Alterations in DNA Methylation, Proteomic, and Metabolomic Profiles in African Ancestry Populations with APOL1 Risk Alleles
Year: 2025
Type: article
Study design: Observational Study
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.
Authors: Xinruo Zhang, Ashley W. Scadden, Amarnath Marthi, Victoria L. Buchanan, Yishu Qu, Kendra R. Ferrier, Brian D. Chen, Mariaelisa Graff, Julian Avila, Eric Boerwinkle, Steven Buyske, Clary B. Clish, Dan Cruz, Myriam Fornage, Robert E. Gerzsten, Christopher R. Gignoux, LaShaunta Glover, Lifang Hou, Anne E. Justice, Charles Kooperberg, Holly Kramer, Leslie Lange, Ruth J.F. Loos, Tara Matise, Josyf C. Mychaleckyj, Opeyemi A. Olabisi, Ulrike Peters, Laura M. Raffield, Alex P. Reiner, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Bing Yu, Yinan Zheng, Kari E. North, Amy K. Mottl, Heather M. Highland, Maggie A. Stanislawski
Institutions: University of North Carolina at Chapel Hill, University of Colorado Anschutz, Northwestern University, Broad Institute, Harvard University, Massachusetts Institute of Technology, The University of Texas Health Science Center at Houston, Rutgers, The State University of New Jersey, Beth Israel Deaconess Medical Center, Duke University, Geisinger Medical Center, Geisinger Health System, Fred Hutch Cancer Center, Loyola University Chicago, University of Copenhagen, Novo Nordisk Foundation Center for Basic Metabolic Research, Icahn School of Medicine at Mount Sinai, University of Virginia, University of California, Los Angeles, The Lundquist Institute, Harbor–UCLA Medical Center
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1121130830, G1213528134, G122677224, G1261793039, MESA, G1276754516, G1295889178, G1349668216, Hispanic Community Health Study, G1462415530, G1539384734, G1586844134, G1625418467, G1640378483, G1732223801, G1803853571, G1818487580, Wake Forest Clinical and Translational Science Award, G1851278524, G2096685756, G2144938473, Rare variants and NHLBI traits in deeply phenotyped cohorts, G22458031, G232264632, G2415573643, MESA, Institute for Clinical and Translational Research (UL1), HISPANIC COMMUNITY HEALTH STUDY - FIELD CENTER, G2580996367, G2648688395, G2809357584, MESA, G2837638605, G290884426, G291913881, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, G3062349281, G3105260470, G3114895611, Hispanic Community Health Study, G339263803, G343705321, G350245564, G3570589137, G3643850837, G36937976, G370977179, MESA, G4030405119, Rare variants and NHLBI traits in deeply phenotyped cohorts, PAGE III: Population Architecture using Genomics and Epidemiology, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), Hispanic Community Health Study, G4429312988, G4563812999, G4583184125, G4819198047, OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, MESA, G50080621, G5108002584, G514410172, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, G5267790454, G5348427392, G536099884, HISPANIC COMMUNITY HEALTH STUDY - COORDINATING CENTER, Genome-Wide Association for Loci Influencing CHD and Other Heart, Lung and Blood, G579045871, G6088185517, G6189111791, G6265038979, Institute for Clinical and Translational Research, G6418484092, MESA, G6615318374, G66341962, SNP HEALTH ASSOCIATION RESOURCE (SHARE), G674475515, G6902273418, G7091571603, G7276788223, G7332203415, MESA, G78770644, Clinical and Translational Science Award, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, G8606882599, G8710722019, G8761005068, The Contribution of Omic Profiles to Weight Loss and Obesity, Diabetes Research Center (DRC), From GWAS loci to blood pressure genes, variants & mechanisms - Renewal, UCLA Clinical and Translational Science Institute, G931818222, G991334795
OpenAlex ID: W4409230595