Adams, T

Agbasi, E

Ahmed, S

Appleby, T

Ashworth, R

Barber, J

Barber, S

Barbini, B

Barbour, L

Berlanga, A

Bhagwandin, P

Binns-Roemer, E

Boateng, V

Booth, JW

Bramham, K

Buckingham, C

Burns, F

Burns, JE

Campbell, L

Campbell, M

Canoso, A

Chadwick, D

Cheetham, T

Clarke, A

Clarke, C

Cleig, R

Cosgrove, C

Cross, R

Crowe, A

David, V

Deng, H

Doctor, J

Driver, L

Duro, S

Flanagan, K

Fox, J

Gamlen, H

Hamlyn, E

Hamzah, L

Hand, J

Hilton, R

Hung, RKY

Jones, R

Jordan, D

Kegg, S

Kennard, V

Klein, MP

Knott, A

Lamont, G

Levy, J

Liskova, M

Lwanga, J

Mahiouz, K

McDonald, C

McQueen, L

Middleditch, H

Minton, J

Murira, J

Murphy, M

Murphy, S

Norcross, C

Nori, A

O'Brien, C

Ohene-Adomako, S

Oliveira, A

Ottaway, Z

Parr, S

Post, FA

Poulton, M

Price, DA

Quinn, K

Rabuya, M

Reid-Amoruso, LE

Richardson, C

Rosenberg, KL

Ryan, F

Sabin, CA

Saiyad, G

Samarawickrama, A

Samuel, I

Santana-Suarez, B

Schoolmeester, A

Solano, T

Soviarova, H

Stocker, RJ

Sullivan, V

Taylor, C

Thomas, C

Trevitt, V

Trotman, D

Ustianowski, A

Uzu, H

Venkateshwaran, S

Wandolo, E

Waters, A

Weir, G

Williams, C

Williams, K

Window, N

Winkler, CA

English

UCL Discovery

RESEARCH LETTERKidneyGSTM1 Copy Number and Kidney Diseasein People With HIVRachel K.Y. Hung1,16, Kerry-Lee Rosenberg2,16, Victor David3, Elizabeth Binns-Roemer3,John W. Booth4, Rachel Hilton5, Julie Fox1,5, Fiona Burns2, Andrew Ustianowski6,Catherine Cosgrove7, Lisa Hamzah7, James E. Burns8,9, Amanda Clarke10,11,David Chadwick12, David A. Price13, Stephen Kegg14, Lucy Campbell1, Kate Bramham1,15,Caroline A. Sabin8, Frank A. Post1,15, Cheryl A. Winkler2, and on behalf of the GEN-AFRICAStudy Group171King’s College London, London, UK; 2Royal Free London Hospital NHS Foundation Trust, London, UK; 3Basic ResearchLaboratory, Frederick National Laboratory for Cancer Research and the National Cancer Institute, Frederick, USA; 4Barts HealthNHS Trust, London, UK; 5Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 6Pennine Acute Hospitals NHS FoundationTrust, Manchester, UK; 7St George’s Hospital NHS Foundation Trust, London, UK; 8University College London, London, UK;9Central and North West London NHS Foundation Trust, London, UK; 10Brighton and Sussex University Hospital NHS Trust,Brighton, UK; 11Brighton and Sussex Medical School Department of Infectious Disease, Brighton, UK; 12South Tees HospitalsNHS Foundation Trust, Middlesbrough, UK; 13The Newcastle Upon Tyne Hospitals, Newcastle, UK; 14Lewisham and GreenwichNHS Trust, London, UK; and 15King’s College Hospital NHS Foundation Trust, London, UKCorrespondence: Rachel Hung, King’s College Hospital NHS Foundation Trust, Weston Education Center, Cutcombe Road,London SE5 9RJ, UK. E-mail: rachel.hung@kcl.ac.uk16RKYH and K-LR contributed equally.17Members of GEN-AFRICA study group are listed in the appendix.Received 1 March 2022; revised 25 April 2022; accepted 2 May 2022Kidney Int Rep (2022) -, -–-; https://doi.org/10.1016/j.ekir.2022.05.003KEYWORDS: Africa; APOL1; GSTM1; HIV; kidney; oxidative stressª 2022 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BYlicense (http://creativecommons.org/licenses/by/4.0/).Oxidative stress has been implicated in the patho-genesis and progression of chronic kidney disease(CKD). An imbalance between increased production ofreactive oxygen species and reduced antioxidant de-fenses results in disruption to downstream cellularsignaling and subsequent renal cell apoptosis andsenescence, fibrosis, and vascular injury.1 Geneticvariants that improve the capacity to mitigate oxidativestress may therefore be protective against the devel-opment of CKD.The glutathione-S-transferases play a role in theconjugation of prooxidant species with glutathione tofacilitate the elimination of reactive oxygen species.GSTM1 is the gene encoding one such isoenzyme. Thisgene copy number has undergone gene deletion andexpansion so chromosomes have no copies, 1 copy or,in rare cases, 2 copies of the gene. Two copies of theactive allele are required for enzymatic activity (hap-loinsufficiency); those homozygous for the null allele,GSTM1(0), completely lack enzyme production. In-dividuals with the inactive GSTM1 genotypes (GSTM10/0 or 1/0) have been found to be at higher risk ofcommon malignancies, atherosclerosis, coronary heartInternational Reports (2022) -, -–-disease, and CKD progression.S1,S2 This study sought toinvestigate the relationship between GSTM1 genotypeand prevalent CKD and the interaction between GSTM1and APOL1 carrier status,2–4 in a cohort of Black peoplewith HIV in the United Kingdom.5,6Characteristics of the 2762 participants are summa-rized in Supplementary Table S1. Of these, 2075(75.1%) had GSTM1 inactive genotypes whereas 687(24.9%) carried 2 or 3 copies (active genotypes). Themean age of the participants was 48 years, and 57%were female. Most participants were established onantiretroviral treatment with suppressed HIV RNAlevels; HIV parameters, hepatitis coinfection status, andprevalence of hypertension, diabetes, and cardiovas-cular disease did not differ by GSTM1 status. Kidneyfunction (estimated glomerular filtration rate [eGFR])and the prevalence of APOL1 risk variants and sicklecell trait were similar for the 2 GSTM1 groups(Figure 1a–c and Supplementary Figure S1).In the overall study population, GSTM1 inactivegenotypes were not associated with an increased risk ofkidney disease (eGFR <60 or <90 ml/min per 1.73 m2or stage 5 CKD), whereas these genotypes were10%10%20%30%40%50%60%70%80%90%100%Inacve AcveGSTM1 statusFull cohortESKD15-2930-5960-89>900%10%20%30%40%50%60%70%80%90%100%Inacve AcveGSTM1 statusAPOL1 low risk genotypesESKD15-2930-5960-89>900%10%20%30%40%50%60%70%80%90%100%Inacve AcveGSTM1 statusAPOL1 high risk genotypesESKD15-2930-5960-89>90a b cFigure 1. Distribution of eGFR in participants stratified by GSTM1 genotype, overall (a) and in those with APOL1 low-risk (b) and high-risk (c)genotypes.RESEARCH LETTERassociated with reduced odds of albuminuria (Table 1).There was no significant interaction between GSTM1genotype and APOL1 status for most kidney outcomes.When participants were stratified by APOL1 status(Supplementary Table S2), GSTM1 inactive genotypesin those with APOL1 low-risk genotypes were associ-ated with reduced odds of eGFR <60 ml/min per 1.73m2 (odds ratio 0.65 [95% CI 0.49–0.87]) and albumin-uria (odds ratio 0.77 [0.61–0.99]). In those with APOL1high-risk genotypes, GSTM1 inactive genotypes werenot associated with eGFR <60 and <90 ml/min per 1.73m2 or stage 5 CKD.In contrast to some existing evidence in Blackpopulations with impaired kidney function,3,4 andconsistent with recent data in people with HIV fromthe Eastern Congo,7 we found no evidence for anincreased risk of kidney disease in individuals withGSTM1 inactive genotypes. In addition, we foundno evidence that GSTM1 inactive genotypes amplifythe deleterious effect of the APOL1 high-riskgenotypes.Table 1. Associations between GSTM1 status (inactive vs. active) and reKidney outcomes Stratification by APOL1 status ORStage 5 CKD All 0.86APOL1 HRG 1.06APOL1 LRG 0.57eGFR <60 ml/min per 1.73 m2 All 0.81APOL1 HRG 1.19APOL1 LRG 0.65eGFR <90 ml/min per 1.73 m2 All 0.87APOL1 HRG 1.35APOL1 LRG 0.81uACR >3 mg/mmol All 0.78APOL1 HRG 0.82APOL1 LRG 0.77uPCR >50 mg/mmol All 0.81APOL1 HRG 0.66APOL1 LRG 0.84CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HRG, high-risk genotyuACR, urine albumin/creatinine ratio; uPCR, urine protein/creatinine ratio.The inactive GSTM1 genotype was defined by carriage of the GSTM1(0) null allele (i.e., GSTM1[1[1/1]). Results from univariable logistic regression analysis.2Data from the African American Study of KidneyDisease and Hypertension revealed an association be-tween GSTM1 inactive genotypes and acceleratedprogression of CKD in a cohort of 692 Black Americanswith hypertensive kidney disease, with worse pro-gression in APOL1 high-risk genotypes.3 Our cohort issubstantially larger than those included in the AfricanAmerican Study of Kidney analyses and differs in thatonly 32% (as compared with all participants in AfricanAmerican Study of Kidney) had a diagnosis of hyper-tension, and that most of our participants had normalkidney function. It is possible that GSTM1 loss isimplicated in the pathogenesis of hypertensive renaldisease but is less significant in other or HIV-associatedpathologies. Alternatively, as oxidative stress isincreased in CKD,8 GSTM1 loss may have had a largerimpact on kidney disease progression in the AfricanAmerican Study of Kidney study. It is possible that thepotential protective effect of GSTM1 becomes impor-tant in declining eGFR and that this association was notcaptured in our cross-sectional study.nal outcomes, overall and stratified by APOL1 status95% CI P valueInteraction between APOL1and GSTM1 genotypes0.55–1.34 0.50 0.190.52–2.19 0.870.31–1.05 0.070.62–1.04 0.10 0.070.67–2.12 0.550.49–0.87 0.0040.73–1.04 0.13 0.100.76–2.37 0.300.68–0.98 0.030.63–0.98 0.04 0.820.43–1.56 0.550.61–0.99 0.040.55–1.18 0.27 0.040.24–1.77 0.410.55–1.27 0.40pe (G1/G1, G1/G2, G2/G2); LRG, low-risk genotype (G0/G0, G1/G0, G2/G0); OR, odds ratio;/0] and GSTM1[0/0]); the GSTM1 active group is homozygous for the active allele (GSTM1Kidney International Reports (2022) -, -–-Murphy, Maurice Murphy); Brighton and SussexUniversity Hospitals, Brighton (Marion Campbell,Amanda Clarke [PI], Celia Richardson, Alyson Knott,Gemma Weir, Rebecca Cleig, Helena Soviarova, LisaBarbour, Tanya Adams, Vicky Kennard, Vittorio Tre-vitt); Chelsea and Westminster Hospital, London(Rachael Jones [PI], Jeremy Levy, Alexandra School-meester, Serah Duro; Guy’s and St Thomas’ Hospital,London (Rachel Hilton [PI], Julie Fox, May Rabuya,Lisa Hamzah, Deborah Jordan, Teresa Solano, HiromiUzu, Karen Williams, Julianne Lwanga, Linda EkaetteReid-Amoruso, Hannah Gamlen, Robert J. Stocker,Fiona Ryan, Anele Waters, Karina Mahiouz, TessCheetham, Claire Williams, Achyuta Nori, CarolineThomas, Sivaraj Venkateshwaran, Jessica Doctor,Andrea Berlanga); King’s College Hospital, London(Frank Post [CI], Beatriz Santana-Suarez, LeighMcQueen, Priya Bhagwandin, Lucy Campbell, BeeBarbini, Emily Wandolo, Tim Appleby, Deborah Jor-dan, Lois Driver, Sophy Parr, Hongbo Deng, JulieBarber, Andrew Crowe, Chris Taylor, Mary Poulton,Vida Boateng, Marie-Pierre Klein, Caitlin O’Brien,Samuel Ohene-Adomako, Christian Buckingham, DanielTrotman, Killian Quinn, Kate Flanagan, Verity Sullivan,Holly Middleditch, Itty Samuel, Elizabeth Hamlyn,Candice McDonald, Ana Canoso, Emeka Agbasi, MariaLiskova, Sarah Barber, Amanda Samarawickrama, ZoeOttaway, Claire Norcross, Amelia Oliveira, Kate Bram-ham); Leeds Teaching Hospitals NHS Trust, Leeds (JaneMinton [PI], Gary Lamont, Ruby Cross, GaushiyaSaiyad, Shadia Ahmed, Rebecca Ashworth, NicolaWindow, J Murira, Khine Phyu); North ManchesterGeneral Hospital, Manchester (Andrew Ustianowski[PI], Gabriella Lindergard, Jonathan Shaw, SarahHolland, Claire Fox, Jan Flaherty, Margaret-AnneBevan, Valerie George); South Tees Hospitals NHSFoundation Trust, Middlesbrough (David Chadwick[PI], Marie Branch, Pauline Lambert, Adele Craggs);Mortimer Market Centre, Central and NorthWestLondon NHS Foundation Trust, London (Sarah Pett[PI], Hinal Lukha, Nina Vora, Marzia Fiorino, MariaMuller Nunez, Deirdre Sally, James E. Burns, EricaPool, Rebecca Matthews); Newcastle upon Tyne Hos-pitals, Newcastle (David Ashley Price [PI], Tara Sto-thard, Bijal Patel, Ian McVittie, Ciara Kennedy, UliShwab, Brendan Payne, Sarah Duncan, Jill Dixon,RESEARCH LETTEREvidence from the Atherosclerosis Risk in Commu-nities Study revealed a 66% increased risk of kidneyfailure in both Black and White individuals withGSTM1 inactive genotypes, compared with those withactive genotypes.4 This study included 2254 Blackparticipants with largely normal kidney function (meaneGFR 112 ml/min per 1.73 m2). The increased riskpersisted after adjustment for clinical risk factors,including diabetes and hypertension. No significantassociation was identified, however, between GSTM1allele status and incident CKD. There is evidence tosuggest that the protective, antioxidant effects ofGSTM1 are of greater importance in a uremic envi-ronment (i.e., at lower GFR), and this may account forthe disparity between risk of incident CKD and kidneyfailure in this cohort.8 However, a large study byZhang et al.9 also failed to reveal an association betweenGSTM1 loss and kidney failure in either Black (n ¼ 796)or White participants (n ¼ 46,187).Our study comprises the largest cohort of Blackparticipants in which the association between GSTM1status and CKD has been explored; the GSTM1groups were indistinguishable in terms of HIV pa-rameters and relevant comorbidities, such as hyper-tension and diabetes, and APOL1 renal risk status.This is also the largest study in which the associationbetween GSTM1 status and kidney outcomes strati-fied by APOL1 genotype has been evaluated. Limi-tations include its cross-sectional study design, thepositive HIV status of all participants which maypreclude extrapolation to non-HIV populations, andthe modest numbers of participants with the GSTM1active genotypes and high-risk APOL1 genotypes,which may have rendered the study underpoweredto detect an interaction between deleterious kidneyoutcomes and APOL1 carrier status. In summary, thiscross-sectional study does not support some earlierobservations that GSTM1 inactive genotype is a riskfactor for kidney disease in Black individuals.Furthermore, GSTM1 inactive genotypes in thispopulation do not seem to amplify the deleteriouseffects of the high-risk APOL1 genotype. Furtherstudies in people with HIV are required to investi-gate the role of GSTM1 inactive genotypes in CKDprogression among those with advanced kidney dis-ease and proteinuria.APPENDIXList of GEN-AFRICA GroupGenetic markers of chronic kidney disease in people ofAfrican ancestry with HIV (GEN-AFRICA) StudyGroup Barts Health NHS Trust, London (John Booth[PI], Anele Waters, James Hand, Chris Clarke, SarahMathias Schmid, Adam Evans, Christopher Duncan,Ewan Hunter, Yusri Taha, Natasha Astill); NationalCancer Institute, Frederick, USA (Cheryl Winkler,Elizabeth Binns-Roemer, Victor David); North Mid-dlesex University Hospital, London (Jonathan Ains-worth, Rachel Vincent [PI]); Queen Elizabeth Hospital,Woolwich (Stephen Kegg [PI], Chloe Saad, SarahSkinner, Hocine Azzoug, Judith Russell, TarikKidney International Reports (2022) -, -–- 3Moussaoui, Celia Richardson, Emily Mabonga, DonnaWard, J. Francoise, W. Larbi, Sue Mitchell, A. Mann-ing, V. Russell); Royal Free London Hospital, London(Fiona Burns [PI], Mark Harber, Nnenna Ngwu, Jona-than Edwards, Nargis Hemat, Tom Fernandez, FilippoFerro, Jorge Ferreira, Alice Nightingale, Tasha Oakes-Monger, Darwin Matila, Pedro Nogueira, VictoriaMutagwanya); St. Georges University Hospitals, Lon-don (Catherine Cosgrove [PI], Lisa Hamzah, CatherineEmily Isitt, Helen Webb, Joyce Popoola, Kate Korley,Mark Mencias, Patricia Ribeiro, Rajeshwar Ramkhe-lawn, Sandra Oliva Lara, Sara Sajijad); Imperial CollegeHealthcare NHS Trust, London (Alan Winston [PI],Jeremy Levy, Amber Shaw, Claire Petersen, Kyle Ring);University Hospital Lewisham, London (MelanieRosenvinge [PI], Chloe Saad, Sarah Skinner, ThembiMoyo, Faith Odong, Katherine Gantert, Tina Ibe); Af-rica Advocacy Foundation (Denis Onyango); UK CHICcohort (Caroline Sabin [PI], Teresa Hill).DISCLOSUREAll the authors declared no competing interests.RESEARCH LETTERACKNOWLEDGMENTSThe authors thank the study participants and all membersof the GEN-AFRICA study group (Appendix). This studywas supported by the Medical Research Council (UnitedKingdom) Confidence in Concept scheme (MC_PC_17164)and in part by the National Institutes of Health and theNational Cancer Institute Intramural Research Program(CAW) and under contract HHSN26120080001E. The con-tent of this publication does not necessarily reflect the viewor policy of the Department of Health and Human Services,nor does mention of trade names, commercial products ororganizations imply endorsement by the government.AUTHOR CONTRIBUTIONSThe study was designed by CAW and FAP. JWB, RH, JF,FB, AU, CC, LH, JEB, AC, DC, DAP, SK, LC, and FAP weresite (principal) investigators and coordinated recruitmentand data collection at their sites. EBR performed the gen-otyping, and RKYH performed the analyses. RKYH, KLR,KB, CAW, and FAP interpreted the findings. KLR wrote thefirst draft of the manuscript with input from RKYH, KB,CAW, and FAP. All authors contributed to and approvedthe final version of the manuscript.4SUPPLEMENTARY MATERIALSupplementary File (PDF)Supplementary Methods.Supplementary References.Figure S1. Distribution of eGFR in participants stratified byGSTM1 copy number, overall (a) and in those with APOL1low-risk (b) and high-risk (c) genotypes.Table S1. Characteristics of study participants stratified byGSTM1 status.Table S2. Characteristics of study participants stratified byAPOL1 and GSTM1 status.REFERENCES1. Duni A, Liakopoulos V, Roumeliotis S, et al. Oxidative stress inthe pathogenesis and evolution of chronic kidney disease:untangling Ariadne’s thread. Int J Mol Sci. 2019;20. https://doi.org/10.3390/ijms201537112. Bodonyi-Kovacs G, Ma JZ, Chang J, et al. Combined effects ofGSTM1 null allele and APOL1 renal risk alleles in CKD pro-gression in the African American study of kidney disease andhypertension trial. J Am Soc Nephrol. 2016;27:3140–3152.https://doi.org/10.1681/ASN.20150504873. Chang J, Ma JZ, Zeng Q, et al. Loss of GSTM1, a NRF2 target,is associated with accelerated progression of hypertensivekidney disease in the African American Study of Kidney Dis-ease (AASK). Am J Physiol Ren Physiol. 2013;304:F348–F355.https://doi.org/10.1152/ajprenal.00568.20124. Tin A, Scharpf R, Estrella MM, et al. The loss of GSTM1 asso-ciates with kidney failure and heart failure. J Am Soc Nephrol.2017;28:3345–3352. https://doi.org/10.1681/ASN.20170302285. Hung RKY, Santana-Suarez B, Binns-Roemer E, et al. Theepidemiology of kidney disease in people of African ancestrywith HIV in the UK. EClinicalMedicine. 2021;38:101006. https://doi.org/10.1016/j.eclinm.2021.1010066. Hung RKY, Binns-Roemer E, Booth JW, et al. Genetic variantsof apolipoprotein L1 are major determinants of kidney failurein people with HIV of African ancestry. Kidney Int Rep. 2022;7:786–796. https://doi.org/10.1016/j.ekir.2022.01.10547. Masimango MI, Jadoul M, Binns-Roemer EA, et al. APOL1renal risk variants and sickle cell trait associations withreduced kidney function in a large Congolese population-based study. Kidney Int Rep. 2022;7:474–482. https://doi.org/10.1016/j.ekir.2021.09.0188. Jerotic D, Suvakov S, Matic M, et al. GSTM1 modulatesexpression of endothelial adhesion molecules in uremicmilieu. Oxid Med Cell Longev. 2021;2021:6678924. https://doi.org/10.1155/2021/66789249. Zhang Y, Zafar W, Hartzel DN, et al. GSTM1 copy number isnot associated with risk of kidney failure in a large cohort.Front Genet. 2019;10:765. https://doi.org/10.3389/fgene.2019.00765Kidney International Reports (2022) -, -–-

GSTM1 Copy Number and Kidney Disease in People With HIV

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GSTM1 Copy Number and Kidney Disease in People With HIV

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