title: Sequencing rare and common APOL1 coding variants to determine kidney disease risk.
abstract: A third of African Americans with sporadic focal segmental glomerulosclerosis (FSGS) or HIV-associated nephropathy (HIVAN) do not carry APOL1 renal risk genotypes. This raises the possibility that other APOL1 variants may contribute to kidney disease. To address this question, we sequenced all APOL1 exons in 1437 Americans of African and European descent, including 464 patients with biopsy-proven FSGS/HIVAN. Testing for association with 33 common and rare variants with FSGS/HIVAN revealed no association independent of strong recessive G1 and G2 effects. Seeking additional variants that might have been under selection by pathogens and could represent candidates for kidney disease risk, we also sequenced an additional 1112 individuals representing 53 global populations. Except for G1 and G2, none of the 7 common codon-altering variants showed evidence of selection or could restore lysis against trypanosomes causing human African trypanosomiasis. Thus, only APOL1 G1 and G2 confer renal risk, and other common and rare APOL1 missense variants, including the archaic G3 haplotype, do not contribute to sporadic FSGS and HIVAN in the US population. Hence, in most potential clinical or screening applications, our study suggests that sequencing APOL1 exons is unlikely to bring additional information compared to genotyping only APOL1 G1 and G2 risk alleles.
authors.affiliation: Molecular Genetic Epidemiology Section, Basic Research Laboratory, Basic Science Program, NCI, Leidos Biomedical Research, Frederick National Laboratory, Frederick, Maryland, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Limou
authors.affiliation: Center for Cancer Research Informatics Core, Leidos Biomedical Research, Frederick National Laboratory, Frederick, Maryland, USA.
authors.forename: George W
authors.initials: GW
authors.lastname: Nelson
authors.affiliation: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lecordier
authors.affiliation: Molecular Genetic Epidemiology Section, Basic Research Laboratory, Basic Science Program, NCI, Leidos Biomedical Research, Frederick National Laboratory, Frederick, Maryland, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, NCI, Leidos Biomedical Research, Frederick National Laboratory, Frederick, Maryland, USA.
authors.forename: Colm S
authors.initials: CS
authors.lastname: O'hUigin
authors.affiliation: Molecular Genetic Epidemiology Section, Basic Research Laboratory, Basic Science Program, NCI, Frederick National Laboratory, Frederick, Maryland, USA.
authors.forename: Victor A
authors.initials: VA
authors.lastname: David
authors.affiliation: Molecular Genetic Epidemiology Section, Basic Research Laboratory, Basic Science Program, NCI, Leidos Biomedical Research, Frederick National Laboratory, Frederick, Maryland, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Binns-Roemer
authors.affiliation: Caribbean Genome Center, Department of Biology, University of Puerto Rico at Mayagüez, Mayagüez, Puerto Rico.
authors.forename: Wilfried M
authors.initials: WM
authors.lastname: Guiblet
authors.affiliation: Caribbean Genome Center, Department of Biology, University of Puerto Rico at Mayagüez, Mayagüez, Puerto Rico.
authors.forename: Taras K
authors.initials: TK
authors.lastname: Oleksyk
authors.affiliation: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Pays
authors.affiliation: Kidney Disease Section, NIDDK, NIH, Bethesda, Maryland, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.affiliation: Molecular Genetic Epidemiology Section, Basic Research Laboratory, Basic Science Program, NCI, Leidos Biomedical Research, Frederick National Laboratory, Frederick, Maryland, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D001741:Black or African American / Q000235:genetics; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000097:blood / Q000235:genetics*; D001706:Biopsy; D016022:Case-Control Studies; D005091:Exons; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005923:Glomerulosclerosis, Focal Segmental / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D006239:Haplotypes; D006790:Host-Parasite Interactions; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood / Q000235:genetics*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D014347:Trypanosoma brucei gambiense / Q000378:metabolism / Q000472:pathogenicity; D016833:Trypanosoma brucei rhodesiense / Q000378:metabolism / Q000472:pathogenicity; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL