A methylation risk score for chronic kidney disease: a HyperGEN study

Alana C Jones; Amit Patki; Vinodh Srinivasasainagendra; Bertha A Hidalgo; Hemant K Tiwari; Nita A Limdi; Nicole D Armstrong; Ninad S Chaudhary; Bré Minniefield; Devin Absher; Donna K Arnett; Leslie A Lange; Ethan M Lange; Bessie A Young; Clarissa J Diamantidis; Stephen S Rich; Josyf C Mychaleckyj; Jerome I Rotter; Kent D Taylor; Holly J Kramer; Russell P Tracy; Peter Durda; Silva Kasela; Tuuli Lappalinen; Yongmei Liu; W Craig Johnson; David J Van Den Berg; Nora Franceschini; Simin Liu; Charles P Mouton; Parveen Bhatti; Steve Horvath; Eric A Whitsel; Marguerite R Irvin

doi:10.1038/s41598-024-68470-z

A methylation risk score for chronic kidney disease: a HyperGEN study

Sci Rep. 2024 Aug 1;14(1):17757. doi: 10.1038/s41598-024-68470-z.

Authors

Alana C Jones^{1

2}, Amit Patki³, Vinodh Srinivasasainagendra³, Bertha A Hidalgo⁴, Hemant K Tiwari³, Nita A Limdi⁵, Nicole D Armstrong⁴, Ninad S Chaudhary⁶, Bré Minniefield⁷, Devin Absher⁸, Donna K Arnett⁹, Leslie A Lange¹⁰, Ethan M Lange¹⁰, Bessie A Young¹¹, Clarissa J Diamantidis¹², Stephen S Rich¹³, Josyf C Mychaleckyj¹⁴, Jerome I Rotter¹⁵, Kent D Taylor¹⁵, Holly J Kramer¹⁶, Russell P Tracy¹⁷, Peter Durda¹⁷, Silva Kasela¹⁸, Tuuli Lappalinen¹⁸, Yongmei Liu¹⁹, W Craig Johnson²⁰, David J Van Den Berg²¹, Nora Franceschini²², Simin Liu²³, Charles P Mouton²⁴, Parveen Bhatti²⁵, Steve Horvath^{26

27}, Eric A Whitsel²², Marguerite R Irvin⁴

Affiliations

¹ Medical Scientist Training Program, University of Alabama at Birmingham, 912 18th St S, Birmingham, AL, 35233, USA. acjones@uab.edu.
² Department of Epidemiology, University of Alabama at Birmingham, 912 18th St S, Birmingham, AL, 35233, USA. acjones@uab.edu.
³ Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
⁴ Department of Epidemiology, University of Alabama at Birmingham, 912 18th St S, Birmingham, AL, 35233, USA.
⁵ Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.
⁶ 23andMe, South San Francisco, CA, USA.
⁷ Department of Biology, Florida State University-Panama City, Panama City, FL, USA.
⁸ HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
⁹ Office of the Provost, University of South Carolina, Columbia, SC, USA.
¹⁰ Department of Biomedical Informatics, University of Colorado-Anschutz, Aurora, CO, USA.
¹¹ Division of Nephrology, University of Washington, Seattle, WA, USA.
¹² Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
¹³ Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA.
¹⁴ Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁵ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁶ Departments of Public Health Sciences and Medicine, Loyola University Medical Center, Taywood, IL, USA.
¹⁷ Department of Pathology and Laboratory Medicine, University of Vermont, Colchester, VT, USA.
¹⁸ Department of Systems Biology, New York Genome Center, Columbia University, New York, NY, USA.
¹⁹ Department of Medicine, Cardiology and Neurology, Duke University Medical Center, Durham, NC, USA.
²⁰ Department of Biostatistics, University of Washington, Seattle, WA, USA.
²¹ Department of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
²² Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²³ Department of Epidemiology, School of Public Health, Brown University, Providence, RI, USA.
²⁴ Department of Family Medicine, University of Texas Medical Branch Health, Galveston, TX, USA.
²⁵ Department of Medicine, School of Population and Public Health, University of British Columbia, Vancouver, BC, CAN, USA.
²⁶ Department of Human Genetics, David Geffen School of Medicine, Gonda Research Center, Los Angeles, CA, USA.
²⁷ Altos Labs, San Diego, CA, USA.

Abstract

Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.

Keywords: Chronic kidney disease; Epigenetics; Methylation risk score; eGFR.

MeSH terms

Adult
Aged
Black or African American / genetics
CpG Islands*
DNA Methylation*
Epigenesis, Genetic
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Glomerular Filtration Rate*
Humans
Male
Middle Aged
Renal Insufficiency, Chronic* / epidemiology
Renal Insufficiency, Chronic* / genetics
Risk Factors

Abstract

MeSH terms

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