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Original ArticleGenetics
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APOL1 Kidney Risk Variants and Proteomics

Teresa K. Chen, Aditya L. Surapaneni, Dan E. Arking, Christie M. Ballantyne, Eric Boerwinkle, Jingsha Chen, Josef Coresh, Anna Köttgen, Katalin Susztak, Adrienne Tin, Bing Yu and Morgan E. Grams
CJASN May 2022, 17 (5) 684-692; DOI: https://doi.org/10.2215/CJN.14701121
Teresa K. Chen
1Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
2Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland
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Aditya L. Surapaneni
2Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland
3Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Dan E. Arking
4McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Christie M. Ballantyne
5Department of Medicine, Baylor College of Medicine, Houston, Texas
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Eric Boerwinkle
6Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas
7Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas
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Jingsha Chen
3Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Josef Coresh
1Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
2Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland
3Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Anna Köttgen
3Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
8Department of Data Driven Medicine, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
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Katalin Susztak
9Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
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Adrienne Tin
10Department of Medicine, The University of Mississippi Medical Center, Jackson, Mississippi
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Bing Yu
6Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas
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Morgan E. Grams
3Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
11Department of Medicine, New York University Langone School of Medicine, New York, New York
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Abstract

Background and objectives The APOL1 risk variants (G1 and G2) are associated with kidney disease among Black adults, but the clinical presentation is heterogeneous. In mouse models and cell systems, increased gene expression of G1 and G2 confers cytotoxicity. How APOL1 risk variants relate to the circulating proteome warrants further investigation.

Design, setting, participants, & measurements Among 461 African American Study of Kidney Disease and Hypertension (AASK) participants (mean age: 54 years; 41% women; mean GFR: 46 ml/min per 1.73 m2), we evaluated associations of APOL1 risk variants with 6790 serum proteins (measured via SOMAscan) using linear regression models. Covariates included age, sex, percentage of European ancestry, and protein principal components 1–5. Associated proteins were then evaluated as mediators of APOL1-associated risk for kidney failure. Findings were replicated among 875 Atherosclerosis Risk in Communities (ARIC) study Black participants (mean age: 75 years; 66% women; mean eGFR: 67 ml/min per 1.73 m2).

Results In the AASK study, having two (versus zero or one) APOL1 risk alleles was associated with lower serum levels of APOL1 (P=3.11E-13; P=3.12E-06 [two aptamers]), APOL2 (P=1.45E-10), CLSTN2 (P=2.66E-06), MMP-2 (P=2.96E-06), SPOCK2 (P=2.57E-05), and TIMP-2 (P=2.98E-05) proteins. In the ARIC study, APOL1 risk alleles were associated with APOL1 (P=1.28E-11); MMP-2 (P=0.004) and TIMP-2 (P=0.007) were associated only in an additive model, and APOL2 was not available. APOL1 high-risk status was associated with a 1.6-fold greater risk of kidney failure in the AASK study; none of the identified proteins mediated this association. APOL1 protein levels were not associated with kidney failure in either cohort.

Conclusions APOL1 risk variants were strongly associated with lower circulating levels of APOL1 and other proteins, but none mediated the APOL1-associated risk for kidney failure. APOL1 protein level was also not associated with kidney failure.

  • AASK (African American Study of Kidney Disease and Hypertension)
  • chronic kidney disease
  • end stage kidney disease
  • epidemiology and outcomes
  • genetic renal disease
  • renal function decline
  • proteomics
  • apolipoprotein L1
  • Received November 11, 2021.
  • Accepted March 17, 2022.
  • Copyright © 2022 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 17 (5)
Clinical Journal of the American Society of Nephrology
Vol. 17, Issue 5
May 2022
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APOL1 Kidney Risk Variants and Proteomics
Teresa K. Chen, Aditya L. Surapaneni, Dan E. Arking, Christie M. Ballantyne, Eric Boerwinkle, Jingsha Chen, Josef Coresh, Anna Köttgen, Katalin Susztak, Adrienne Tin, Bing Yu, Morgan E. Grams
CJASN May 2022, 17 (5) 684-692; DOI: 10.2215/CJN.14701121

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APOL1 Kidney Risk Variants and Proteomics
Teresa K. Chen, Aditya L. Surapaneni, Dan E. Arking, Christie M. Ballantyne, Eric Boerwinkle, Jingsha Chen, Josef Coresh, Anna Köttgen, Katalin Susztak, Adrienne Tin, Bing Yu, Morgan E. Grams
CJASN May 2022, 17 (5) 684-692; DOI: 10.2215/CJN.14701121
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Keywords

  • AASK (African American Study of Kidney Disease and Hypertension)
  • chronic kidney disease
  • end stage kidney disease
  • epidemiology and outcomes
  • genetic renal disease
  • renal function decline
  • proteomics
  • apolipoprotein L1

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