title: Association of trypanolytic ApoL1 variants with kidney disease in African Americans.
abstract: African Americans have higher rates of kidney disease than European Americans. Here, we show that, in African Americans, focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) are associated with two independent sequence variants in the APOL1 gene on chromosome 22 {FSGS odds ratio = 10.5 [95% confidence interval (CI) 6.0 to 18.4]; H-ESKD odds ratio = 7.3 (95% CI 5.6 to 9.5)}. The two APOL1 variants are common in African chromosomes but absent from European chromosomes, and both reside within haplotypes that harbor signatures of positive selection. ApoL1 (apolipoprotein L-1) is a serum factor that lyses trypanosomes. In vitro assays revealed that only the kidney disease-associated ApoL1 variants lysed Trypanosoma brucei rhodesiense. We speculate that evolution of a critical survival factor in Africa may have contributed to the high rates of renal disease in African Americans.
authors.affiliation: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Genovese
authors.forename: David J
authors.initials: DJ
authors.lastname: Friedman
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ross
authors.forename: Laurence
authors.initials: L
authors.lastname: Lecordier
authors.forename: Pierrick
authors.initials: P
authors.lastname: Uzureau
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Taras K
authors.initials: TK
authors.lastname: Oleksyk
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Uscinski Knob
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Bernhardy
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hicks
authors.forename: George W
authors.initials: GW
authors.lastname: Nelson
authors.forename: Benoit
authors.initials: B
authors.lastname: Vanhollebeke
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.forename: Etienne
authors.initials: E
authors.lastname: Pays
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
mesh_terms: D000349:Africa; D001741:Black or African American / Q000235:genetics*; D000483:Alleles; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005923:Glomerulosclerosis, Focal Segmental / Q000208:ethnology / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000150:complications; D007113:Immunity, Innate; D007676:Kidney Failure, Chronic / Q000208:ethnology / Q000209:etiology / Q000235:genetics*; D015810:Linkage Disequilibrium; D008075:Lipoproteins, HDL / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D016015:Logistic Models; D020409:Molecular Motor Proteins / Q000235:genetics; D018995:Myosin Heavy Chains / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000378:metabolism; D012641:Selection, Genetic; D017384:Sequence Deletion; D016833:Trypanosoma brucei rhodesiense / Q000378:metabolism*; D014353:Trypanosomiasis, African / Q000235:genetics / Q000469:parasitology
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D011994:Recombinant Proteins; D018995:Myosin Heavy Chains