Genetic Variants of APOL1 Are Major Determinants of Kidney Failure in People of African Ancestry With HIV

Rachel K Y Hung, Elizabeth Binns-Roemer, John W Booth, Rachel Hilton, Mark Harber, Beatriz Santana-Suarez, Lucy Campbell, Julie Fox, Andrew Ustianowski, Catherine Cosgrove, James E Burns, Amanda Clarke, David A Price, David Chadwick, Denis Onyango, Lisa Hamzah, Kate Bramham, Caroline A Sabin, Cheryl A Winkler, Frank A Post, GEN-AFRICA Study Group, John Booth, Anele Waters, James Hand, Chris Clarke, Sarah Murphy, Maurice Murphy, Marion Campbell, Amanda Clarke, 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, Rachel Hilton, 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, Frank Post, 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, Jane Minton, Gary Lamont, Ruby Cross, Gaushiya Saiyad, Shadia Ahmed, Rebecca Ashworth, Nicola Window, J Murira, Khine Phyu, Andrew Ustianowski, Gabriella Lindergard, Jonathan Shaw, Sarah Holland, Claire Fox, Jan Flaherty, Margaret-Anne Bevan, Valerie George, David Chadwick, Marie Branch, Pauline Lambert, Adele Craggs, Sarah Pett, Hinal Lukha, Nina Vora, Marzia Fiorino, Maria Muller Nunez, Deirdre Sally, James E Burns, Erica Pool, Rebecca Matthews, David Ashley Price, 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, Cheryl Winkler, Elizabeth Binns-Roemer, Victor David, Jonathan Ainsworth, Rachel Vincent, Stephen Kegg, 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, Fiona Burns, 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, Catherine Cosgrove, Lisa Hamzah, Catherine Emily 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, Caroline Sabin, Teresa Hill, Rachel K Y Hung, Elizabeth Binns-Roemer, John W Booth, Rachel Hilton, Mark Harber, Beatriz Santana-Suarez, Lucy Campbell, Julie Fox, Andrew Ustianowski, Catherine Cosgrove, James E Burns, Amanda Clarke, David A Price, David Chadwick, Denis Onyango, Lisa Hamzah, Kate Bramham, Caroline A Sabin, Cheryl A Winkler, Frank A Post, GEN-AFRICA Study Group, John Booth, Anele Waters, James Hand, Chris Clarke, Sarah Murphy, Maurice Murphy, Marion Campbell, Amanda Clarke, 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, Rachel Hilton, 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, Frank Post, 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, Jane Minton, Gary Lamont, Ruby Cross, Gaushiya Saiyad, Shadia Ahmed, Rebecca Ashworth, Nicola Window, J Murira, Khine Phyu, Andrew Ustianowski, Gabriella Lindergard, Jonathan Shaw, Sarah Holland, Claire Fox, Jan Flaherty, Margaret-Anne Bevan, Valerie George, David Chadwick, Marie Branch, Pauline Lambert, Adele Craggs, Sarah Pett, Hinal Lukha, Nina Vora, Marzia Fiorino, Maria Muller Nunez, Deirdre Sally, James E Burns, Erica Pool, Rebecca Matthews, David Ashley Price, 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, Cheryl Winkler, Elizabeth Binns-Roemer, Victor David, Jonathan Ainsworth, Rachel Vincent, Stephen Kegg, 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, Fiona Burns, 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, Catherine Cosgrove, Lisa Hamzah, Catherine Emily 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, Caroline Sabin, Teresa Hill

Abstract

Introduction: Variants of the APOL1 gene are associated with chronic kidney disease (CKD) in people of African ancestry, although evidence for their impact in people with HIV are sparse.

Methods: We conducted a cross-sectional study investigating the association between APOL1 renal risk alleles and kidney disease in people of African ancestry with HIV in the UK. The primary outcome was end-stage kidney disease (ESKD; estimated glomerular filtration rate [eGFR] of <15 ml/min per 1.73 m2, chronic dialysis, or having received a kidney transplant). The secondary outcomes included renal impairment (eGFR <60 ml/min per 1.73 m2), albuminuria (albumin-to-creatinine ratio [ACR] >30 mg/mmol), and biopsy-proven HIV-associated nephropathy (HIVAN). Multivariable logistic regression was used to estimate the associations between APOL1 high-risk genotypes (G1/G1, G1/G2, G2/G2) and kidney disease outcomes.

Results: A total of 2864 participants (mean age 48.1 [SD 10.3], 57.3% female) were genotyped, of whom, 354 (12.4%) had APOL1 high-risk genotypes, and 99 (3.5%) had ESKD. After adjusting for demographic, HIV, and renal risk factors, individuals with APOL1 high-risk genotypes were at increased odds of ESKD (odds ratio [OR] 10.58, 95% CI 6.22-17.99), renal impairment (OR 5.50, 95% CI 3.81-7.95), albuminuria (OR 3.34, 95% CI 2.00-5.56), and HIVAN (OR 30.16, 95% CI 12.48-72.88). An estimated 49% of ESKD was attributable to APOL1 high-risk genotypes.

Conclusion: APOL1 high-risk genotypes were strongly associated with kidney disease in people of African ancestry with HIV and accounted for approximately half of ESKD cases in this cohort.

Keywords: APOL1; Africa; HIV; HIVAN; diaspora; kidney.

© 2022 International Society of Nephrology. Published by Elsevier Inc.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Distribution of APOL1 alleles by region of African ancestry, in (a) all participants and (b) those with ESKD. East, South, Central, and West refer to regions within sub-Saharan Africa; ESKD includes participants with eGFR. Numerical data are shown in Supplementary Table S7. eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease.
Figure 2
Figure 2
Kidney function, kidney pathology and APOL1 genotype. Distribution of (a) eGFR, (b) uPCR, (c) uACR, and (d) cases of HIVAN/FSGS by APOL1 status, and prevalence of APOL1 high-risk genotypes by (e) eGFR, (f) PCR, (g) ACR categories, and (h) HIVAN/FSGS status. eGFR, estimated glomerular filtration rate; FSGS, focal and segmental glomerulosclerosis; HIVAN, HIV-associated nephropathy; RRT, renal replacement therapy; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio.

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