1. Sequencing rare and common APOL1 coding variants to determine kidney disease risk.
- Author
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Limou S, Nelson GW, Lecordier L, An P, O'hUigin CS, David VA, Binns-Roemer EA, Guiblet WM, Oleksyk TK, Pays E, Kopp JB, and Winkler CA
- Subjects
- AIDS-Associated Nephropathy diagnosis, AIDS-Associated Nephropathy ethnology, Black or African American genetics, Apolipoprotein L1, Apolipoproteins blood, Biopsy, Case-Control Studies, Exons, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Glomerulosclerosis, Focal Segmental diagnosis, Glomerulosclerosis, Focal Segmental ethnology, Haplotypes, Host-Parasite Interactions, Humans, Lipoproteins, HDL blood, Male, Phenotype, Risk Assessment, Risk Factors, Sequence Analysis, DNA, Trypanosoma brucei gambiense metabolism, Trypanosoma brucei gambiense pathogenicity, Trypanosoma brucei rhodesiense metabolism, Trypanosoma brucei rhodesiense pathogenicity, United States epidemiology, White People genetics, AIDS-Associated Nephropathy genetics, Apolipoproteins genetics, Glomerulosclerosis, Focal Segmental genetics, Lipoproteins, HDL genetics, Polymorphism, Single Nucleotide
- 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.
- Published
- 2015
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