APOL1, Black Race, and Kidney Disease: Turning Attention to Structural Racism

Abstract

The incidence of kidney failure is nearly 3 times higher in Black relative to White Americans.1Saran R. Robinson B. Abbott K.C. et al.US Renal Data System 2018 Annual Data Report: epidemiology of kidney disease in the United States.Am J Kidney Dis. 2019; 73 (3)(suppl 1):A7-A8Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar A significant body of biomedical literature links this racial inequity to polymorphic variation in the gene encoding apolipoprotein L1 (APOL1). In fact, in a PubMed search of “APOL1” and “kidney disease,” 86% of results feature abstracts mentioning African ancestry or African American, Black, or non-White race. Multiple recent articles state that APOL1 genetic variants are found “exclusively” in people, or chromosomes, of “African” origin.2Kopp J.B. Winkler C.A. Genetics, genomics, and precision medicine in end-stage kidney disease.Semin Nephrol. 2018; 38: 317-324Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 3Cheatham A.M. Davis S.E. Khatua A.K. Popik W. Blocking the 5′ splice site of exon 4 by a morpholino oligomer triggers APOL1 protein isoform switch.Sci Rep. 2018; 8: 8739Crossref PubMed Scopus (8) Google Scholar, 4Hughson M.D. Hoy W.E. Mott S.A. Bertram J.F. Winkler C.A. Kopp J.B. APOL1 risk variants independently associated with early cardiovascular disease death.Kidney Int Rep. 2018; 3: 89-98Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Further, an ongoing clinical trial—the APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) study—seeks to examine the relationship between APOL1 genotype and racial disparities in allograft survival and in kidney failure among living kidney donors.5Freedman B.I. Moxey-Mims M.M. Alexander A.A. et al.APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO): design and rationale.Kidney Int Rep. 2020; 5: 278-288Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Such tight coupling of APOL1 variation and Black race lends the impression that racial disparities in kidney disease are genetically determined and homogeneously distributed across persons labeled as “Black,” a misguided hypothesis that can skew investment toward interventions with limited effect. In this editorial, we summarize the current literature on APOL1, discuss the scientific flaws of linking particular APOL1 variants with Black race, and emphasize the role of structural racism as a determinant of racial disparities in kidney disease. Genetic variation on chromosome 22q has been associated with increased susceptibility to focal segmental glomerulosclerosis, HIV-associated nephropathy, and hypertension-attributed kidney failure. In particular, strong signals have been identified in association with 2 nonsynonymous coding variants (for amino acids 342 and 384) of APOL1, termed G1, and with a 6-base-pair deletion that removes 2 amino acids (388-389), termed G2.6Genovese G. Friedman D.J. Ross M.D. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1340) Google Scholar Patterns of linkage disequilibrium in the region of G1 and G2 provide strong evidence for positive selection. In particular, because the APOL1 variants evade activity of the serum resistance–associated protein of T. b. rhodiense—one of the vectors of African sleeping sickness—it is hypothesized that heterozygosity for these alleles confers a selective advantage against the disease.7Thomson R. Genovese G. Canon C. et al.Evolution of the primate trypanolytic factor APOL1.PNAS. 2014; 111: E2130-E2139Crossref PubMed Scopus (152) Google Scholar Furthermore, the presence of these variants in Yoruban populations from Nigeria and in some Black Americans, and their relative scarcity in European and Asian populations, evince the likelihood of a recent selection event in West Africa.6Genovese G. Friedman D.J. Ross M.D. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1340) Google Scholar,8Simino J. Rao D.C. Freedman B.I. Novel findings and future directions on the genetics of hypertension.Curr Opin Nephrol Hypertens. 2012; 21: 500-507Crossref PubMed Scopus (34) Google Scholar Together, these genetic data have led clinical investigators to focus on APOL1 polymorphisms as a key, rather than a contributory, explanatory variable in racial disparities in kidney disease. For instance, in a recent editorial, Kopp and Winkler9Kopp J.B. Winkler C.A. Genetic testing for APOL1 genetic variants in clinical practice: finally starting to arrive.CJASN. 2020; 15: 126-128Crossref PubMed Scopus (11) Google Scholar name “variants in APOL1 as major driver[s] of kidney disease in Blacks” and accordingly discuss recommendations for clinical testing of risk genotypes. This approach, however, is based upon a misapplication of population genetics and exacerbated by conflation of genetic ancestry and race. Race is a social and political construct perpetuated by those in power and should not be used as a substitute for thoughtful, hypothesis-driven genetic analyses.10Tsai J. Cerdeña J.P. Khazanchi R. et al.There is no ‘African American Physiology’: the fallacy of racial essentialism.J Intern Med. 2020; 288: 368-370Crossref PubMed Scopus (12) Google Scholar Human genetic and phenotypic variants, including superficial physical differences like skin color and hair texture, are clinally distributed across geographic space and do not map neatly to races or continents.11American Association of Physical AnthropologistsAAPA statement on race & racism. March 27, 2019.https://physanth.org/about/position-statements/aapa-statement-race-and-racism-2019Google Scholar,12The American Society of Human GeneticsASHG denounces attempts to link genetics and racial supremacy.Am J Hum Genet. 2018; 103: 636Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Researchers may lean on terms like “ancestry,” which imply evolutionary history and may carry biological significance at an individual level of analysis13Yudell M. Roberts D. DeSalle R. Tishkoff S. Taking race out of human genetics.Science. 2016; 351: 564-565Crossref PubMed Scopus (294) Google Scholar,14Bolnick D. Individual ancestry inference and the reification of race as a biological phenomenon.in: Lee S. Koenig B. Richardson S.S. Revisiting Race in a Genomic Age. Rutgers University Press, 2008: 70-85Google Scholar; however, when paired with a wide geographical modifier (ie, “African”), such phrases lose meaning and become little more than a substitute for race. Genetic conclusions cannot be made about the populations of entire continents or entire races; accordingly, discussing APOL1-associated kidney disease as a concern of—and exclusive to—people of “African descent” reflects racist practice in medicine and research,15Cerdeña J.P. Plaisime M.V. Tsai J. From race-based to race-conscious medicine: how anti-racist uprisings call us to act.Lancet. 2020; 396: 1125-1128Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar even if and often done unconsciously. In this section, we identify specific flaws inherent in the logic of associating APOL1 G1 and G2 alleles with Black race and outline potential harms to patients. Sweeping associations between certain APOL1 polymorphisms and Black race risk overlooking the impact of APOL1-associated nephropathy on other populations. Although APOL1 G1 and G2 are most often seen in people of West African descent, other groups—including European American, Pakistani, and Latin American patients—also carry these polymorphisms.16Kopp J.B. Nelson G.W. Sampath K. et al.APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy.J Am Soc Nephrol. 2011; 22: 2129-2137Crossref PubMed Scopus (557) Google Scholar, 17Limou S. Nelson G.W. Kopp J.B. Winkler C.A. APOL1 kidney risk alleles: population genetics and disease associations.Adv Chronic Kidney Dis. 2014; 21: 426-433Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 18Nadkarni G.N. Gignoux C.R. Sorokin E.P. et al.Worldwide frequencies of APOL1 renal risk variants.N Engl J Med. 2018; 379: 2571-2572Crossref PubMed Scopus (41) Google Scholar Even though this is likely owing to admixture, these findings suggest that limiting clinical inquiries about APOL1-associated kidney disease to “Black” patients inappropriately excludes patients of other racial or ethnic backgrounds. The APOLLO study, for instance, only recruits Black kidney donors, restricting insights into the role of the APOL1 genotype on clinical outcomes to an artificially smaller population. Researchers may be reluctant to generalize their findings to White, Asian, and Latinx patients who carry G1 and G2 alleles who would otherwise benefit. Moreover, the frequency of the G1 and G2 alleles varies widely across the African continent. For instance, the frequency of G1 among the Igbo in Nigeria is 30.2% but 0% among the Lemande of Cameroon.17Limou S. Nelson G.W. Kopp J.B. Winkler C.A. APOL1 kidney risk alleles: population genetics and disease associations.Adv Chronic Kidney Dis. 2014; 21: 426-433Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Yet, patients from both of these ethnic groups would be racialized as “Black” in the United States. Additionally, even among genetically similar ethnic groups, significant variation in allelic frequency is evident. Genetic research comparing the genotypes of the Yoruba of Nigeria and the Luhya of Kenya, 2 ethnic groups of high genetic similarity, found that no other sites were as differentiated between the 2 groups as G1. This large variation cannot be explained by genetic drift and instead points to a selection event occurring within a narrowly circumscribed population in West Africa.7Thomson R. Genovese G. Canon C. et al.Evolution of the primate trypanolytic factor APOL1.PNAS. 2014; 111: E2130-E2139Crossref PubMed Scopus (152) Google Scholar Therefore, conclusions about APOL1 polymorphisms cannot be generalized to all residents of the African continent, nor to all individuals of African descent. Because many enslaved Africans were captured from the West African coast during the trans-Atlantic slave trade, Black Americans descended from slaves may be expected to exhibit higher frequencies of G1 and G2. Indeed, current research suggests that over 20% of Black Americans carry 1 of these variants and 13% carry 2.19Dummer P.D. Limou S. Rosenberg A.Z. et al.APOL1 kidney disease risk variants: an evolving landscape.Semin Nephrol. 2015; 35: 222-236Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar However, recent patterns of Black African migration reveal an influx from Northern and Eastern Africa, regions where the G1 and G2 alleles are far less prevalent.20Capps R. McCabe K. Fix M. Diverse Streams: Black African Migration to the United States. Migration Policy Institute, 2012: 1-23https://www.fcd-us.org/assets/2016/04/African-Migration-to-the-United-States.pdfGoogle Scholar Accordingly, given the continued inflow of Black migrants from diverse regions of Africa—and ongoing admixture between descendants of the enslaved with genetically distinct populations—wide heterogeneity in frequency of APOL1 variants among individuals racialized as “Black” may be expected, depending on population sampling. In summary, sweeping attributions of kidney disease risk among Black Americans to particular APOL1 alleles overlook the increasing genetic diversity within this community and others. Incautious conflation of APOL1 genotype and Black race can promote misinformed conclusions that all Black patients experience genetic predisposition toward kidney disease.21Gordon E.J. Amórtegui D. Blancas I. Wicklund C. Friedewald J. Sharp R.R. A focus group study on African American living donors’ treatment preferences, sociocultural factors, and health beliefs about apolipoprotein L1 genetic testing.Prog Transpl. 2019; 29: 239-247Crossref PubMed Scopus (5) Google Scholar This is reflected in the Kidney Donor Risk Index, a tool that includes Black race in its calculation of allograft longevity for donated kidneys. Substitution of APOL1 genotype for race in the equation would improve the Kidney Donor Risk Index for 85% to 90% of Black donors, likely reducing discard of high-demand kidneys.22Julian B.A. Gaston R.S. Brown W.M. et al.Effect of replacing race with apolipoprotein L1 genotype in calculation of kidney donor risk index.Am J Transplant. 2017; 17: 1540-1548Crossref PubMed Scopus (42) Google Scholar Thus, generalizations about Black race and APOL1 G1 and G2 alleles are scientifically inappropriate and contribute to health care waste. Finally, the link between APOL1 polymorphisms and kidney disease is not as straightforward as some research implies. Although possessing 2 “risk” alleles yields an odds ratio of 10.5 and 7.3 for focal segmental glomerulosclerosis and hypertension-attributed kidney failure, respectively,6Genovese G. Friedman D.J. Ross M.D. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1340) Google Scholar the overall lifetime risk is just 4% and 12%. Additionally, possessing 2 “risk” alleles explains just 37%, 18%, and 7% of the variance in risk for HIV-associated nephropathy, focal segmental glomerulosclerosis, and hypertension-attributed kidney failure, respectively,19Dummer P.D. Limou S. Rosenberg A.Z. et al.APOL1 kidney disease risk variants: an evolving landscape.Semin Nephrol. 2015; 35: 222-236Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar while most reports find no association with diabetic nephropathy, the leading cause of kidney disease.17Limou S. Nelson G.W. Kopp J.B. Winkler C.A. APOL1 kidney risk alleles: population genetics and disease associations.Adv Chronic Kidney Dis. 2014; 21: 426-433Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar APOL1 variants account for roughly 30% of the excess nondiabetic kidney disease in Black Americans,23Kaufman J.S. Rushani D. Cooper R.S. Nature versus nurture in the explanations for racial/ethnic health disparities.in: Suzuki K. Von Vacano D.A. Reconsidering Race: Social Science Perspectives on Racial Categories in the Age of Genomics. Oxford University Press, 2018: 120Google Scholar highlighting the importance of environmental factors underpinning racial disparities in kidney disease. Racial groups are not clearly demarcated by patterns of genetic variation; however, in the United States, histories of inequitable distribution of resources along racial lines have systematically created unequal environments and life opportunities between Black and White communities, which differentially impact their health. Structural racism refers to “the totality of ways in which societies foster racial discrimination through mutually reinforcing systems.”24Bailey Z.D. Krieger N. Agénor M. Graves J. Linos N. Bassett M.T. Structural racism and health inequities in the USA: evidence and interventions.Lancet. 2017; 389: 1453-1463Abstract Full Text Full Text PDF PubMed Scopus (1534) Google Scholar Disparities in kidney disease derive from unequal conditions in wealth, employment, residence, toxic environmental exposures, nutrition, education, health care access, and psychosocial stress.25Nicholas S.B. Kalantar-Zadeh K. Norris K.C. 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COVID-19, racism, and racial disparities in kidney disease: galvanizing the kidney community response.JASN. 2020; 31: 1-3Crossref Scopus (19) Google Scholar Mediators of kidney failure—such as diabetes, hypertension, and HIV—can be traced to racialization of the US food system,30Ayazi H. Elsheikh E. The US Farm Bill: Corporate Power and Structural Racialization in the US Food System. UC Berkeley Othering & Belonging Institute. October 28, 2015.https://escholarship.org/uc/item/55v6q06xGoogle Scholar mass incarceration,31Wang E.A. Pletcher M. Lin F. et al.Incarceration, incident hypertension, and access to health care: findings from the Coronary Artery Risk Development in Young Adults (CARDIA) Study.Arch Intern Med. 2009; 169: 687-693Crossref PubMed Scopus (88) Google Scholar and poverty.32Arnold E.A. Rebchook G.M. Kegeles S.M. “Triply cursed”: racism, homophobia and HIV-related stigma are barriers to regular HIV testing, treatment adherence and disclosure among young Black gay men.Cult Health Sex. 2014; 16: 710-722Crossref PubMed Scopus (226) Google Scholar Structural determinants of health thereby deserve at least as many dedicated resources as those afforded to genetic inquiry, yet research and funding streams consistently favor investigation into biological and genetic underpinnings of racial disparities in health over issues of racism or racialization.33Hardeman R.R. Karbeah J. Examining racism in health services research: a disciplinary self-critique.Health Serv Res. 2020; 55: 777-780Crossref PubMed Scopus (55) Google Scholar,34Krieger N. Stormy weather: race, gene expression, and the science of health disparities.Am J Public Health. 2005; 95: 2155-2160Crossref PubMed Scopus (155) Google Scholar In fact, a simple Boolean search of the terms “kidney disease” and “racism” in the National Institutes of Health Research Portfolio Online Reporting Tools Database for 2019 to 2020 yields just 5 results, whereas pairing “kidney disease” with “genetic” yields 754 results.33Hardeman R.R. Karbeah J. Examining racism in health services research: a disciplinary self-critique.Health Serv Res. 2020; 55: 777-780Crossref PubMed Scopus (55) Google Scholar Racism itself can induce multiple physiologic changes involved in the pathogenesis of kidney disease. Chronic stress from interpersonal and structural racism can initiate long-term activation of the hypothalamic-pituitary-adrenal axis, which can constitutively increase vascular tension. Such stress can also lead to failure to downregulate the inflammatory response and increased production of reactive oxygen species, which can promote interstitial fibrosis.25Nicholas S.B. Kalantar-Zadeh K. Norris K.C. Racial disparities in kidney disease outcomes.Semin Nephrol. 2013; 33: 409-415Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Further, epigenetic modifications—such as those resulting through fetal programming when racial discrimination increases prenatal cortisol exposure—may contribute to the excess risk for kidney disease among Black Americans.35Kuzawa C.W. Sweet E. Epigenetics and the embodiment of race: developmental origins of US racial disparities in cardiovascular health.Am J Hum Biol. 2009; 21: 2-15Crossref PubMed Scopus (416) Google Scholar Thus, although race is a poor proxy for population genetics, adverse social conditions experienced by marginalized populations are consistent and powerful contributors to disease risk. Overemphasis on racialized genetics—rather than racism—may result in insufficient examination of structural inequities as major determinants of racial disparities in kidney disease. Future research should examine how racist—and antiracist—policies affect kidney health. Studies can assess the effects of policies like Medicaid expansion,36Sommers B.D. Blendon R.J. Orav E.J. Epstein A.M. Changes in utilization and health among low-income adults after Medicaid expansion or expanded private insurance.JAMA Intern Med. 2016; 176: 1501-1509Crossref PubMed Scopus (317) Google Scholar,37Kurella-Tamura M. Goldstein B.A. Hall Y.N. Mitani A.A. Winkelmayer W.C. State Medicaid coverage, ESRD incidence, and access to care.JASN. 2014; 25: 1321-1329Crossref Scopus (34) Google Scholar decriminalization,38Grucza R.A. Vuolo M. Krauss M.J. et al.Cannabis decriminalization: a study of recent policy change in five U.S. states.Int J Drug Policy. 2018; 59: 67-75Crossref PubMed Scopus (24) Google Scholar or, in the future, reparations39Vigdor N. North Carolina City Approves Reparations for Black Residents. The New York Times. July 16, 2020; section A:15.https://www.nytimes.com/2020/07/16/us/reparations-asheville-nc.htmlGoogle Scholar on kidney health. Racism should be identified and carefully analyzed: Research that merely examines race as a “risk factor”—or provides a genetic basis for racial differences in health outcomes—should be scrupulously critiqued.40Boyd R.W. Lindo E.G. Weeks L.D. McLemore M.R. On Racism: A New Standard For Publishing On Racial Health Inequities. Health Affairs: Health Affairs Blog. July 2, 2020.https://www.healthaffairs.org/do/10.1377/hblog20200630.939347/full/Google Scholar Understanding the effects of policy on health can inform both public and private action, dismantling the oppressive structures that contribute to racial disparities. Carrying 2 APOL1 “risk” alleles significantly increases an individual’s odds of developing kidney disease; however, even with a high-risk genotype, overall lifetime risk remains relatively low and much of the variance in risk is explained by other factors, including structural racism. Although some Black Americans carry high levels of West African ancestry owing to the shameful history of chattel slavery, wide variation in APOL1 “risk” allele frequency is expected among all individuals racialized as “Black.” It is therefore inappropriate to conclude that APOL1 mutations increase risk for kidney disease among all Black Americans or to limit research or testing of APOL1 genotypes to Black individuals: Such determinations may constrain clinical decision making and misdirect resources to the detriment of patients. Decisions regarding APOL1 testing in clinical care should engage key stakeholders, including a diverse group of patients, nephrologists, primary care providers, researchers, and bioethicists, considering opportunities for patient counseling and the need to develop targeted treatments.41Young B.A. Blacksher E. Cavanaugh K.L. et al.Apolipoprotein L1 testing in African Americans: involving the community in policy discussions.Am J Nephrol. 2019; 50: 303-311Crossref PubMed Scopus (14) Google Scholar Finally, since APOL1 polymorphisms cannot fully explain the racial disparities in kidney disease, research that examines how structural racism mediates impairments in kidney function deserves closer attention.