A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy.
Inheritance of apolipoprotein L1 gene (APOL1) renal-risk variants in a recessive pattern strongly associates with non-diabetic end-stage kidney disease (ESKD). Further evidence supports risk modifiers in APOL1-associated nephropathy; some studies demonstrate that heterozygotes possess excess risk for ESKD or show earlier age at ESKD, relative to those with zero risk alleles. Nearby loci are also associated with ESKD in non-African Americans.



We assessed the role of the APOL3 null allele rs11089781 on risk of non-diabetic ESKD. Four cohorts containing 2781 ESKD cases and 2474 controls were analyzed.



Stratifying by APOL1 risk genotype (recessive) and adjusting for African ancestry identified a significant additive association between rs11089781 and ESKD in each stratum and in a meta-analysis [meta-analysis P  =  0.0070; odds ratio (OR) = 1.29]; ORs were consistent across APOL1 risk strata. The biological significance of this association is supported by the finding that the APOL3 gene is co-regulated with APOL1, and that APOL3 protein was able to bind to APOL1 protein.



Taken together, the genetic and biological data support the concept that other APOL proteins besides APOL1 may also influence the risk of non-diabetic ESKD.
Department of Genetics and Developmental Biology, Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel.|Department of Nephrology, Rambam Health Care Campus, Haifa, Israel.
Karl L
KL
Skorecki
Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Jessica H
JH
Lee
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Carl D
CD
Langefeld
School of Mathematical Sciences, Tel Aviv University, Tel Aviv, Israel.
Saharon
S
Rosset
Department of Genetics and Developmental Biology, Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel.|Department of Nephrology, Rambam Health Care Campus, Haifa, Israel.
Shay
S
Tzur
Department of Nephrology, Rambam Health Care Campus, Haifa, Israel.|Mayanei HaYeshua Medical Center, Bnei Brak, Israel.
Walter G
WG
Wasser
Department of Genetics and Developmental Biology, Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel.
Revital
R
Shemer
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Gregory A
GA
Hawkins
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Jasmin
J
Divers
Division of Pediatric Nephrology, Hospital for Sick Children, Toronto, Ontario, Canada.|Child Health Evaluative Sciences, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada.
Rulan S
RS
Parekh
Division of Nephrology, University of Utah, Salt Lake City, UT, USA.|Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
Man
M
Li
Division of Nephrology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
Matthew G
MG
Sampson
Department of Internal Medicine - Nephrology, University of Michigan at Ann Arbor Medical School, Ann Arbor, MI, USA.
Matthias
M
Kretzler
Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Martin R
MR
Pollak
Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Shrijal
S
Shah
Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Daniel
D
Blackler
Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Brendan
B
Nichols
Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Michael
M
Wilmot
Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Seth L
SL
Alper
Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Barry I
BI
Freedman
Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
David J
DJ
Friedman
D000075943:Apolipoproteins L / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005921:Glomerulonephritis / Q000235:genetics*; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics*; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis
C000609028:APOL3 protein, human; D000075943:Apolipoproteins L
APOL1; APOL3; African American; FSGS; chronic kidney disease