Abstract: FR-PO311
Multi-Ethnic Polygenic Risk Modifies the Association Between APOL1 High Risk Genotypes and 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
- Vy, Thi ha my, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Gulamali, Faris F., Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Nadkarni, Girish N., Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background
The burden of advanced chronic kidney disease (CKD) falls disproportionately on minorities including African Americans (AAs) and Hispanic Americans (HAs) with admixed ancestry. Even though APOL1 high-risk genotypes increase risk of kidney disease, their penetrance is incomplete i.e., only some individuals with high-risk genotypes develop kidney disease. This indicates that alongside interactions with social determinants, common single nucleotide polymorphisms (SNPs) may attenuate the effect of APOL1’s high risk genotypes on kidney disease via epistasis. Prior studies have only shown a small number of epistatic SNPs with small effect sizes, indicating that the modification of APOL1 high risk may be polygenic
Methods
For each individual, we calculated two polygenic risk scores using summary statistics for Stage 3 CKD from two training sources: a publicly available European summary statistics generated for 118,147 individuals of European ancestry and an African summary statistics generated for 8,398 individuals of African ancestry from UK biobank. A multiethnic PRS was then derived as the linear combination of the two PRS with mixing weights α1 and α2 estimated from a single regression of Stage 3 CKD against each PRS. Association between PRS and risk of Stage 3 CKD was modeled using logistic regression adjusting for age, sex, type 2 diabetes (T2D), and the first ten genetic principal components to account for population stratification.
Results
Using mixing weights estimated from the joint model, we computed a multi-ethnic PRS and tested for the association with CKD stage 3. As expected, we observed strong association (p=0.002) with odds ratio=1.46 (1.16-1.96) per standard deviation increment in PRS. When sttratifying individuals into distinct groups by PRS quintiles: low, intermediate and high-risk groups, the intermediate-risk group had 1.49-fold (95% CI 0.89-2.56; p=0.14) and the high-risk group had 1.82-fold increased risk of CKD (95% CI 1.04-3.29; p=0.04) compared to the low-risk group.
Conclusion
Standardizing population screening for CKD by including APOL1 high-risk genotypes and polygenic risk score may improve risk stratification and outcomes. PRS may serve as another feature in comprehensive models for risk prediction to power precision medicine approaches to address health disparities in kidney disease.
Funding
- NIDDK Support