Abstract: FR-PO0107
DNA Methylation Stratifies CKD Risk and Implicates Aberrant Endoplasmic Reticulum Trafficking Among Individuals with APOL1 High-Risk Genotype
Session Information
- Hereditary Glomerular and Tubulointerstitial Kidney Diseases
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)
Authors
- Guga, Suri, King's College London, London, England, United Kingdom
- Kular, Dalvir, King's College London, London, England, United Kingdom
- Hayward, Samantha JL, Bristol University, Bristol, United Kingdom
- Simpson, Michael A., King's College London, London, England, United Kingdom
- Bramham, Kate, King's College London, London, England, United Kingdom
- Koziell, Ania B., King's College London, London, England, United Kingdom
Background
Individuals carrying two APOL1 risk alleles (G1/G2) have markedly elevated genetic susceptibility to chronic kidney disease (CKD), However, only a subset progress to clinical disease, suggesting that additional factors modulate APOL1 phenotypic penetrance. There is growing evidence for a dynamic relationship between environmental exposures and APOL1 biology suggests DNA methylation (DNAm) as a modifier, integrating signals from the environment, immune activation and kidney injury.
Methods
We analysed whole blood DNAm(Illumina EPIC array) from 1,024 African ancestry participants without CKD at baseline in the Genetic Epidemiology Network of Arteriopathy (GENOA) cohort. Participants were stratified by APOL1 genetic risk: the high-risk group (n = 84) was defined by the presence of two risk alleles (G1/G1, G2/G2, or G1/G2), while the low-risk group (n = 940) comprised individuals with zero or one risk allele. Key findings were subsequently validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Three complementary EWAS analyses were performed. Gene set enrichment analysis (GSEA) and probe-level methylGSA (FDR < 0.05) were applied across GO, KEGG, and Reactome databases. Expression quantitative trait methylation (eQTM) analyses were conducted.
Results
In the full cohort, incorporating an APOL1 genotype interaction term, we identified genotype-dependent associations between baseline blood DNA methylation and kidney outcomes. For CKD status (cross-sectional EWAS), 4 CpG sites and 103 DMRs reached significance (HMFDR < 0.05). For longitudinal kidney function decline, 102 DMRs were associated with annualised eGFR change fromm baseline (HMFDR < 0.05).
Gene set enrichment analysis of EWAS results for eGFR decline identified pathways related to endoplasmic reticulum–Golgi trafficking, including COPI-mediated anterograde transport and Golgi processing.
Conclusion
We propose that individuals with APOL1 high-risk genotypes exhibit distinct baseline blood DNA methylation signatures that are associated with long-term kidney disease progression and may improve risk discrimination beyond clinical factors. These findings suggest that epigenetic variation may modify APOL1-associated kidney disease, and that baseline methylation profiling could complement APOL1 genotyping for CKD risk stratification.
Acknowledgment
We thank the Genoa and Mesa cohort for their participation and involvement.