Apolipoprotein L1 Gene Variants in Deceased Organ Donors Are Associated With Renal Allograft Failure

Freedman, Barry I.; Julian, Bruce A.; Pastan, Stephen O.; Israni, Ajay K.; Schladt, David; Gautreaux, Michael D.; Hauptfeld, Věra; Bray, Robert A.; Gebel, Howard M.; Kirk, Allan D.; Gaston, Robert S.; Rogers, Jeffrey; Farney, Alan C.; Orlando, Giuseppe; Stratta, Robert J.; Mohan, Sumit; Ma, Lijun; Langefeld, Carl D.; Hicks, Pamela J.; Palmer, Nicholette D.; Adams, Patricia L.; Palanisamy, A.; Reeves‐Daniel, Amber; Divers, Jasmin

doi:10.1111/ajt.13223

Cited by 155 publications

(154 citation statements)

References 44 publications

Supporting

Mentioning

147

Contrasting

Order By: Relevance

“…Due to the abundance of APOL1 in human serum and uptake of free APOL1 into podocytes in vitro ( 5 ), it was initially hypothesized that circulating APOL1 protein might contribute to APOL1 -associated nephropathy. Subsequent kidney transplantation studies failed to support this hypothesis (18)(19)(20); however, potential roles for circulating APOL1 protein in CVD and HDLcholesterol metabolism remain plausible ( 7 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of circulating APOL1 protein complexes in African Americans

Weckerle

Snipes

Cheng

et al. 2016

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org G1 and G2 renal-risk variants on chromosome 22q13.1 ( 1-3 ). Although APOL1 mRNA and APOL1 protein are present in human kidney ( 4, 5 ), the major APOL1 reservoir appears to be circulating protein ( 5, 6 ). APOL1 was initially discovered as a minor apolipoprotein of plasma HDLs ( 6 ); however, its distribution among HDL subfractions has not been well-defi ned. APOL1 nephropathy variants associate with HDL subfraction concentrations ( 7 ) and CVD risk, although controversial results have been reported with CVD ( 8-11 ). Trypanosome lytic factors (TLF1 and TLF2) contain APOL1 protein ( 12 ) and are minor HDL subfractions in humans that contribute to innate immunity via protection from infection, including from African trypanosomes ( 13 ).Association was not observed between plasma APOL1 concentrations and APOL1 genotype in African Americans with treated HIV infection; plasma APOL1 levels also did not associate with the risk of HIV-associated nephropathy or chronic kidney disease ( 14 ). Whether serum APOL1 protein levels and their distribution among HDL particles are associated with APOL1 genotypes in healthy individuals is unknown. Because free APOL1 protein may be taken up by podocytes in vitro ( 5 ), it remains critical to determine whether serum APOL1 concentrations or the structure/composition of variant APOL1 proteins and their associated complexes are specifi c to the G1 and G2 renalrisk variants, relative to nonrisk G0.To address these issues, serum APOL1 protein levels and size distribution were examined in age-and gender-matched African Americans without kidney disease based on APOL1 genotype using fast protein LC (FPLC) and immunoblot analysis. Proteomics analysis was performed to compare the composition of APOL1 protein-containing complexes. These 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. A major breakthrough in human molecular genetics was identifi cation of the powerful contribution of APOL1 gene ...

show abstract

Section: Discussionmentioning

confidence: 99%

Characterization of circulating APOL1 protein complexes in African Americans

Weckerle

Snipes

Cheng

et al. 2016

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…In a single center study from North Carolina, Reeves-Daniel et al examined outcomes from 106 African American deceased donors, of whom 22 (21%) had two APOL1 copies, and found that two APOL1 variants in a deceased donor was independently associated with a greater risk of graft failure (HR 3.84; p ¼ 0.0.84) (4). In this issue of AJT, Freedman et al follow-up on this original report from North Carolina by including new deceased donors from their state as well as from Alabama (5). In this analysis, they report outcomes on 675 kidney transplants performed at 55 centers (two centers accounted for 62% of transplants) from 368 African American deceased donors.…”

mentioning

confidence: 99%

APOL1 Genotyping of African American Deceased Organ Donors: Not Just Yet

Knoll

2015

American Journal of Transplantation

View full text Add to dashboard Cite

“…However, little is known about its exact function. Until now, apoL1 gene variants have been associated with increased incidence and progression of chronic kidney disease (30), and with renal allograft failure (31) in African Americans, having been proposed as key factors in the future of renal diagnosis (32). Furthermore, it has been shown that these specific apoL1 variants, containing missense residues or presenting deletions of amino acids in the C-terminal domain, contribute to atherosclerotic cardiovascular risk, as a genetic determinant to cardiovascular risk in individuals of African ancestry (29).…”

Section: Blood Collection Biochemical Analysis and Sample Preparationmentioning

confidence: 99%

ApoL1 levels in high density lipoprotein and cardiovascular event presentation in patients with familial hypercholesterolemia

Cubedo¹,

Padró²,

Alonso

et al. 2016

Journal of Lipid Research

View full text Add to dashboard Cite

Familial hypercholesterolemia (FH) is one of the most prevalent genetic disorders associated with premature coronary artery disease (CAD) (1). This disorder appears by mutations in the gene that encodes the LDL receptor (LDLR) and it is characterized by a lifelong exposure to high plasma LDL-cholesterol levels (LDL-C). FH patients show an important decrease in their life expectancy because of an increase in CAD frequency, the principal causes of mortality being sudden death and myocardial infarction (2). Clinical expression of CAD in FH patients varies considerably across cohorts and individual patients treated to guidelines (3, 4), suggesting the contribution of additional factors to the atherosclerotic burden in these patients. Indeed, a recent study has reported lipoprotein (a) [Lp(a)] levels as one of those additional factors that influence CVD in FH patients (5).HDLs have proved to be atheroprotective in several epidemiological, clinical, and experimental studies (6-13). Indeed, HDLs are considered key players in the progression of CAD because of their multiple antiatherogenic effects (14) in addition to their role in reverse cholesterol transport. Increasing evidence suggests that HDL atheroprotective effects lie in HDL composition, highlighting the importance of HDL quality rather that HDL quantity in CVD (14-17). Moreover, the existence of several HDL subpopulations with differential contribution to these HDL-related antiatherogenic properties has underscored the relevance of HDL composition in HDL functionality (15,18).A recent study has demonstrated that FH is associated with quantitative and qualitative modifications of HDL Abstract HDL composition rather than HDL-cholesterol (HDL-C) levels seems to be a key determinant of HDL-induced atheroprotection. Heterozygous familial hypercholesterolemia (FH) patients, with lifelong exposure to high LDL levels, show a high prevalence of premature coronary artery disease. We hypothesized that HDL of FH patients might have a modified protein composition and investigated the proteomic signature of HDL obtained from FH patients and their unaffected relatives. HDLs were characterized by 2D electrophoresis/MS in 10 families from the SAFE-HEART cohort (3 individuals/family: 2 with genetic FH diagnosis and 1 non-FH relative) clinically characterized and treated as per guidelines. FH patients had lower apoA-I levels and a differential HDL distribution profile of apoL1 and apoA-IV. ELISA validation revealed decreased apoL1 serum levels in FH patients. ApoL1 levels were able to predict presentation of an ischemic cardiac event, and apoL1/HDL-C ratio was associated with the survival rate after the event. FH patients who died because of a fatal cardiac event had lower apoL1 and LCAT content in HDL3 an average of 3.5 years before the event than those who survived. Changes in HDL protein composition could affect patients' prognosis. The proteomic profile of apoL1 is modified in HDLs of high cardiovascular risk patients, and apoL1 plasma levels are significantly lower in serum...

show abstract

Apolipoprotein L1 Gene Variants in Deceased Organ Donors Are Associated With Renal Allograft Failure

Cited by 155 publications

References 44 publications

Characterization of circulating APOL1 protein complexes in African Americans

Characterization of circulating APOL1 protein complexes in African Americans

APOL1 Genotyping of African American Deceased Organ Donors: Not Just Yet

ApoL1 levels in high density lipoprotein and cardiovascular event presentation in patients with familial hypercholesterolemia

Contact Info

Product

Resources

About