miércoles, 21 de julio de 2010

Association of Trypanolytic ApoL1 Variants with Kidney Disease in African-Americans -- Genovese et al., 10.1126/science.1193032 -- Science


Published Online July 15, 2010
Science DOI: 10.1126/science.1193032
Science Express Index

Reports
Association of Trypanolytic ApoL1 Variants with Kidney Disease in African-Americans
Giulio Genovese,1,2,* David J. Friedman,1,3,* Michael D. Ross,4 Laurence Lecordier,5 Pierrick Uzureau,5 Barry I. Freedman,6 Donald W. Bowden,7,8,9,10,11,12 Carl D. Langefeld,9,10,11,12 Taras K. Oleksyk,13 Andrea Uscinski Knob,4 Andrea J. Bernhardy,1 Pamela J. Hicks,7,8,9,10,11,12 George W. Nelson,15 Benoit Vanhollebeke,5 Cheryl A. Winkler,14 Jeffrey B. Kopp,15 Etienne Pays,5, Martin R. Pollak1,16,


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. Apolipoprotein L-1 (ApoL1) 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.

1 Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
2 Department of Mathematics, Dartmouth College, Hanover, NH 03755, USA.
3 Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
4 Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02215, USA.
5 Laboratory of Molecular Parasitology, Institute of Molecular Biology and Medicine (IBMM), Université Libre de Bruxelles, B-6041 Gosselies, Belgium.
6 Department of Internal Medicine, Section on Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
7 Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
8 Center for Diabetes Research, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
9 Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
10 Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
11 Center for Public Health Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
12 Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
13 Department of Biology, University of Puerto Rico at Mayaguez, Mayaguez, Puerto Rico 00681.
14 Laboratory of Genomic Diversity, SAIC-Frederick, Inc, NCI-Frederick, Frederick, MD 21702, USA.
15 Kidney Disease Section, National Institute of Diabetes, Digestive, and Kidney Disease, National Institutes of Health, Bethesda, MD 20892, USA.
16 Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
* These authors contributed equally to this work.


To whom correspondence should be addressed. E-mail: mpollak@bidmc.harvard.edu (M.R.P.); epays@ulb.ac.be (E.P.)

Association of Trypanolytic ApoL1 Variants with Kidney Disease in African-Americans -- Genovese et al., 10.1126/science.1193032 -- Science

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