Abstract Body: Introduction: Angiopoietin-like protein 3 (ANGPTL3) is a liver-secreted protein with well-characterized effects on inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL) activity, thus increasing levels of circulating triglycerides, LDL-C, and HDL-C. However, the effects of loss-of-function variants in this gene on kidney disease risk are not well understood. In this study, we identified a missense variant M259T in ANGPTL3 and characterized its protective role against kidney disease. The variant is most strongly represented in the African population with a gnomAD minor allele frequency (MAF) of 0.05 compared to a European population MAF of 7.30E-05.
Methods: We leveraged the Penn Medicine Biobank as our study cohort both for its extensive phenotyping from the electronic health records and its population diversity in that over 25% of individuals with genetic sequencing data are of African (AFR) ancestry (n = 11,198). All variant-phenotype associations were performed using a generalized linear mixed model controlling for age, sex, ancestry-specific genetic principal components, and genetic relatedness. Quantitative traits were all rank-based inverse normal transformed.
Results: In the AFR population, the M259T variant was found to be associated with decreased triglycerides (beta = -0.09, P = 5.09E-03), consistent with loss-of-function of ANGPTL3. This association was replicated (beta = -0.08, P = 1.24E-10) in the AFR population (n = 121,790) from the Million Veteran Program (MVP). Interestingly, this variant was also significantly associated with increased eGFR (beta = 0.10, P = 2.82E-04) and decreased creatinine (beta = -0.10, P = 5.59E-04) in PMBB. The association with decreased creatinine almost reached significance in MVP (beta = -0.01, P = 0.06). Further stratifying the PMBB cohort by their APOL1 G1/G2 risk carrier status, we observed strong persistent protective effects including increased eGFR (beta = 0.09, P = 1.49E-03) and decreased creatinine (beta = -0.09, P = 3.67E-03) in low-risk individuals who carry either 0 or 1 copy of G1/G2. The protective signals were slightly weaker in high-risk individuals who carry 2 copies of G1/G2, likely due to the large risk-conferring effects of the APOL1 risk alleles.
Conclusion: Our results suggest that loss-of-function in ANGPTL3 may play an independent protective role in kidney disease risk, but additional analyses are required to confirm and uncover the biological mechanisms involved.