GSTM1 Copy Number and Kidney Disease in People With HIV
2022; Elsevier BV; Volume: 7; Issue: 8 Linguagem: Inglês
10.1016/j.ekir.2022.05.003
ISSN2468-0249
AutoresRachel Hung, Kerry-Lee Rosenberg, Victor A. David, Elizabeth Binns-Roemer, John Booth, Rachel Hilton, Julie Fox, Fiona Burns, Andrew Ustianowski, Catherine Cosgrove, Lisa Hamzah, James E. Burns, Amanda Clarke, David Chadwick, Ashley Price, Stephen Kegg, Lucy Campbell, Kate Bramham, Caroline Sabin, Frank A. Post, Cheryl A. Winkler, Anele Waters, James Hand, Chris Clarke, Sarah Murphy, Maurice Murphy, Marion Campbell, Celia Richardson, Alyson Knott, Gemma Weir, Rebecca Cleig, Helena Soviarova, Lisa Barbour, Tanya Adams, Vicky Kennard, Vittorio Trevitt, Rachael Jones, Jeremy Levy, Alexandra Schoolmeester, Serah Duro, May Rabuya, Deborah Jordan, Teresa Solano, Hiromi Uzu, Karen Williams, Julianne Lwanga, Linda Ekaette Reid-Amoruso, Hannah Gamlen, Robert J. Stocker, Fiona Ryan, Anele Waters, Karina Mahiouz, Tess Cheetham, Claire Williams, Achyuta Nori, Caroline Thomas, Sivaraj Venkateshwaran, Jessica Doctor, Andrea Berlanga, Beatriz Santana-Suarez, Leigh McQueen, Priya Bhagwandin, Bee Barbini, Emily Wandolo, Tim Appleby, Deborah Jordan, Lois Driver, Sophy Parr, Hongbo Deng, Julie Barber, Andrew Crowe, Chris Taylor, M Poulton, Vida Boateng, Marie-Pierre Klein, Caitlin E. O’Brien, Samuel Ohene-Adomako, Christian Buckingham, Daniel Trotman, Killian Quinn, Kate Flanagan, Verity Sullivan, Holly Middleditch, Itty Samuel, Elizabeth Hamlyn, Candice McDonald, Ana Canoso, Emeka Agbasi, Maria Liskova, Sarah Barber, Amanda Samarawickrama, Zoë Ottaway, Claire Norcross, Amelia Oliveira, Jane Minton, G Lamont, Ruby Cross, Gaushiya Saiyad, Shadia Ahmed, Rebecca Ashworth, Nicola Window, Jennifer Murira, Khine Phyu, Gabriella Lindergard, Jonathan Shaw, Sarah Holland, Julie Fox, Jan Flaherty, Margaret-Anne Bevan, Valérie George, Marie Branch, Pauline Lambert, Adele Craggs, Sarah Pett, Hinal Lukha, Nina Vora, Marzia Fiorino, Maria Muller Nunez, Deirdre Sally, Erica Pool, Rebecca Matthews, Tara Stothard, Bijal Patel, Ian McVittie, Ciara Kennedy, Uli Shwab, Brendan Payne, Sarah Duncan, Jill Dixon, Mathias Schmid, Adam Evans, C.J. Duncan, Ewan Hunter, Yusri Taha, Natasha Astill, Jonathan Ainsworth, Rachel Vincent, Chloe Saad, Sarah Skinner, Hocine Azzoug, Judith Russell, Tarik Moussaoui, Celia Richardson, Emily Mabonga, Donna Ward, J. Francoise, W. Larbi, Sue Mitchell, Alex Manning, V. Russell, Mark Harber, Nnenna Ngwu, Jonathan Edwards, Nargis Hemat, Tom Fernandez, Filippo Maria Ferro, Jorge Ferreira, Alice Nightingale, Tasha Oakes-Monger, Darwin Matila, Pedro Nogueira, Victoria Mutagwanya, Catherine Isitt, Helen Webb, Joyce Popoola, Kate Korley, Mark Mencias, Patricia Ribeiro, Rajeshwar Ramkhelawn, Sandra Oliva Lara, Sara Sajijad, Alan Winston, Jeremy Levy, Amber Shaw, Claire Petersen, Kyle Ring, Melanie Rosenvinge, Chloe Saad, Sarah Skinner, Thembi Moyo, Faith Odong, Katherine Gantert, Tina Ibe, Denis Onyango, Teresa Hill,
Tópico(s)Dialysis and Renal Disease Management
ResumoOxidative stress has been implicated in the pathogenesis and progression of chronic kidney disease (CKD). An imbalance between increased production of reactive oxygen species and reduced antioxidant defenses results in disruption to downstream cellular signaling and subsequent renal cell apoptosis and senescence, fibrosis, and vascular injury.1Duni A. Liakopoulos V. Roumeliotis S. et al.Oxidative stress in the pathogenesis and evolution of chronic kidney disease: untangling Ariadne's thread.Int J Mol Sci. 2019; 20https://doi.org/10.3390/ijms20153711Crossref PubMed Scopus (109) Google Scholar Genetic variants that improve the capacity to mitigate oxidative stress may therefore be protective against the development of CKD. The glutathione-S-transferases play a role in the conjugation of prooxidant species with glutathione to facilitate the elimination of reactive oxygen species. GSTM1 is the gene encoding one such isoenzyme. This gene copy number has undergone gene deletion and expansion so chromosomes have no copies, 1 copy or, in rare cases, 2 copies of the gene. Two copies of the active allele are required for enzymatic activity (haploinsufficiency); those homozygous for the null allele, GSTM1(0), completely lack enzyme production. Individuals with the inactive GSTM1 genotypes (GSTM1 0/0 or 1/0) have been found to be at higher risk of common malignancies, atherosclerosis, coronary heart disease, and CKD progression.S1,S2 This study sought to investigate the relationship between GSTM1 genotype and prevalent CKD and the interaction between GSTM1 and APOL1 carrier status,2Bodonyi-Kovacs G. Ma J.Z. Chang J. et al.Combined effects of GSTM1 null allele and APOL1 renal risk alleles in CKD progression in the African American study of kidney disease and hypertension trial.J Am Soc Nephrol. 2016; 27: 3140-3152https://doi.org/10.1681/ASN.2015050487Crossref PubMed Scopus (24) Google Scholar, 3Chang J. Ma J.Z. Zeng Q. et al.Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK).Am J Physiol Ren Physiol. 2013; 304: F348-F355https://doi.org/10.1152/ajprenal.00568.2012Crossref PubMed Scopus (42) Google Scholar, 4Tin A. Scharpf R. Estrella M.M. et al.The loss of GSTM1 associates with kidney failure and heart failure.J Am Soc Nephrol. 2017; 28: 3345-3352https://doi.org/10.1681/ASN.2017030228Crossref PubMed Scopus (24) Google Scholar in a cohort of Black people with HIV in the United Kingdom.5Hung R.K.Y. Santana-Suarez B. Binns-Roemer E. et al.The epidemiology of kidney disease in people of African ancestry with HIV in the UK.EClinicalMedicine. 2021; 38: 101006https://doi.org/10.1016/j.eclinm.2021.101006Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar,6Hung R.K.Y. Binns-Roemer E. Booth J.W. et al.Genetic variants of apolipoprotein L1 are major determinants of kidney failure in people with HIV of African ancestry.Kidney Int Rep. 2022; 7: 786-796https://doi.org/10.1016/j.ekir.2022.01.1054Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Characteristics of the 2762 participants are summarized in Supplementary Table S1. Of these, 2075 (75.1%) had GSTM1 inactive genotypes whereas 687 (24.9%) carried 2 or 3 copies (active genotypes). The mean age of the participants was 48 years, and 57% were female. Most participants were established on antiretroviral treatment with suppressed HIV RNA levels; HIV parameters, hepatitis coinfection status, and prevalence of hypertension, diabetes, and cardiovascular disease did not differ by GSTM1 status. Kidney function (estimated glomerular filtration rate [eGFR]) and the prevalence of APOL1 risk variants and sickle cell trait were similar for the 2 GSTM1 groups (Figure 1a–c and Supplementary Figure S1). In the overall study population, GSTM1 inactive genotypes were not associated with an increased risk of kidney disease (eGFR <60 or <90 ml/min per 1.73 m2 or stage 5 CKD), whereas these genotypes were associated with reduced odds of albuminuria (Table 1). There was no significant interaction between GSTM1 genotype and APOL1 status for most kidney outcomes. When participants were stratified by APOL1 status (Supplementary Table S2), GSTM1 inactive genotypes in those with APOL1 low-risk genotypes were associated with reduced odds of eGFR <60 ml/min per 1.73 m2 (odds ratio 0.65 [95% CI 0.49–0.87]) and albuminuria (odds ratio 0.77 [0.61–0.99]). In those with APOL1 high-risk genotypes, GSTM1 inactive genotypes were not associated with eGFR <60 and <90 ml/min per 1.73 m2 or stage 5 CKD.Table 1Associations between GSTM1 status (inactive vs. active) and renal outcomes, overall and stratified by APOL1 statusKidney outcomesStratification by APOL1 statusOR95% CIP valueInteraction between APOL1 and GSTM1 genotypesStage 5 CKDAll0.860.55–1.340.500.19APOL1 HRG1.060.52–2.190.87APOL1 LRG0.570.31–1.050.07eGFR <60 ml/min per 1.73 m2All0.810.62–1.040.100.07APOL1 HRG1.190.67–2.120.55APOL1 LRG0.650.49–0.870.004eGFR 3 mg/mmolAll0.780.63–0.980.040.82APOL1 HRG0.820.43–1.560.55APOL1 LRG0.770.61–0.990.04uPCR >50 mg/mmolAll0.810.55–1.180.270.04APOL1 HRG0.660.24–1.770.41APOL1 LRG0.840.55–1.270.40CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HRG, high-risk genotype (G1/G1, G1/G2, G2/G2); LRG, low-risk genotype (G0/G0, G1/G0, G2/G0); OR, odds ratio; uACR, 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[1/0] and GSTM1[0/0]); the GSTM1 active group is homozygous for the active allele (GSTM1[1/1]). Results from univariable logistic regression analysis. Open table in a new tab CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HRG, high-risk genotype (G1/G1, G1/G2, G2/G2); LRG, low-risk genotype (G0/G0, G1/G0, G2/G0); OR, odds ratio; uACR, 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[1/0] and GSTM1[0/0]); the GSTM1 active group is homozygous for the active allele (GSTM1[1/1]). Results from univariable logistic regression analysis. In contrast to some existing evidence in Black populations with impaired kidney function,3Chang J. Ma J.Z. Zeng Q. et al.Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK).Am J Physiol Ren Physiol. 2013; 304: F348-F355https://doi.org/10.1152/ajprenal.00568.2012Crossref PubMed Scopus (42) Google Scholar,4Tin A. Scharpf R. Estrella M.M. et al.The loss of GSTM1 associates with kidney failure and heart failure.J Am Soc Nephrol. 2017; 28: 3345-3352https://doi.org/10.1681/ASN.2017030228Crossref PubMed Scopus (24) Google Scholar and consistent with recent data in people with HIV from the Eastern Congo,7Masimango M.I. Jadoul M. Binns-Roemer E.A. et al.APOL1 renal risk variants and sickle cell trait associations with reduced kidney function in a large Congolese population-based study.Kidney Int Rep. 2022; 7: 474-482https://doi.org/10.1016/j.ekir.2021.09.018Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar we found no evidence for an increased risk of kidney disease in individuals with GSTM1 inactive genotypes. In addition, we found no evidence that GSTM1 inactive genotypes amplify the deleterious effect of the APOL1 high-risk genotypes. Data from the African American Study of Kidney Disease and Hypertension revealed an association between GSTM1 inactive genotypes and accelerated progression of CKD in a cohort of 692 Black Americans with hypertensive kidney disease, with worse progression in APOL1 high-risk genotypes.3Chang J. Ma J.Z. Zeng Q. et al.Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK).Am J Physiol Ren Physiol. 2013; 304: F348-F355https://doi.org/10.1152/ajprenal.00568.2012Crossref PubMed Scopus (42) Google Scholar Our cohort is substantially larger than those included in the African American Study of Kidney analyses and differs in that only 32% (as compared with all participants in African American Study of Kidney) had a diagnosis of hypertension, and that most of our participants had normal kidney function. It is possible that GSTM1 loss is implicated in the pathogenesis of hypertensive renal disease but is less significant in other or HIV-associated pathologies. Alternatively, as oxidative stress is increased in CKD,8Jerotic D. Suvakov S. Matic M. et al.GSTM1 modulates expression of endothelial adhesion molecules in uremic milieu.Oxid Med Cell Longev. 2021; 2021: 6678924https://doi.org/10.1155/2021/6678924Crossref PubMed Scopus (3) Google Scholar GSTM1 loss may have had a larger impact on kidney disease progression in the African American Study of Kidney study. It is possible that the potential protective effect of GSTM1 becomes important in declining eGFR and that this association was not captured in our cross-sectional study. Evidence from the Atherosclerosis Risk in Communities Study revealed a 66% increased risk of kidney failure in both Black and White individuals with GSTM1 inactive genotypes, compared with those with active genotypes.4Tin A. Scharpf R. Estrella M.M. et al.The loss of GSTM1 associates with kidney failure and heart failure.J Am Soc Nephrol. 2017; 28: 3345-3352https://doi.org/10.1681/ASN.2017030228Crossref PubMed Scopus (24) Google Scholar This study included 2254 Black participants with largely normal kidney function (mean eGFR 112 ml/min per 1.73 m2). The increased risk persisted after adjustment for clinical risk factors, including diabetes and hypertension. No significant association was identified, however, between GSTM1 allele status and incident CKD. There is evidence to suggest that the protective, antioxidant effects of GSTM1 are of greater importance in a uremic environment (i.e., at lower GFR), and this may account for the disparity between risk of incident CKD and kidney failure in this cohort.8Jerotic D. Suvakov S. Matic M. et al.GSTM1 modulates expression of endothelial adhesion molecules in uremic milieu.Oxid Med Cell Longev. 2021; 2021: 6678924https://doi.org/10.1155/2021/6678924Crossref PubMed Scopus (3) Google Scholar However, a large study by Zhang et al.9Zhang Y. Zafar W. Hartzel D.N. et al.GSTM1 copy number is not associated with risk of kidney failure in a large cohort.Front Genet. 2019; 10: 765https://doi.org/10.3389/fgene.2019.00765Crossref PubMed Scopus (2) Google Scholar also failed to reveal an association between GSTM1 loss and kidney failure in either Black (n = 796) or White participants (n = 46,187). Our study comprises the largest cohort of Black participants in which the association between GSTM1 status and CKD has been explored; the GSTM1 groups were indistinguishable in terms of HIV parameters and relevant comorbidities, such as hypertension and diabetes, and APOL1 renal risk status. This is also the largest study in which the association between GSTM1 status and kidney outcomes stratified by APOL1 genotype has been evaluated. Limitations include its cross-sectional study design, the positive HIV status of all participants which may preclude extrapolation to non-HIV populations, and the modest numbers of participants with the GSTM1 active genotypes and high-risk APOL1 genotypes, which may have rendered the study underpowered to detect an interaction between deleterious kidney outcomes and APOL1 carrier status. In summary, this cross-sectional study does not support some earlier observations that GSTM1 inactive genotype is a risk factor for kidney disease in Black individuals. Furthermore, GSTM1 inactive genotypes in this population do not seem to amplify the deleterious effects of the high-risk APOL1 genotype. Further studies in people with HIV are required to investigate the role of GSTM1 inactive genotypes in CKD progression among those with advanced kidney disease and proteinuria. The authors thank the study participants and all members of the GEN-AFRICA study group (Appendix). This study was supported by the Medical Research Council (United Kingdom) Confidence in Concept scheme (MC_PC_17164) and in part by the National Institutes of Health and the National Cancer Institute Intramural Research Program (CAW) and under contract HHSN26120080001E. The content of this publication does not necessarily reflect the view or policy of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the government. The study was designed by CAW and FAP. JWB, RH, JF, FB, AU, CC, LH, JEB, AC, DC, DAP, SK, LC, and FAP were site (principal) investigators and coordinated recruitment and data collection at their sites. EBR performed the genotyping, and RKYH performed the analyses. RKYH, KLR, KB, CAW, and FAP interpreted the findings. KLR wrote the first draft of the manuscript with input from RKYH, KB, CAW, and FAP. All authors contributed to and approved the final version of the manuscript. Download .pdf (.32 MB) Help with pdf files Supplementary File (PDF) Supplementary Methods. Supplementary References. Figure S1. Distribution of eGFR in participants stratified by GSTM1 copy number, overall (a) and in those with APOL1 low-risk (b) and high-risk (c) genotypes. Table S1. Characteristics of study participants stratified by GSTM1 status. Table S2. Characteristics of study participants stratified by APOL1 and GSTM1 status. Genetic markers of chronic kidney disease in people of African ancestry with HIV (GEN-AFRICA) Study Group Barts Health NHS Trust, London (John Booth [PI], Anele Waters, James Hand, Chris Clarke, Sarah Murphy, Maurice Murphy); Brighton and Sussex University Hospitals, Brighton (Marion Campbell, Amanda Clarke [PI], Celia Richardson, Alyson Knott, Gemma Weir, Rebecca Cleig, Helena Soviarova, Lisa Barbour, Tanya Adams, Vicky Kennard, Vittorio Trevitt); Chelsea and Westminster Hospital, London (Rachael Jones [PI], Jeremy Levy, Alexandra Schoolmeester, Serah Duro; Guy's and St Thomas' Hospital, London (Rachel Hilton [PI], Julie Fox, May Rabuya, Lisa Hamzah, Deborah Jordan, Teresa Solano, Hiromi Uzu, Karen Williams, Julianne Lwanga, Linda Ekaette Reid-Amoruso, Hannah Gamlen, Robert J. Stocker, Fiona Ryan, Anele Waters, Karina Mahiouz, Tess Cheetham, Claire Williams, Achyuta Nori, Caroline Thomas, Sivaraj Venkateshwaran, Jessica Doctor, Andrea Berlanga); King's College Hospital, London (Frank Post [CI], Beatriz Santana-Suarez, Leigh McQueen, Priya Bhagwandin, Lucy Campbell, Bee Barbini, Emily Wandolo, Tim Appleby, Deborah Jordan, Lois Driver, Sophy Parr, Hongbo Deng, Julie Barber, Andrew Crowe, Chris Taylor, Mary Poulton, Vida Boateng, Marie-Pierre Klein, Caitlin O'Brien, Samuel Ohene-Adomako, Christian Buckingham, Daniel Trotman, Killian Quinn, Kate Flanagan, Verity Sullivan, Holly Middleditch, Itty Samuel, Elizabeth Hamlyn, Candice McDonald, Ana Canoso, Emeka Agbasi, Maria Liskova, Sarah Barber, Amanda Samarawickrama, Zoe Ottaway, Claire Norcross, Amelia Oliveira, Kate Bramham); Leeds Teaching Hospitals NHS Trust, Leeds (Jane Minton [PI], Gary Lamont, Ruby Cross, Gaushiya Saiyad, Shadia Ahmed, Rebecca Ashworth, Nicola Window, J Murira, Khine Phyu); North Manchester General Hospital, Manchester (Andrew Ustianowski [PI], Gabriella Lindergard, Jonathan Shaw, Sarah Holland, Claire Fox, Jan Flaherty, Margaret-Anne Bevan, Valerie George); South Tees Hospitals NHS Foundation Trust, Middlesbrough (David Chadwick [PI], Marie Branch, Pauline Lambert, Adele Craggs); Mortimer Market Centre, Central and NorthWest London NHS Foundation Trust, London (Sarah Pett [PI], Hinal Lukha, Nina Vora, Marzia Fiorino, Maria Muller Nunez, Deirdre Sally, James E. Burns, Erica Pool, Rebecca Matthews); Newcastle upon Tyne Hospitals, Newcastle (David Ashley Price [PI], Tara Stothard, Bijal Patel, Ian McVittie, Ciara Kennedy, Uli Shwab, Brendan Payne, Sarah Duncan, Jill Dixon, Mathias Schmid, Adam Evans, Christopher Duncan, Ewan Hunter, Yusri Taha, Natasha Astill); National Cancer Institute, Frederick, USA (Cheryl Winkler, Elizabeth Binns-Roemer, Victor David); North Middlesex University Hospital, London (Jonathan Ainsworth, Rachel Vincent [PI]); Queen Elizabeth Hospital, Woolwich (Stephen Kegg [PI], Chloe Saad, Sarah Skinner, Hocine Azzoug, Judith Russell, Tarik Moussaoui, Celia Richardson, Emily Mabonga, Donna Ward, J. Francoise, W. Larbi, Sue Mitchell, A. Manning, V. Russell); Royal Free London Hospital, London (Fiona Burns [PI], Mark Harber, Nnenna Ngwu, Jonathan Edwards, Nargis Hemat, Tom Fernandez, Filippo Ferro, Jorge Ferreira, Alice Nightingale, Tasha Oakes-Monger, Darwin Matila, Pedro Nogueira, Victoria Mutagwanya); St. Georges University Hospitals, London (Catherine Cosgrove [PI], Lisa Hamzah, Catherine Emily Isitt, Helen Webb, Joyce Popoola, Kate Korley, Mark Mencias, Patricia Ribeiro, Rajeshwar Ramkhelawn, Sandra Oliva Lara, Sara Sajijad); Imperial College Healthcare NHS Trust, London (Alan Winston [PI], Jeremy Levy, Amber Shaw, Claire Petersen, Kyle Ring); University Hospital Lewisham, London (Melanie Rosenvinge [PI], Chloe Saad, Sarah Skinner, Thembi Moyo, Faith Odong, Katherine Gantert, Tina Ibe); Africa Advocacy Foundation (Denis Onyango); UK CHIC cohort (Caroline Sabin [PI], Teresa Hill). All the authors declared no competing interests.
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