Association of trypanolytic ApoL1 variants with kidney disease in African Americans.
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.
Genovese
Giulio
G
Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Friedman
David J
DJ
Ross
Michael D
MD
Lecordier
Laurence
L
Uzureau
Pierrick
P
Freedman
Barry I
BI
Bowden
Donald W
DW
Langefeld
Carl D
CD
Oleksyk
Taras K
TK
Uscinski Knob
Andrea L
AL
Bernhardy
Andrea J
AJ
Hicks
Pamela J
PJ
Nelson
George W
GW
Vanhollebeke
Benoit
B
Winkler
Cheryl A
CA
Kopp
Jeffrey B
JB
Pays
Etienne
E
Pollak
Martin R
MR
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
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