engl J Med. 2003 Dec 18;349(25):2399-406
pubmed: 14681505
J Am Coll Cardiol. 2018 Jan 2;71(1):53-65
pubmed: 29301628
Int J Mol Sci. 2022 Jun 30;23(13):
pubmed: 35806341
J Immunol. 2014 Jun 15;192(12):5459-68
pubmed: 24907379
Platelets. 2020 Oct 2;31(7):952-959
pubmed: 31934818
Arterioscler Thromb Vasc Biol. 2021 Feb;41(2):854-864
pubmed: 33297754
Bioinformatics. 2016 Sep 15;32(18):2847-9
pubmed: 27207943
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
J Immunol. 1991 Aug 15;147(4):1338-43
pubmed: 1831223
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Arthritis Rheum. 1982 Nov;25(11):1271-7
pubmed: 7138600
Sci Adv. 2021 Sep 10;7(37):eabh2434
pubmed: 34516880
J Thromb Haemost. 2019 Mar;17(3):532-537
pubmed: 30638300
Ann Intern Med. 2005 Jun 21;142(12 Pt 1):953-62
pubmed: 15968009
Circ Res. 2018 Jan 19;122(2):337-351
pubmed: 29348254
OMICS. 2012 May;16(5):284-7
pubmed: 22455463
Nat Rev Rheumatol. 2018 Mar 21;14(4):195-213
pubmed: 29559714
Arthritis Rheum. 2001 Oct;44(10):2331-7
pubmed: 11665973
Genome Biol. 2014;15(12):550
pubmed: 25516281
Sci Transl Med. 2019 Nov 6;11(517):
pubmed: 31694925
Nat Genet. 2000 May;25(1):25-9
pubmed: 10802651
Br J Haematol. 2001 Nov;115(2):451-9
pubmed: 11703349
Arthritis Rheum. 2012 Aug;64(8):2677-86
pubmed: 22553077
Blood. 2020 Dec 17;136(25):2933-2945
pubmed: 33331924
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Lupus Sci Med. 2019 Aug 13;6(1):e000270
pubmed: 31497305
Arthritis Rheumatol. 2019 Sep;71(9):1400-1412
pubmed: 31385462
Genet Test Mol Biomarkers. 2010 Dec;14(6):839-46
pubmed: 20973705
Arthritis Rheum. 1997 Sep;40(9):1725
pubmed: 9324032
J Rheumatol. 2002 Feb;29(2):288-91
pubmed: 11838846
Nephrol Dial Transplant. 2004 Jun;19(6):1427-31
pubmed: 15004265
F1000Res. 2018 Aug 24;7:1338
pubmed: 30254741
BMC Bioinformatics. 2008 Dec 29;9:559
pubmed: 19114008
Am J Epidemiol. 1997 Mar 1;145(5):408-15
pubmed: 9048514
Arterioscler Thromb Vasc Biol. 2017 Apr;37(4):707-716
pubmed: 28153882
J Rheumatol. 2009 Feb;36(2):288-94
pubmed: 19208561
Lupus Sci Med. 2019 Dec 30;6(1):e000365
pubmed: 31921432
Best Pract Res Clin Rheumatol. 2017 Jun;31(3):415-428
pubmed: 29224681
J Clin Invest. 1996 Mar 1;97(5):1348-54
pubmed: 8636449