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

Abstract

We aimed to elucidate potential methylation, proteomic, and metabolomic mechanisms by which <i>APOL1</i> variants may be linked to kidney disease. We report distinct methylation profiling between <i>APOL1</i> risk allele carriers and noncarriers, many near <i>APOL</i> gene family. We report higher APOL1 protein and lower C18:1 cholesteryl ester in two risk allele carriers. The <i>APOL1</i> 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 <i>APOL1</i> risk variants increase the risk for kidney disease and its progression have not been fully elucidated. We compared methylation (<i>N</i>=3191; 715 [22%] carriers), proteomic (<i>N</i>=1240; 169 [14%] carriers), and metabolomic (<i>N</i>=6309; 674 [11%] carriers) profiles in African and Hispanic/Latino carriers of two <i>APOL1</i> 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 <i>APOL1</i> 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. Significant associations were observed between <i>APOL1</i> high-risk haplotype and methylation at 52 CpG sites, with 48 located on chromosome 22 and 18 in the vicinity of <i>APOL1–4</i> and <i>MYH9</i>. All significant CpG sites near <i>APOL2</i> were hypomethylated, whereas those near <i>APOL3</i> and <i>APOL4</i> were hypermethylated. <i>APOL1</i>-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 <i>APOL1</i> risk alleles. Further analyses of the 52 CpG sites identified two near <i>APOL4</i> exhibiting G1-specific effects, eight associated with CKD but none with eGFR, and three showing heterogeneity by CKD status. In addition, carrying two <i>APOL1</i> risk alleles was associated with higher plasma APOL1 protein (<i>β</i>=1.12, <i>P</i>_<i>FDR</i> = 2.26e-70) and lower C18:1 cholesteryl ester metabolite (Z=−4.50, <i>P</i>_FDR = 4.83e-3). Our results demonstrate differential methylation, proteomic, and metabolomic profiles associated with <i>APOL1</i> high-risk haplotypes.