title: Plasma Levels of Risk-Variant APOL1 Do Not Associate with Renal Disease in a Population-Based Cohort.
abstract: Two common missense variants in APOL1 (G1 and G2) have been definitively linked to CKD in black Americans. However, not all individuals with the renal-risk genotype develop CKD, and little is known about how APOL1 variants drive disease. Given the association of APOL1 with HDL particles, which are cleared by the kidney, differences in the level or quality of mutant APOL1‑HDL particles could be causal for disease and might serve as a useful risk stratification marker. We measured plasma levels of G0 (low risk), G1, and G2 APOL1 in 3450 individuals in the Dallas Heart Study using a liquid chromatography-MS method that enabled quantitation of the different variants. Additionally, we characterized native APOL1‑HDL from donors with no or two APOL1 risk alleles by size-exclusion chromatography and analysis of immunopurified APOL1‑HDL particles. Finally, we identified genetic loci associated with plasma APOL1 levels and tested for APOL1-dependent association with renal function. Although we replicated the previous association between APOL1 variant status and renal function in nondiabetic individuals, levels of circulating APOL1 did not associate with microalbuminuria or GFR. Furthermore, the size or known components of APOL1‑HDL did not consistently differ in subjects with the renal-risk genotype. Genetic association studies implicated variants in loci harboring haptoglobin-related protein (HPR), APOL1, and ubiquitin D (UBD) in the regulation of plasma APOL1 levels, but these variants did not associate with renal function. Collectively, these data demonstrate that the risk of renal disease associated with APOL1 is probably not related to circulating levels of the mutant protein.
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Julia
authors.initials: J
authors.lastname: Kozlitina
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Haihong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Brown
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Rory J
authors.initials: RJ
authors.lastname: Rohm
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Gulesi
authors.initials: G
authors.lastname: Ayanoglu
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Du
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Eric
authors.initials: E
authors.lastname: Rimmer
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Dermot F
authors.initials: DF
authors.lastname: Reilly
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Roddy
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Doris F
authors.initials: DF
authors.lastname: Cully
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Vogt
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey maarten_hoek@merck.com daniel.x.blom@gsk.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Blom
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey maarten_hoek@merck.com daniel.x.blom@gsk.com.
authors.forename: Maarten
authors.initials: M
authors.lastname: Hoek
mesh_terms: D000328:Adult; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000097:blood* / Q000235:genetics; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood* / Q000235:genetics; D008297:Male; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D012307:Risk Factors
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL
keywords: Epidemiology and outcomes; Pathophysiology of Renal Disease and Progression; chronic kidney disease; genetic renal disease; human genetics; risk factors