Alterations in DNA Methylation, Proteomic, and Metabolomic Profiles in African Ancestry Populations with APOL1 Risk Alleles

Key Points We aimed to elucidate potential methylation, proteomic, and metabolomic mechanisms by which APOL1 variants may be linked to kidney disease. We report distinct methylation profiling between APOL1 risk allele carriers and noncarriers, many near APOL gene family. We report higher APOL1 protein and lower C18:1 cholesteryl ester in two risk allele carriers. Background The APOL1 high-risk haplotype has been associated with CKD and the deterioration of kidney function, particularly in populations with West African ancestry. However, the mechanisms by which APOL1 risk variants increase the risk for kidney disease and its progression have not been fully elucidated. Methods We compared methylation ( N =3191; 715 [22%] carriers), proteomic ( N =1240; 169 [14%] carriers), and metabolomic ( N =6309; 674 [11%] carriers) profiles in African and Hispanic/Latino carriers of two APOL1 high-risk alleles (G1/G1, G2/G2, G1/G2) and noncarriers (G0/G0), excluding heterozygotes (G0/G1, G0/G2), from the Population Architecture using Genomics and Epidemiology Consortium and UK Biobank. In each study, the associations between the APOL1 high-risk haplotype and up to 722,719 cytosine-phosphate-guanine (CpG) sites, 2923 proteins, or 836 metabolites were estimated using covariate-adjusted linear regression models, followed by fixed-effects sample size–weighted meta-analyses. Results Significant associations were observed between APOL1 high-risk haplotype and methylation at 52 CpG sites, with 48 located on chromosome 22 and 18 in the vicinity of APOL1–4 and MYH9 . All significant CpG sites near APOL2 were hypomethylated, whereas those near APOL3 and APOL4 were hypermethylated. APOL1 -associated CpG sites were also identified in genes involved in ion transport and mitochondrial stress pathways. Sensitivity analyses indicated consistent yet attenuated effects among heterozygotes, supporting an additive effect of APOL1 risk alleles. Further analyses of the 52 CpG sites identified two near APOL4 exhibiting G1-specific effects, eight associated with CKD but none with eGFR, and three showing heterogeneity by CKD status. In addition, carrying two APOL1 risk alleles was associated with higher plasma APOL1 protein ( β =1.12, P FDR = 2.26e-70) and lower C18:1 cholesteryl ester metabolite (Z=−4.50, P FDR = 4.83e-3). Conclusions Our results demonstrate differential methylation, proteomic, and metabolomic profiles associated with APOL1 high-risk haplotypes.

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Journal
Journal of the American Society of Nephrology
Published
2025-04-07
DOI
https://doi.org/10.1681/asn.0000000688
Citations
1
Primary Topic
Renal Diseases and Glomerulopathies
Type
article
Field-Weighted Citation Impact
1.43
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article

Alterations in DNA Methylation, Proteomic, and Metabolomic Profiles in African Ancestry Populations with APOL1 Risk Alleles

Josyf C. Mychaleckyj, Amy K. Mottl, Opeyemi A. Olabisi, Lifang Hou et al.
1 citations
Journal of the American Society of Nephrology
Renal Diseases and Glomerulopathies
1.43
article

Alterations in DNA Methylation, Proteomic, and Metabolomic Profiles in African Ancestry Populations with APOL1 Risk Alleles

Josyf C. Mychaleckyj, Amy K. Mottl, Opeyemi A. Olabisi, Lifang Hou, Maggie A. Stanislawski, Eric Boerwinkle, Ruth J. F. Loos, Daniel E. Cruz, Steven Buyske, Kendra Ferrier, Yishu Qu, Robert E. Gerzsten, Julián Ávila-Pacheco, LáShauntá Glover, Laura M. Raffield, Yinan Zheng, Mariaelisa Graff, Victoria L. Buchanan, Tara C. Matise, Clary B. Clish, Holly Kramer, Anne E. Justice, Kari E. North, Bing Yu, Brian D. Chen, Stephen S. Rich, Alex P. Reiner, Amarnath Marthi, Charles Kooperberg, Christopher R. Gignoux, Heather M. Highland, Annette Peters, Ashley W. Scadden, Leslie A. Lange, Xinruo Zhang, Jerome I. Rotter, Kent D. Taylor, Myriam Fornage
article en
1 citations

Abstract

Key Points We aimed to elucidate potential methylation, proteomic, and metabolomic mechanisms by which APOL1 variants may be linked to kidney disease. We report distinct methylation profiling between APOL1 risk allele carriers and noncarriers, many near APOL gene family. We report higher APOL1 protein and lower C18:1 cholesteryl ester in two risk allele carriers. Background The APOL1 high-risk haplotype has been associated with CKD and the deterioration of kidney function, particularly in populations with West African ancestry. However, the mechanisms by which APOL1 risk variants increase the risk for kidney disease and its progression have not been fully elucidated. Methods We compared methylation ( N =3191; 715 [22%] carriers), proteomic ( N =1240; 169 [14%] carriers), and metabolomic ( N =6309; 674 [11%] carriers) profiles in African and Hispanic/Latino carriers of two APOL1 high-risk alleles (G1/G1, G2/G2, G1/G2) and noncarriers (G0/G0), excluding heterozygotes (G0/G1, G0/G2), from the Population Architecture using Genomics and Epidemiology Consortium and UK Biobank. In each study, the associations between the APOL1 high-risk haplotype and up to 722,719 cytosine-phosphate-guanine (CpG) sites, 2923 proteins, or 836 metabolites were estimated using covariate-adjusted linear regression models, followed by fixed-effects sample size–weighted meta-analyses. Results Significant associations were observed between APOL1 high-risk haplotype and methylation at 52 CpG sites, with 48 located on chromosome 22 and 18 in the vicinity of APOL1–4 and MYH9 . All significant CpG sites near APOL2 were hypomethylated, whereas those near APOL3 and APOL4 were hypermethylated. APOL1 -associated CpG sites were also identified in genes involved in ion transport and mitochondrial stress pathways. Sensitivity analyses indicated consistent yet attenuated effects among heterozygotes, supporting an additive effect of APOL1 risk alleles. Further analyses of the 52 CpG sites identified two near APOL4 exhibiting G1-specific effects, eight associated with CKD but none with eGFR, and three showing heterogeneity by CKD status. In addition, carrying two APOL1 risk alleles was associated with higher plasma APOL1 protein ( β =1.12, P FDR = 2.26e-70) and lower C18:1 cholesteryl ester metabolite (Z=−4.50, P FDR = 4.83e-3). Conclusions Our results demonstrate differential methylation, proteomic, and metabolomic profiles associated with APOL1 high-risk haplotypes.

Journal of the American Society of NephrologyVol. 36(8)
Rutgers, The State University of New Jersey (US), Broad Institute (US), Northwestern University (US), University of North Carolina at Chapel Hill (US), University of Copenhagen (DK), Beth Israel Deaconess Medical Center (US), University of North Carolina Health Care (US), Colorado School of Public Health (US), Duke University (US), Loyola University Chicago (US), Novo Nordisk Foundation (DK), UCLA Medical Center (US), Fred Hutch Cancer Center (US), Environmental and Occupational Health Sciences Institute (US), Duke University Hospital (US), The University of Texas Health Science Center (US), Harbor–UCLA Medical Center (US), University of Virginia (US), University of Colorado Anschutz Medical Campus (US), Geisinger Health System (US), The University of Texas Health Science Center at Houston (US), Icahn School of Medicine at Mount Sinai (US)
Good health and well-being
Openalex Percentile: Top 21%
Renal Diseases and Glomerulopathies
1.43
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