DOCSLIB.ORG

(APOL1) Gene and Nondiabetic Nephropathy in African Americans

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(APOL1) Gene and Nondiabetic Nephropathy in African Americans CLINICAL COMMENTARY www.jasn.org The Apolipoprotein L1 (APOL1) Gene and Nondiabetic Nephropathy in African Americans Barry I. Freedman,* Jeffrey B. Kopp,† Carl D. Langefeld,‡ Giulio Genovese,§ ࿣ David J. Friedman,§ George W. Nelson, Cheryl A. Winkler,¶ Donald W. Bowden,** and Martin R. Pollak§†† *Department of Internal Medicine/Nephrology, ‡Department of Public Health Sciences/Biostatistical Sciences, and **Department of Biochemistry and Centers for Diabetes Research and Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina; †Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; §Department of Internal Medicine/Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; ¶Basic Research Laboratory, ࿣ SAIC-National Cancer Institute, National Institutes of Health–Frederick, Frederick, Maryland; and ††Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts ABSTRACT Mapping by admixture linkage disequilibrium (LD) detected strong association be- some 22q was detected using admixture tween nonmuscle myosin heavy chain 9 gene (MYH9) variants on chromosome 22 and mapping (mapping by admixture link- nondiabetic nephropathy in African Americans. MYH9-related variants were posited to age disequilibrium [LD]) followed by be the probable, but not necessarily the definitive, causal variants as a result of fine mapping.5 MYH9, expressed in the impressive statistical evidence of association, renal expression, and a role in autosomal kidney and previously associated with dominant MYH9 disorders characterized by progressive glomerulosclerosis (Epstein glomerulosclerosis in patients with auto- and Fechtner syndromes). Dense mapping within MYH9 revealed striking LD patterns somal dominant MYH9 disorders,6 was and racial variation in risk allele frequencies, suggesting population genetic factors rapidly identified as potentially responsi- such as selection may be operative in this region. Genovese and colleagues examined ble in independent reports from two in- large chromosomal regions adjacent to MYH9 using genome-wide association meth- vestigative groups (National Institute of ods and non-HapMap single nucleotide polymorphisms identified in Yoruba from the Diabetes and Digestive and Kidney Dis- 1000 Genomes project. Statistically stronger associations were detected between two eases [NIDDK] and National Cancer In- independent sequence variants in the Apolipoprotein L1 gene (APOL1) and nondia- stitute) and the NIDDK-supported Fam- betic nephropathy in African Americans, with odds ratios of 10.5 in idiopathic FSGS ily Investigation of Nephropathy and and 7.3 in hypertension-attributed ESRD. These kidney disease risk variants likely rose Diabetes [FIND].1,2 Marked association to high frequency in Africa because they confer resistance to trypanosomal infection was also demonstrated in African Amer- and protect from African sleeping sickness. Risk variants in MYH9 and APOL1 are in strong LD, and the genetic risk that was previously attributed to MYH9 may reside, in Published online ahead of print. Publication date part or in whole, in APOL1, although more complex models of risk cannot be excluded. available at www.jasn.org. This association likely explains racial disparities in nondiabetic nephropathy as a result The views in this article are those of the authors and of the high prevalence of risk alleles in individuals of African ancestry. do not necessarily represent the views of the De- partment of Health and Human Services; neither J Am Soc Nephrol 21: 1422–1426, 2010. doi: 10.1681/ASN.2010070730 does mention of trade names, commercial products, or organizations imply endorsement by the US gov- ernment (C.A.W. and G.W.N.). Correspondence: Dr. Barry I. Freedman, Section on Polymorphisms in the nonmuscle myo- E1 risk haplotype associations in idio- Nephrology, Wake Forest University School of Medi- cine, Medical Center Boulevard, Winston-Salem, NC sin heavy chain 9 (MYH9) gene exhibit pathic FSGS and HIV-associated collaps- 27157-1053. Phone: 336-716-6192; Fax: 336-716- strong association with nondiabetic ing glomerulopathy (also termed HIV- 4318; E-mail: [email protected]; or Dr. Martin R. chronic kidney disease (CKD) in African associated nephropathy) ranges from 5 Pollak, Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA Americans. The increased risk attribut- in African Americans to 8 in European 02215. Phone: 617-632-9880; Fax: 617-632-9890; E- able to this genomic region is among the Americans with statistical evidence mail: [email protected] Ͻ ϫ Ϫ27 highest observed in any complex genetic reaching P 1.0 10 . Copyright © 2010 by the American Society of trait.1–4 The odds ratio (OR) for MYH9 Evidence for association on chromo- Nephrology 1422 ISSN : 1046-6673/2109-1422 J Am Soc Nephrol 21: 1422–1426, 2010 www.jasn.org CLINICAL COMMENTARY icans with ESRD clinically attributed APOL1 is the only member in this family could be due to rare and as-yet-undiscov- to hypertension in the absence of a kidney that produces a secreted protein, a prod- ered variation in this region of chromo- biopsy, thereby linking hypertension- uct known to be associated with HDL some 22. attributed ESRD (HA-ESRD) with FSGS particles in the circulation.11 These findings were extended to HA- and focal global glomerulosclerosis An association analysis comparing ESRD, including 1030 African American (FGGS).3,4 Furthermore, preliminary 205 African Americans who had biopsy- patients with HA-ESRD and 1025 geo- analysis of the African American Study of proven FSGS with 180 African American graphically matched control subjects Kidney Disease and Hypertension control subjects without nephropathy from the southeastern United States.10 (AASK) indicated that propensity to lose was performed using novel SNPs identi- This patient group again reveals the kidney function over time is associated fied in Yoruba participating in the 1000 strongest disease association with the G1 with MYH9 risk variants.7 Genomes project.10 These SNPs reveal tag SNP rs73885319 (S342G; P ϭ 1.1 ϫ The consistent evidence of associa- the strongest evidence of association 10Ϫ39); controlling for rs73885319, G2 tion provided an explanation for the within a 10-kb region in the last exon of indel rs71785313 was also strongly asso- long-observed excess risk for ESRD in in- APOL1, not in MYH9. The most robust ciated (P ϭ 8.8 ϫ 10Ϫ18). The OR for the dividuals of African ancestry relative to signal in this small sample includes a G1-G2 association with HA-ESRD was European ancestry. Much has transpired two-SNP haplotype consisting of de- 7.3 (95% CI 5.6 to 9.5), with a combined in the short time since the MYH9 associ- rived nonsynonymous coding variants G1-G2 P ϭ 10Ϫ63. This P value is 35 or- ation with CKD was first detected. Every- rs73885319 (S342G) and rs60910145 ders of magnitude stronger than for one has been awaiting identification of (I384M) in perfect LD (r2 ϭ 1.0), MYH9 in the same study population, causative polymorphisms and demon- termed the “G1” allele. The frequency with no overlap in OR (e.g., OR 2.38; stration that these affect renal function of the 342G:384M G1 allele was 52% in 95% CI 1.93 to 2.95; P ϭ 1.22 ϫ 10Ϫ15 and histology in animal and cell culture case patients and 18% in control sub- recessive, for the MYH9 E1 haplotype). models. Dense mapping and sequencing jects. After controlling for effects of the As for FSGS, controlling for the G1 and of MYH9 suggested the strongest associ- G1 allele, a second strong APOL1 signal G2 alleles revealed no residual associa- ations with CKD are with single nucleo- was identified, a 6-bp deletion termed tions in patients with HA-ESRD. tide polymorphisms (SNPs) in the 3Ј “G2” (rs71785313), which removes two The observed mode of inheritance of (centromeric) portion of the gene but amino acid residues. Because of the low the APOL1 kidney risk variants was fully have not identified functional variants.8 likelihood of recombination as a conse- recessive in the FSGS cohort (no effect for The global allele frequency patterns for quence of the close proximity of these al- one risk allele and an OR 10.5 for two risk MYH9 risk alleles and the extended hap- leles and the recent origin of these muta- alleles), whereas a mild dominant effect lotype homozygosity in West Africans tions, G2 seems mutually exclusive from was observed in the larger cohort with HA- suggest that the region encompassing G1; that is, they never appear together on ESRD (OR 1.26 for one risk allele and OR MYH9 may be under selective pressure.9 the same chromosome. The frequency of 7.3 for two risk alleles). Although a mild Recently Genovese et al.10 observed the G2 allele is 23% in case patients and dominant effect cannot be fully excluded, that genetic variation in the APOL1 gene, 15% in control subjects. The OR for asso- it is entirely possible that such an effect located immediately centromeric of ciation with biopsy-proven FSGS, contrast- could be explained by as-yet-undiscovered MYH9, is also strongly associated with ing patients with zero or one G1-G2 variants or by sporadic mutations in pa- nondiabetic CKD, and they presented risk alleles with those who have two tients with the recessive model. evidence that the statistical association is risk alleles (recessive effect), was 10.5 Importantly, these findings do not ex- stronger than that of MYH9. They sug- (95% confidence interval [CI] 6.0 to clude the possibility that additional rare gested these coding variants are in fact 18.4). Controlling for the effects of both variants in APOL1, MYH9, or nearby causally related to kidney disease and the G1 and G2 alleles by statistical tech- genes are involved in kidney disease sus- provided an explanation for selection of niques, no additional significant associa- ceptibility. Extended LD exists in this re- APOL1 kidney disease risk polymor- tions were observed, including in MYH9.
Load more

Recommended publications
  • Protein Identities in Evs Isolated from U87-MG GBM Cells As Determined by NG LC-MS/MS
    Protein identities in EVs isolated from U87-MG GBM cells as determined by NG LC-MS/MS. No. Accession Description Σ Coverage Σ# Proteins Σ# Unique Peptides Σ# Peptides Σ# PSMs # AAs MW [kDa] calc. pI 1 A8MS94 Putative golgin subfamily A member 2-like protein 5 OS=Homo sapiens PE=5 SV=2 - [GG2L5_HUMAN] 100 1 1 7 88 110 12,03704523 5,681152344 2 P60660 Myosin light polypeptide 6 OS=Homo sapiens GN=MYL6 PE=1 SV=2 - [MYL6_HUMAN] 100 3 5 17 173 151 16,91913397 4,652832031 3 Q6ZYL4 General transcription factor IIH subunit 5 OS=Homo sapiens GN=GTF2H5 PE=1 SV=1 - [TF2H5_HUMAN] 98,59 1 1 4 13 71 8,048185945 4,652832031 4 P60709 Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 - [ACTB_HUMAN] 97,6 5 5 35 917 375 41,70973209 5,478027344 5 P13489 Ribonuclease inhibitor OS=Homo sapiens GN=RNH1 PE=1 SV=2 - [RINI_HUMAN] 96,75 1 12 37 173 461 49,94108966 4,817871094 6 P09382 Galectin-1 OS=Homo sapiens GN=LGALS1 PE=1 SV=2 - [LEG1_HUMAN] 96,3 1 7 14 283 135 14,70620005 5,503417969 7 P60174 Triosephosphate isomerase OS=Homo sapiens GN=TPI1 PE=1 SV=3 - [TPIS_HUMAN] 95,1 3 16 25 375 286 30,77169764 5,922363281 8 P04406 Glyceraldehyde-3-phosphate dehydrogenase OS=Homo sapiens GN=GAPDH PE=1 SV=3 - [G3P_HUMAN] 94,63 2 13 31 509 335 36,03039959 8,455566406 9 Q15185 Prostaglandin E synthase 3 OS=Homo sapiens GN=PTGES3 PE=1 SV=1 - [TEBP_HUMAN] 93,13 1 5 12 74 160 18,68541938 4,538574219 10 P09417 Dihydropteridine reductase OS=Homo sapiens GN=QDPR PE=1 SV=2 - [DHPR_HUMAN] 93,03 1 1 17 69 244 25,77302971 7,371582031 11 P01911 HLA class II histocompatibility antigen,
    [Show full text]
  • The Capacity of Long-Term in Vitro Proliferation of Acute Myeloid
    The Capacity of Long-Term in Vitro Proliferation of Acute Myeloid Leukemia Cells Supported Only by Exogenous Cytokines Is Associated with a Patient Subset with Adverse Outcome Annette K. Brenner, Elise Aasebø, Maria Hernandez-Valladares, Frode Selheim, Frode Berven, Ida-Sofie Grønningsæter, Sushma Bartaula-Brevik and Øystein Bruserud Supplementary Material S2 of S31 Table S1. Detailed information about the 68 AML patients included in the study. # of blasts Viability Proliferation Cytokine Viable cells Change in ID Gender Age Etiology FAB Cytogenetics Mutations CD34 Colonies (109/L) (%) 48 h (cpm) secretion (106) 5 weeks phenotype 1 M 42 de novo 241 M2 normal Flt3 pos 31.0 3848 low 0.24 7 yes 2 M 82 MF 12.4 M2 t(9;22) wt pos 81.6 74,686 low 1.43 969 yes 3 F 49 CML/relapse 149 M2 complex n.d. pos 26.2 3472 low 0.08 n.d. no 4 M 33 de novo 62.0 M2 normal wt pos 67.5 6206 low 0.08 6.5 no 5 M 71 relapse 91.0 M4 normal NPM1 pos 63.5 21,331 low 0.17 n.d. yes 6 M 83 de novo 109 M1 n.d. wt pos 19.1 8764 low 1.65 693 no 7 F 77 MDS 26.4 M1 normal wt pos 89.4 53,799 high 3.43 2746 no 8 M 46 de novo 26.9 M1 normal NPM1 n.d. n.d. 3472 low 1.56 n.d. no 9 M 68 MF 50.8 M4 normal D835 pos 69.4 1640 low 0.08 n.d.
    [Show full text]
  • Genetics/ Genomics and HIV Nephropathy
    Genetics/ Genomics and HIV Nephropathy Sarala Naicker MB ChB(Natal), FRCP(Lond), PhD(Natal) Emeritus Professor of Medicine School of Clinical Medicine University of the Witwatersrand Johannesburg KDIGOSouth Africa KDIGO Conference Yaounde, Cameroon 18-20 March 2017 CKD prevalence § Esmated 3,2million people on RRT, with CKD incidence growing by 6% annually (WHO) § Cumulave lifeme risk for CKD varies by ancestry § African descent are the most affected (4X more likely than of European origin) § HIV CKD 18-50X increase in KDIGO people of African descent Rates adjusted for age and gender (USRDS 2012) More details Map of early human migrations[25] 1. Homo sapiens 2. Neanderthals 3. Early hominins NordNordWest - File:Spreading homo sapiens ru.svg by Urutseg Spreading of Homo sapiens •Migraon out of Africa Public Domain • File:SpreadingKDIGO homo sapiens la.svg • Created: 12 August 2014 About | Discussion | Help Human diversity, migration and origins KDIGO Floyd Reed and Sarah Tishkoff Renal histology in HIV infection- Africa JHB1 JHB2 JHB3 DBN4 CT5 CT6 Nigeria7 N 99 84 636 37 145 192 10 HIVAN (%) 27 15 25.8 83 55 57.3 70 IC Disease (%) 21 9 9.6 8.3 21.9* Other GN (%) 41 27 27.3 7 15.9 12.5 [FSGS] [13] [14.5] Tubulo-Int 21 6.3 10 13 70 Disease (%) KDIGO Other (%) 10 15 4.9 16 1. Gerntholtz et al. Kidney Int. 2006; 69: 1885-1891 Abbreviations 2. Rahmanian S. MMed, Wits 2015 3. Diana et al. WCN 2015 poster JHB= Johannesburg 4. Han et al. Kidney Int. 2006; 69: 2243-2250 DBN= Durban 6.
    [Show full text]
  • Nº Ref Uniprot Proteína Péptidos Identificados Por MS/MS 1 P01024
    Document downloaded from http://www.elsevier.es, day 26/09/2021. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Nº Ref Uniprot Proteína Péptidos identificados 1 P01024 CO3_HUMAN Complement C3 OS=Homo sapiens GN=C3 PE=1 SV=2 por 162MS/MS 2 P02751 FINC_HUMAN Fibronectin OS=Homo sapiens GN=FN1 PE=1 SV=4 131 3 P01023 A2MG_HUMAN Alpha-2-macroglobulin OS=Homo sapiens GN=A2M PE=1 SV=3 128 4 P0C0L4 CO4A_HUMAN Complement C4-A OS=Homo sapiens GN=C4A PE=1 SV=1 95 5 P04275 VWF_HUMAN von Willebrand factor OS=Homo sapiens GN=VWF PE=1 SV=4 81 6 P02675 FIBB_HUMAN Fibrinogen beta chain OS=Homo sapiens GN=FGB PE=1 SV=2 78 7 P01031 CO5_HUMAN Complement C5 OS=Homo sapiens GN=C5 PE=1 SV=4 66 8 P02768 ALBU_HUMAN Serum albumin OS=Homo sapiens GN=ALB PE=1 SV=2 66 9 P00450 CERU_HUMAN Ceruloplasmin OS=Homo sapiens GN=CP PE=1 SV=1 64 10 P02671 FIBA_HUMAN Fibrinogen alpha chain OS=Homo sapiens GN=FGA PE=1 SV=2 58 11 P08603 CFAH_HUMAN Complement factor H OS=Homo sapiens GN=CFH PE=1 SV=4 56 12 P02787 TRFE_HUMAN Serotransferrin OS=Homo sapiens GN=TF PE=1 SV=3 54 13 P00747 PLMN_HUMAN Plasminogen OS=Homo sapiens GN=PLG PE=1 SV=2 48 14 P02679 FIBG_HUMAN Fibrinogen gamma chain OS=Homo sapiens GN=FGG PE=1 SV=3 47 15 P01871 IGHM_HUMAN Ig mu chain C region OS=Homo sapiens GN=IGHM PE=1 SV=3 41 16 P04003 C4BPA_HUMAN C4b-binding protein alpha chain OS=Homo sapiens GN=C4BPA PE=1 SV=2 37 17 Q9Y6R7 FCGBP_HUMAN IgGFc-binding protein OS=Homo sapiens GN=FCGBP PE=1 SV=3 30 18 O43866 CD5L_HUMAN CD5 antigen-like OS=Homo
    [Show full text]
  • New Mesh Headings for 2018 Single Column After Cutover
    New MeSH Headings for 2018 Listed in alphabetical order with Heading, Scope Note, Annotation (AN), and Tree Locations 2-Hydroxypropyl-beta-cyclodextrin Derivative of beta-cyclodextrin that is used as an excipient for steroid drugs and as a lipid chelator. Tree locations: beta-Cyclodextrins D04.345.103.333.500 D09.301.915.400.375.333.500 D09.698.365.855.400.375.333.500 AAA Domain An approximately 250 amino acid domain common to AAA ATPases and AAA Proteins. It consists of a highly conserved N-terminal P-Loop ATPase subdomain with an alpha-beta-alpha conformation, and a less-conserved C- terminal subdomain with an all alpha conformation. The N-terminal subdomain includes Walker A and Walker B motifs which function in ATP binding and hydrolysis. Tree locations: Amino Acid Motifs G02.111.570.820.709.275.500.913 AAA Proteins A large, highly conserved and functionally diverse superfamily of NTPases and nucleotide-binding proteins that are characterized by a conserved 200 to 250 amino acid nucleotide-binding and catalytic domain, the AAA+ module. They assemble into hexameric ring complexes that function in the energy-dependent remodeling of macromolecules. Members include ATPASES ASSOCIATED WITH DIVERSE CELLULAR ACTIVITIES. Tree locations: Acid Anhydride Hydrolases D08.811.277.040.013 Carrier Proteins D12.776.157.025 Abuse-Deterrent Formulations Drug formulations or delivery systems intended to discourage the abuse of CONTROLLED SUBSTANCES. These may include physical barriers to prevent chewing or crushing the drug; chemical barriers that prevent extraction of psychoactive ingredients; agonist-antagonist combinations to reduce euphoria associated with abuse; aversion, where controlled substances are combined with others that will produce an unpleasant effect if the patient manipulates the dosage form or exceeds the recommended dose; delivery systems that are resistant to abuse such as implants; or combinations of these methods.
    [Show full text]
  • The Relationship Between APOL1 Structure and Function: Clinical Implications
    Kidney360 Publish Ahead of Print, published on November 4, 2020 as doi:10.34067/KID.0002482020 The relationship between APOL1 structure and function: Clinical implications Sethu M. Madhavan1, Matthias Buck2 1Department of Medicine, The Ohio State University, Columbus, OH, 2Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH Corresponding author: Sethu M. Madhavan, M.D. 495 W 12th Avenue Columbus, OH 43210 Email: [email protected] Phone: 614-293-6389 1 Copyright 2020 by American Society of Nephrology. Abstract Common variants in the APOL1 gene are associated with an increased risk of nondiabetic kidney disease in individuals of African ancestry. Mechanisms by which APOL1 variants mediate kidney disease pathogenesis are not well understood. Amino acid changes resulting from the kidney disease-associated APOL1 variants alter the three-dimensional structure and conformational dynamics of the C-terminal α- helical domain of the protein, which can rationalize the functional consequences. Understanding the three-dimensional structure of the protein with and without the risk variants can provide insights into the pathogenesis of kidney diseases mediated by APOL1 variants. Introduction Population-based studies have established a strong association of two variants in the APOL1 gene with the excess risk of nondiabetic chronic kidney disease (CKD) in individuals of African ancestry.1-5 One variant involves the substitution of two amino acids (S342G and I384M; termed G1), and the other the deletion of two consecutive amino acids (N388 and Y389; termed G2) compared to the ancestral nonrisk allele termed G0. APOL1 G1 and G2 variants are common in individuals with African ancestry, with at least 50 % of individuals carrying one copy of the risk allele and 15 % with two copies of the risk allele.1,3 Despite the strong association of APOL1 variants with kidney disease, the molecular mechanisms by which these APOL1 variants contribute to CKD pathogenesis and progression remains unclear.
    [Show full text]
  • The Genetics of Renal Disease
    RENALCONSULT The Genetics of Renal Disease I have heard about a gene that causes high TABLE 1 Q blood pressure. Did I Risk Associated With APOL1 Variations hear that right? Is testing for APOL1 gene Hypertension Hypertension- Sleeping this gene available now? allele variation risk related CKD risk sickness risk African-Americans have a higher risk for chronic kidney dis- Zero altered Average Average High ease (CKD), including end-stage renal disease (ESRD; defined as One altered H igher than H igher than Moderate kidney failure requiring dialysis average average or transplant), than any other ra- Two altered Highest risk Highest risk Low to absent cial or ethnic group in the United States.1 Previously, this has been attributed to poorly controlled hy- Foster et al reported that black APOL1 gene may have a higher pertension and diabetes, as well patients with two altered alleles risk for failure.6 as socioeconomic factors such as had a 31% higher risk for CKD and Genotyping for APOL1 (CPT limited access to health care. ESRD, compared with individu- code: 81479) is available in select Research now shows that auto- als with hypertension-induced laboratories at a cost of approxi- somal recessive genetic variations nephrosclerosis who had zero to mately $400.7 For a family that has a on chromosome 22q, the gene one altered alleles.4 Nondiabetic member affected by kidney failure that encodes apolipoprotein-1 black patients with CKD who have at a young age, knowing whether (APOL1; an HDL protein), pro- two altered alleles are at highest the APOL1 gene is carried in the mote hypertension.
    [Show full text]
  • Innate Immunity Pathways Regulate the Nephropathy Gene Apolipoprotein L1
    Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1 The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Nichols, B., P. Jog, J. Lee, D. Blackler, M. Wilmot, V. D’Agati, G. Markowitz, et al. 2014. “Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1.” Kidney international 87 (2): 332-342. doi:10.1038/ki.2014.270. http://dx.doi.org/10.1038/ ki.2014.270. Published Version doi:10.1038/ki.2014.270 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:21462528 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA NIH Public Access Author Manuscript Kidney Int. Author manuscript; available in PMC 2015 August 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Kidney Int. 2015 February ; 87(2): 332–342. doi:10.1038/ki.2014.270. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1 Brendan Nichols1,2, Prachi Jog, M.D.1,2, Jessica Lee1,2, Daniel Blackler1,2, Michael Wilmot1,2, Vivette D’Agati, M.D.4, Glen Markowitz, M.D.4, Jeffrey Kopp, M.D.5, Seth L. Alper, M.D, Ph.D.1, Martin R. Pollak, M.D.1,3, and David J. Friedman, M.D.1,2 1Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
    [Show full text]
  • (Apol1) in Cancer and Chronic Kidney Disease ⇑ Chien-An A
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 586 (2012) 947–955 journal homepage: www.FEBSLetters.org Review Human apolipoprotein L1 (ApoL1) in cancer and chronic kidney disease ⇑ Chien-An A. Hu a,b, , Edward I. Klopfer a,b, Patricio E. Ray c,d a Department of Biochemistry and Molecular Biology, University of New Mexico, Health Sciences Center, Albuquerque, NM 87131, USA b UNM Cancer Center, University of New Mexico, Health Sciences Center, Albuquerque, NM 87131, USA c Children’s National Medical Center, Washington, DC 20010, USA d School of Medicine & Health Sciences, Department of Pediatrics, The George Washington University, Washington, DC 20010, USA article info abstract Article history: Human apolipoprotein L1 (ApoL1) possesses both extra- and intra-cellular functions crucial in host Received 28 November 2011 defense and cellular homeostatic mechanisms. Alterations in ApoL1 function due to genetic, envi- Revised 28 February 2012 ronmental, and lifestyle factors have been associated with African sleeping sickness, atherosclerosis, Accepted 1 March 2012 lipid disorders, obesity, schizophrenia, cancer, and chronic kidney disease (CKD). Importantly, two Available online 8 March 2012 alleles of APOL1 carrying three coding-sequence variants have been linked to CKD, particularly in Edited by Noboru Mizushima Sub-Saharan Africans and African Americans. Intracellularly, elevated ApoL1 can induce autophagy and autophagy-associated cell death, which may be critical in the maintenance of cellular homeo- stasis in the kidney. Similarly, ApoL1 may protect kidney cells against renal cell carcinoma (RCC). Keywords: Apolipoprotein L (ApoL) We summarize the role of ApoL1 in RCC and CKD, highlighting the critical function of ApoL1 in ApoL1 autophagy.
    [Show full text]
  • Stage Kidney Disease and Associated Phenotypes in African and European Americans
    Evaluation of Genetic Variants Influencing Susceptibility to Type 2 Diabetes Associated End- Stage Kidney Disease and Associated Phenotypes in African and European Americans By Jason Andrew Bonomo A Dissertation Submitted to the Graduate Faculty of Wake Forest University Graduate School of Arts and Sciences in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Molecular Medicine and Translational Science May 2014 Winston Salem, NC Approved By: Donald W. Bowden, Ph.D., Advisor Examining Committee: Barry I. Freedman, M.D., Chairman Maggie C.Y. Ng, Ph.D. Nicholette D. P. Allred, Ph.D. Timothy D. Howard, Ph.D. Acknowledgements Foremost, I would like to thank my advisor, Dr. Donald W. Bowden, for allowing me the opportunity to work in the Bowden lab, and providing extensive mentorship. During my time in the lab I appreciated your unique insights on many subjects including the genetics of complex diseases, NIH grant writing, and manuscript preparation. The environment fostered by your mentorship promotes an open environment which encourages critical thinking, collaboration, guidance, and supports student-led hypotheses. I would not be the scientist I am today without your guidance, Dr. Bowden. To Dr. Barry I. Freedman, I cannot say how appreciative I am of your support, the opportunities you offered to work with collaborators across the country, clinical mentorship, visits to dialysis facilities, help with manuscript revisions, and physician related life advice you’ve given to me over the years. Without your dedication and passion for understanding the genetic bases of nephropathies we would not have had access to many of the samples you have recruited over the decades.
    [Show full text]
  • Structures of the Apol1 and Apol2 N-Terminal Domains Reveal a Non-Classical Four-Helix Bundle Motif
    ARTICLE https://doi.org/10.1038/s42003-021-02387-5 OPEN Structures of the ApoL1 and ApoL2 N-terminal domains reveal a non-classical four-helix bundle motif Mark Ultsch1, Michael J. Holliday 2, Stefan Gerhardy2, Paul Moran 2, Suzie J. Scales 3, Nidhi Gupta 3, Francesca Oltrabella 3, Cecilia Chiu 4, Wayne Fairbrother 2, Charles Eigenbrot 1 & ✉ Daniel Kirchhofer 2 Apolipoprotein L1 (ApoL1) is a circulating innate immunity protein protecting against try- panosome infection. However, two ApoL1 coding variants are associated with a highly 1234567890():,; increased risk of chronic kidney disease. Here we present X-ray and NMR structures of the N- terminal domain (NTD) of ApoL1 and of its closest relative ApoL2. In both proteins, four of the five NTD helices form a four-helix core structure which is different from the classical four- helix bundle and from the pore-forming domain of colicin A. The reactivity with a conformation-specific antibody and structural models predict that this four-helix motif is also present in the NTDs of ApoL3 and ApoL4, suggesting related functions within the small ApoL family. The long helix 5 of ApoL1 is conformationally flexible and contains the BH3-like region. This BH3-like α-helix resembles true BH3 domains only in sequence and structure but not in function, since it does not bind to the pro-survival members of the Bcl-2 family, suggesting a Bcl-2-independent role in cytotoxicity. These findings should expedite a more comprehensive structural and functional understanding of the ApoL immune protein family. 1 Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA.
    [Show full text]
  • UBD Modifies APOL1-Induced Kidney Disease Risk
    UBD modifies APOL1-induced kidney disease risk Jia-Yue Zhanga,b,1, Minxian Wanga,b,1,2,3, Lei Tianc, Giulio Genovesed, Paul Yana,b, James G. Wilsone, Ravi Thadhanif,4, Amy K. Mottlg, Gerald B. Appelh, Alexander G. Bickf,i, Matthew G. Sampsonj, Seth L. Alpera,b,i, David J. Friedmana,b, and Martin R. Pollaka,b,i,2 aDivision of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215; bDepartment of Medicine, Harvard Medical School, Boston, MA 02115; cStanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305; dStanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142; eDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216; fDepartment of Medicine, Massachusetts General Hospital, Boston, MA 02114; gUniversity of North Carolina Kidney Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599; hCenter for Glomerular Diseases, Columbia University Medical Center, New York, NY 10032; iBroad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142; and jDepartment of Pediatrics, University of Michigan School of Medicine, Ann Arbor, MI 48109 Contributed by Martin R. Pollak, January 28, 2018 (sent for review September 22, 2017; reviewed by Ali Gharavi and Susan E. Quaggin) People of recent African ancestry develop kidney disease at much do some people with the high-risk genotype develop kidney disease higher rates than most other groups. Two specific coding variants but not others? Why do some develop early-onset FSGS and others in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the late-onset progressive CKD and ESRD? Both genetic and nongenetic causal drivers of much of this difference in risk, following a re- factors likely can modify the clinical phenotype associated with a high- cessive pattern of inheritance.
    [Show full text]