Phenome-wide association analysis suggests the APOL1 linked disease spectrum primarily drives kidney-specific pathways.

David L Birtwell, Katalin Susztak, Scott M Damrauer, C Michael Stein, Daniel J Rader, Joshua C Denny, Regeneron Genetics Center, Jinbo Chen, Christian M Shaffer, Heather Williams, Archna Bajaj, Roy D Bloom, Marjorie Risman, Rachel L Kember, QiPing Feng, Lisa Bastarache, Wei-Qi Wei, Aeron M Small, Chengxiang Qiu, Andrea Ihegword

Journal: Kidney international 2021;97(5):1032-1041

PMID: 32247630

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Abstract

The relationship between commonly occurring genetic variants (G1 and G2) in the APOL1 gene in African Americans and different disease traits, such as kidney disease, cardiovascular disease, and pre-eclampsia, remains the subject of controversy. Here we took a genotype-first approach, a phenome-wide association study, to define the spectrum of phenotypes associated with APOL1 high-risk variants in 1,837 African American participants of Penn Medicine Biobank and 4,742 African American participants of Vanderbilt BioVU. In the Penn Medicine Biobank, outpatient creatinine measurement-based estimated glomerular filtration rate and multivariable regression models were used to evaluate the association between high-risk APOL1 status and renal outcomes. In meta-analysis of both cohorts, the strongest phenome-wide association study associations were for the high-risk APOL1 variants and diagnoses codes were highly significant for "kidney dialysis" (odds ratio 3.75) and "end stage kidney disease" (odds ratio 3.42). A number of phenotypes were associated with APOL1 high-risk genotypes in an analysis adjusted only for demographic variables. However, no associations were detected with non-renal phenotypes after controlling for chronic/end stage kidney disease status. Using calculated estimated glomerular filtration rate -based phenotype analysis in the Penn Medicine Biobank, APOL1 high-risk status was associated with prevalent chronic/end stage kidney disease /kidney transplant (odds ratio 2.27, 95% confidence interval 1.67-3.08). In high-risk participants, the estimated glomerular filtration rate was 15.4 mL/min/1.73m; significantly lower than in low-risk participants. Thus, although APOL1 high-risk variants are associated with a range of phenotypes, the risks for other associated phenotypes appear much lower and in our dataset are driven by a primary effect on renal disease.

Address: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Medicine, Yale-New Haven Hospital, New Haven, Connecticut, USA.; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.; Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA; VISN 4 Mental Illness Research, Education, and Clinical Center, Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Regeneron Genetics Center, Tarrytown, New York, USA.; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.; Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Surgery, Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA. Electronic address: [email protected].; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address: [email protected].

DOI: 10.1016/j.kint.2020.01.027

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MeSH Terms: Apolipoprotein L1, Creatinine, Genetic Predisposition to Disease, Genotype, Glomerular Filtration Rate, Humans, Kidney, Risk Factors