Kidney Week

Abstract: FR-PO319

N6-Methyladenosine Methylation Regulatory Genes Modified the Effect of APOL1 Risk Genotype on Progression of CKD

Session Information

• Genetic Diseases: Models, Mechanisms, Treatments
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Li, Changwei, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, United States

Changwei Li,

• Westbrook, Adrianna, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, United States

Adrianna Westbrook,

• Zhang, Ruiyuan, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, United States

Ruiyuan Zhang,

• Hamm, L. Lee, Tulane University School of Medicine, New Orleans, Louisiana, United States

L. Lee Hamm,

• Chen, Jing, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, United States

Jing Chen,

• He, Jiang, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, United States

Jiang He,

• Kelly, Tanika, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, United States

Tanika Kelly,

Background

The APOL1 risk alleles is a major cause of chronic kidney disease (CKD) and its progression among Blacks. N(6)-methyladenosine (m6A) is the most abundant modification in mammalian mRNA and regulates all stages of RNA life cycle. M6A is regulated by 10 writer genes encoding m6A methyltransferase enzymes, 9 reader genes encoding m6A binding proteins to stabilize, splice and translate mRNA, and 2 eraser genes encoding m6A demethylase enzymes. We aim to evaluate whether expression quantitative trait loci (eQTLs) of the m6A regulatory genes modify the effect of APOL1 risk alleles on CKD progression.

Methods

A total of 666 independent (r²≤0.3) eQTLs of m6A regulatory genes (Writer genes: METTL3, METTL14, WTAP, VIRMA, HAKAI, ZC3H13, RBM15, RBM15B, METTL16, PCIF1/CAPAM; Reader genes: YTHDC1, YTHDF1, YTHDF2, YTHDF3, YTHDC2, HNRNPA2B1, FMR1/FMRP, HNRNPC, and HNRNPG; and Eraser genes: FTO and ALKBH5) were retrieved from the GTEx. The variants were tested for interactions with APOL1 risk status on CKD progression among 1,224 Black participants of the Chronic Renal Insufficiency Cohort (CRIC) in Cox regression models. We adjusted for age, sex, study site, and the first 10 ancestry principal components (PCs) in the base model and additionally adjusted for baseline kidney function in the full model. We also performed stratified analyses to evaluate APOL1 risk allele effects on CKD progression according to genotypes of the significant variants.

Results

After Bonferroni correction, a cluster of four LAMTOR5 variants (lead SNP: rs6671673, P=6.58×10^-5) modified the effect of APOL1 risk alleles on CKD progression. The LAMTOR5 rs6671673 is an eQTL for the writer gene RMB15, with major T allele increasing expression of RMB15 in the whole blood (P=5.4×10^-5). In stratified analyses, effects of APOL1 risk alleles on CKD progression decreased with the number of T alleles of LAMTOR5 rs6671673. Hazard ratios and their corresponding 95% confidence intervals associated with the APOL1 risk alleles were 1.87 (1.18-2.97), 1.39 (1.13-1.71) and 0.85 (0.67-1.07), respectively, for participants carrying 0, 1, and 2 T alleles at the LAMTOR5 rs6671673.

Conclusion

An eQTL for the m6A writer gene RMB15 reduced the risk of APOL1 associated CKD progression, and stablizing APOL1 mRNA may reduce the risk of CKD progression.

Funding

• Other NIH Support