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. 2023 Nov 1;18(11):1416-1425.
doi: 10.2215/CJN.0000000000000257. Epub 2023 Aug 3.

Differences in the Circulating Proteome in Individuals with versus without Sickle Cell Trait

Yanwei Cai  1 , Nora Franceschini  2 , Aditya Surapaneni  3   4 , Melanie E Garrett  5 , Usman A Tahir  6   7 , Li Hsu  1 , Marilyn J Telen  5   8 , Bing Yu  9 , Hua Tang  10 , Yun Li  11 , Simin Liu  12 , Robert E Gerszten  6   7 , Josef Coresh  3   4 , JoAnn E Manson  13 , Genevieve L Wojcik  3 , Charles Kooperberg  2 , Paul L Auer  14 , Matthew W Foster  15 , Morgan E Grams  16 , Allison E Ashley-Koch  5 , Laura M Raffield  11 , Alex P Reiner  1   17
Affiliations

Differences in the Circulating Proteome in Individuals with versus without Sickle Cell Trait

Yanwei Cai et al. Clin J Am Soc Nephrol. .

Abstract

Background: Sickle cell trait affects approximately 8% of Black individuals in the United States, along with many other individuals with ancestry from malaria-endemic regions worldwide. While traditionally considered a benign condition, recent evidence suggests that sickle cell trait is associated with lower eGFR and higher risk of kidney diseases, including kidney failure. The mechanisms underlying these associations remain poorly understood. We used proteomic profiling to gain insight into the pathobiology of sickle cell trait.

Methods: We measured proteomics ( N =1285 proteins assayed by Olink Explore) using baseline plasma samples from 592 Black participants with sickle cell trait and 1:1 age-matched Black participants without sickle cell trait from the prospective Women's Health Initiative cohort. Age-adjusted linear regression was used to assess the association between protein levels and sickle cell trait.

Results: In age-adjusted models, 35 proteins were significantly associated with sickle cell trait after correction for multiple testing. Several of the sickle cell trait-protein associations were replicated in Black participants from two independent cohorts (Atherosclerosis Risk in Communities study and Jackson Heart Study) assayed using an orthogonal aptamer-based proteomic platform (SomaScan). Many of the validated sickle cell trait-associated proteins are known biomarkers of kidney function or injury ( e.g. , hepatitis A virus cellular receptor 1 [HAVCR1]/kidney injury molecule-1 [KIM-1], uromodulin [UMOD], ephrins), related to red cell physiology or hemolysis (erythropoietin [EPO], heme oxygenase 1 [HMOX1], and α -hemoglobin stabilizing protein) and/or inflammation (fractalkine, C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 [MCP-1], and urokinase plasminogen activator surface receptor [PLAUR]). A protein risk score constructed from the top sickle cell trait-associated biomarkers was associated with incident kidney failure among those with sickle cell trait during Women's Health Initiative follow-up (odds ratio, 1.32; 95% confidence interval, 1.10 to 1.58).

Conclusions: We identified and replicated the association of sickle cell trait with a number of plasma proteins related to hemolysis, kidney injury, and inflammation.

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Conflict of interest statement

J. Coresh consultancy for Healthy.io and SomaLogic, ownership interest in Healthy.io, research funding from the National Institute of Health and National Kidney Foundation, and an advisory or leadership role for SomaLogic. M.W. Foster reports research funding from Biomilq, Circumvent Pharmaceuticals, and Oerth Bio. N. Franceschini reports advisory or leadership roles for Women's Health Initiative Chair of Ancillary Committee and Women's Health Initiative Publication and Presentation Committee. M.E. Grams reports advisory or leadership roles for the American Journal of Kidney Diseases, ASN Publication Committee, CJASN, JASN Editorial Fellowship Committee, KDIGO Executive Committee (co-chair elect), NKF Scientific Advisory Board, and USRDS Scientific Advisory Board; grant funding from NKF, which receives funding from multiple pharmaceutical companies; grant funding from NIH; payment from academic institutions for grand rounds; and payment from NephSAP. S. Liu reports consultancy for Novo Nordisk and TwinHealth. J.E. Manson reports research funding from Mars Edge. L.M. Raffield reports consultancy for TOPMed Administrative Coordinating Center (through Westat). M.J. Telen reports consultancy from Novartis and Pfizer, Inc.; research funding from BioMedomics, CSL Behring, NIH, Novartis, Novo Nordisk, and Pfizer; and honoraria from Novartis and Pfizer. All remaining authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Volcano plot showing 35 significant protein associations with sickle cell trait in the WHI cohort. Effect estimates (β value) are noted on the x axis on the SD scale. All significant associations are labeled in red, but only the top eight proteins with association in the positive direction are labeled because of space constraints. AHSP, α-hemoglobin–stabilizing protein; EPHB4, ephrin type-B receptor 4; HAVCR1, hepatitis A virus cellular receptor 1; HMOX1, heme oxygenase 1; IL10RB, interleukin-10 receptor subunit β; MMP7, matrilysin; TGFBR2, TGF-β receptor type-2; UMOD, uromodulin; WHI, Women's Health Initiative.
Figure 2
Figure 2
Heat map and dendrogram of pairwise correlations between 35 sickle cell trait–associated proteins.
See this image and copyright information in PMC

Comment in

  • Sickle Cell Trait and Circulating Proteome.
    Naik R, Lebensburger J. Naik R, et al. Clin J Am Soc Nephrol. 2023 Nov 1;18(11):1391-1392. doi: 10.2215/CJN.0000000000000320. Epub 2023 Oct 2. Clin J Am Soc Nephrol. 2023. PMID: 37783470 Free PMC article. No abstract available.

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