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Characterization of circulating APOL1 protein complexes in African Americans
Allison Weckerle1, James A Snipes2, Dongmei Cheng1
1Department of Internal Medicine, Sections on Molecular Medicine Wake Forest School of Medicine, Winston-Salem, NC 27157.
Insights
Researchers investigated the APOL1 gene in African Americans, finding that circulating APOL1 variant proteins form distinct complexes, not associated with HDL or LDL. These complexes may influence cardiovascular disease risk.
Area of Science:
- Genetics and Cardiovascular Health
- Lipoprotein Metabolism Research
- Proteomics and Disease Biomarkers
Background:
- APOL1 gene variants are linked to kidney disease and cardiovascular disease (CVD) in African Americans.
- The behavior of circulating APOL1 variant proteins, particularly their interaction with lipoproteins like HDL, remains largely uncharacterized.
Purpose of the Study:
- To investigate if serum APOL1 protein concentrations or lipoprotein distributions differ between individuals with APOL1 G1/G2 risk variants and those with the G0 non-risk genotype.
- To characterize the nature of circulating APOL1 protein complexes in African Americans without nephropathy.
Main Methods:
- Serum samples from African Americans without nephropathy were analyzed based on APOL1 genotype (G0, G1, G2).
- APOL1 protein concentrations and distributions within serum were assessed using size-exclusion chromatography and proteomics.
- Complexes were analyzed for their association with HDL and LDL, and their protein composition was determined.
Main Results:
- Serum APOL1 protein concentrations were similar across all APOL1 genotypes.
- Circulating APOL1 protein was found in two distinct complexes (A and B) unrelated to HDL or LDL.
- Complex B showed reduced haptoglobin-related protein (HPR) abundance in individuals with G1/G2 risk variants compared to G0.
Conclusions:
- Circulating APOL1 proteins form distinct complexes (A and B) that do not associate with HDL or LDL.
- Reduced HPR in complex B among individuals with APOL1 risk variants suggests a potential role in disease pathogenesis.
- These novel circulating complexes may be involved in HDL metabolism and cardiovascular disease susceptibility.
Abstract:
APOL1 gene renal-risk variants are associated with nephropathy and CVD in African Americans; however, little is known about the circulating APOL1 variant proteins which reportedly bind to HDL. We examined whether APOL1 G1 and G2 renal-risk variant serum concentrations or lipoprotein distributions differed from nonrisk G0 APOL1 in African Americans without nephropathy. Serum APOL1 protein concentrations were similar regardless of APOL1 genotype. In addition, serum APOL1 protein was bound to protein complexes in two nonoverlapping peaks, herein referred to as APOL1 complex A (12.2 nm diameter) and complex B (20.0 nm diameter). Neither of these protein complexes associated with HDL or LDL. Proteomic analysis revealed that complex A was composed of APOA1, haptoglobin-related protein (HPR), and complement C3, whereas complex B contained APOA1, HPR, IgM, and fibronectin. Serum HPR was less abundant on complex B in individuals with G1 and G2 renal-risk variant genotypes, relative to G0 (P = 0.0002-0.037). These circulating complexes may play roles in HDL metabolism and susceptibility to CVD.
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