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APOL1 and Cardiovascular Disease

2017; Lippincott Williams & Wilkins; Volume: 37; Issue: 9 Linguagem: Inglês

10.1161/atvbaha.117.309756

1524-4636

Archna Bajaj, Katalin Suszták, Scott M. Damrauer,

Celiac Disease Research and Management

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 37, No. 9APOL1 and Cardiovascular Disease Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAPOL1 and Cardiovascular DiseaseA Story in Evolution Archna Bajaj, Katalin Susztak and Scott M. Damrauer Archna BajajArchna Bajaj From the Division of General Internal Medicine, Department of Medicine (A.B.), Renal Electrolyte and Hypertension Division, Department of Medicine (K.S.), Department of Genetics (K.S.), Division of Vascular Surgery, Department of Surgery (S.M.D.), University of Pennsylvania, Philadelphia; and Department of Surgery, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA (S.M.D.) , Katalin SusztakKatalin Susztak From the Division of General Internal Medicine, Department of Medicine (A.B.), Renal Electrolyte and Hypertension Division, Department of Medicine (K.S.), Department of Genetics (K.S.), Division of Vascular Surgery, Department of Surgery (S.M.D.), University of Pennsylvania, Philadelphia; and Department of Surgery, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA (S.M.D.) and Scott M. DamrauerScott M. Damrauer From the Division of General Internal Medicine, Department of Medicine (A.B.), Renal Electrolyte and Hypertension Division, Department of Medicine (K.S.), Department of Genetics (K.S.), Division of Vascular Surgery, Department of Surgery (S.M.D.), University of Pennsylvania, Philadelphia; and Department of Surgery, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA (S.M.D.) Originally published1 Sep 2017https://doi.org/10.1161/ATVBAHA.117.309756Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37:1587–1589Observational studies have long established that African Americans have a higher risk for developing chronic kidney disease (CKD) with faster progression to end-stage renal disease compared with Americans not of African descent, independent of socioeconomic and traditional clinical risk factors.1–3 But it was not until 2010 that the genetic basis behind this association became more apparent when 2 separate genome-wide association studies identified DNA variants in the APOL1 gene that were strongly associated with kidney disease in blacks.4,5 The story of the APOL1 gene that emerged is a fascinating example of natural selection against infectious disease, and discovery of its link to renal, and possibly cardiovascular, diseases has opened a new field of questions.See accompanying article on page 1765APOL1 encodes for apolipoprotein L-I, a component of dense high-density lipoprotein 3 particles.6 Circulating apolipoprotein L-I has the ability to lyse the parasite Trypanosoma brucei, which is found only in sub-Saharan Africa.7 Over time, 2 subspecies of T. brucei, T. brucei gambiense and T. brucei rhodesiense, evolved resistance by producing a protein that binds and neutralizes apolipoprotein L-I. Subsequently, 2 APOL1 variants (G1 and G2) emerged, producing apolipoprotein L-I with decreased affinity for the trypanosome protein, conferring resistance to African sleeping sickness in carriers of these alleles.8 Although being protected from 1 disease, however, blacks with the APOL1 variant alleles have been shown to be at increased risk for renal disease, as well as a faster progression to end-stage renal disease.9 Individuals that are homozygous for either variant, or compound heterozygotes, have been found to have a 10× to 17× higher odds for focal segmental glomerulosclerosis,5,10 a 7× higher odds for hypertension-associated end-stage renal disease,5 and 29× to 89× higher odds for HIV-associated nephropathy.10,11 Because of the initial natural selection, the prevalence of these variants in the population is significant: ≈40% of blacks carry 1 risk allele whereas 10% to 15% carry 2 risk alleles.5,12,13APOL1 is broadly expressed, including in the kidney and vasculature.14 Although the mechanistic role of APOL1 variants in disease development has yet to be fully elucidated, recent work in mouse models has demonstrated that the expression of APOL1 risk alleles alters podocyte function and results in kidney disease.15Beyond the risk for kidney disease, African Americans are also disproportionately at greater risk for cardiovascular disease (CVD),16 prompting the question of whether or not APOL1 variants underlie this association as well. In this issue of ATVB, Chen et al17 report on the association between the APOL1 risk alleles and CVD outcomes in the AASK (African American Study of Kidney Disease and Hypertension), a well-characterized cohort of individuals with CKD attributed to hypertension. The study's authors compared the 160 AASK participants with 2 APOL1 risk alleles (high-risk) with the 533 who had either 1 or no risk allele (low-risk). Using a broad composite definition of CVD, including cardiovascular death, myocardial infarction, cardiac revascularization, heart failure, and stroke, the authors failed to detect a significant difference in risk for CVD between the high- and low-risk groups in both unadjusted and adjusted models. Arguably, the study by Chen et al17 may have been underpowered to detect an association, and thus, a negative result is difficult to interpret. Based on 693 participants and 144 composite events during 12 years of follow-up, they had 80% power to detect a minimum hazard ratio of 1.85. Although this is within the range of some of the previously reported studies, the divergent nature of the published literature suggests that the true hazard ratio may in fact be below their level of detection. Nonetheless, these results contribute important additional data to our still evolving knowledge of the relationship between APOL1 and CVD.Prior studies on the association of APOL1 variants and CVD outcomes have generated a field of conflicting data. In 2014, Ito et al18 demonstrated that among 1959 black participants in the Jackson Heart Study, individuals with 2 APOL1 high-risk alleles were at twice the risk of incident CVD when compared with those without any risk alleles. The authors then replicated this association in 749 participants of African ancestry and without baseline CKD in the Women's Health Initiative. This was further bolstered by findings from Mukamal et al19 who showed that in >6000 blacks in the Cardiovascular Health Study, participants with high-risk APOL1 genotypes had an 80% greater risk of incident myocardial infarction as compared with those with zero or only 1 risk allele; similar results were also found for peripheral vascular disease, suggesting a broader association between APOL1 and atherosclerosis.In contrast to these initial reports, and in keeping with the work by Chen et al17 presented in this issue, a 2015 study of 2571 black participants from the SPRINT (Systolic Blood Pressure Intervention Trial) failed to demonstrate an association between high-risk APOL1 genotypes and CVD, despite showing a strong association with CKD.20 Similarly, investigators with the ARIC study (Atherosclerosis Risk in Communities) found a strong association between the high-risk APOL1 genotype and end-stage renal disease but failed to demonstrate any association with incident CVD in 3676 black participants.21The discovery of the association of APOL1 variants with CKD was an exciting start to a story that is still unfolding. The question remains as to whether there is a link between APOL1 risk genotypes and CVD and if so, if it is distinct from a pathway to CVD driven by impairment in renal function (Figure). The results reported by Chen et al17 alone do not offer a definitive answer but rather provide one more piece to the puzzle. Given the wealth of data available, a meta-analysis of the existing literature offers a path forward to clarifying the true association between APOL1 and CVD. One of the challenges of assessing the present collection of studies, and in contemplating a meta-analysis, however, is the heterogeneity of outcomes used to define CVD and the range of underlying pathophysiological processes these represent; almost every published study has used a different composite CVD definition. Accordingly, future studies that evaluate APOL1 risk genotypes will need to carefully define outcomes. Electronic health records–based cohorts that allow for detailed phenotyping at a population scale represent a second pathway to elucidating the relationship between APOL1 and CVD. Such cohorts will have the sample sizes large enough to provide the necessary statistical power to detect, or not, associations between APOL1 genotypes and CVD outcomes, which are likely smaller than those seen with renal pathologies; both the current Veterans Affairs Million Veteran Program22 and the developing National Institute of Health's All of Us Research Program23 will be key resources in this area. Discovering the pathways in which APOL1 connects to renal disease and CVD may guide the development of future therapies, preventive measures, and precision medicine in the high-risk black population.Download figureDownload PowerPointFigure. APOL1 risk genotypes are known to associate with chronic kidney disease, dramatically increasing the risk of renal dysfunction. Although kidney disease in general leads to increased rates of cardiovascular disease (CVD) outcomes, the contribution of APOL1 risk genotypes to the latter remains uncertain. Conflicting results have been reported with respect to the relationship between APOL1 risk genotypes and CVD, leaving the question open as to the association of APOL1 risk genotype and CVD.Sources of FundingK. Susztak is supported by N.I.H. R01 DK105821.DisclosuresNone.FootnotesCorrespondence to Scott M. Damrauer, MD, Division of Vascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St, 4 Silverstein Pavilion, Philadelphia, PA 19104. E-mail [email protected]References1. McClellan W, Tuttle E, Issa A. Racial differences in the incidence of hypertensive end-stage renal disease (ESRD) are not entirely explained by differences in the prevalence of hypertension.Am J Kidney Dis. 1988; 12:285–290.CrossrefMedlineGoogle Scholar2. Cowie CC, Port FK, Wolfe RA, Savage PJ, Moll PP, Hawthorne VM. Disparities in incidence of diabetic end-stage renal disease according to race and type of diabetes.N Engl J Med. 1989; 321:1074–1079. doi: 10.1056/NEJM198910193211603.CrossrefMedlineGoogle Scholar3. Lipworth L, Mumma MT, Cavanaugh KL, Edwards TL, Ikizler TA, Tarone RE, McLaughlin JK, Blot WJ. Incidence and predictors of end stage renal disease among low-income blacks and whites.PLoS One. 2012; 7:e48407. doi: 10.1371/journal.pone.0048407.CrossrefMedlineGoogle Scholar4. Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, Bekele E, Bradman N, Wasser WG, Behar DM, Skorecki K. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene.Hum Genet. 2010; 128:345–350. doi: 10.1007/s00439-010-0861-0.CrossrefMedlineGoogle Scholar5. Genovese G, Friedman DJ, Ross MD, et al. 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Weiner DE, Tighiouart H, Amin MG, Stark PC, MacLeod B, Griffith JL, Salem DN, Levey AS, Sarnak MJ. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies.J Am Soc Nephrol. 2004; 15:1307–1315.CrossrefMedlineGoogle Scholar17. Chen TK, Appel LJ, Grams ME, Tin A, Choi MJ, Lipkowitz MS, Winkler CA, Estrella MM. APOL1 risk variants and cardiovascular disease: results from the AASK (African American Study of Kidney Disease and Hypertension).Arterioscler Thromb Vasc Biol. 2017; 37:1765–1769. doi: 10.1161/ATVBAHA.117.309384.LinkGoogle Scholar18. Ito K, Bick AG, Flannick J, et al. Increased burden of cardiovascular disease in carriers of APOL1 genetic variants.Circ Res. 2014; 114:845–850. doi: 10.1161/CIRCRESAHA.114.302347.LinkGoogle Scholar19. Mukamal KJ, Tremaglio J, Friedman DJ, Ix JH, Kuller LH, Tracy RP, Pollak MR. 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A new initiative on precision medicine.N Engl J Med. 2015; 372:793–795. doi: 10.1056/NEJMp1500523.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Guan H, Shi T, Liu M, Wang X and Guo F (2022) C1QL1/CTRP14 Is Largely Dispensable for Atherosclerosis Formation in Apolipoprotein-E-Deficient Mice, Journal of Cardiovascular Development and Disease, 10.3390/jcdd9100341, 9:10, (341) Yang Y, Poudel B, Frederick J, Dhillon P, Shrestha R, Ma Z, Wu J, Okamoto K, Kopp J, Booten S, Gattis D, Watt A, Palmer M, Aghajan M and Susztak K (2022) Antisense oligonucleotides ameliorate kidney dysfunction in podocyte-specific APOL1 risk variant mice, Molecular Therapy, 10.1016/j.ymthe.2022.04.007, 30:7, (2491-2504), Online publication date: 1-Jul-2022. Wu J, Ma Z, Raman A, Beckerman P, Dhillon P, Mukhi D, Palmer M, Chen H, Cohen C, Dunn T, Reilly J, Meyer N, Shashaty M, Arany Z, Haskó G, Laudanski K, Hung A and Susztak K (2021) APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis, Immunity, 10.1016/j.immuni.2021.10.004, 54:11, (2632-2649.e6), Online publication date: 1-Nov-2021. Ronsein G, Vaisar T, Davidson W, Bornfeldt K, Probstfield J, O'Brien K, Zhao X and Heinecke J (2021) Niacin Increases Atherogenic Proteins in High-Density Lipoprotein of Statin-Treated Subjects, Arteriosclerosis, Thrombosis, and Vascular Biology, 41:8, (2330-2341), Online publication date: 1-Aug-2021. Cyrus C, Al-Mueilo S, Vatte C, Chathoth S, Li Y, Qutub H, Al Ali R, Al-Muhanna F, Lanktree M, Alkharsah K, Al-Rubaish A, Kim-Mozeleski B, Keating B and Al Ali A (2018) Assessing known chronic kidney disease associated genetic variants in Saudi Arabian populations, BMC Nephrology, 10.1186/s12882-018-0890-9, 19:1, Online publication date: 1-Dec-2018. Dron J, Lazarte J and Hegele R (2018) Recent Highlights of ATVB, Arteriosclerosis, Thrombosis, and Vascular Biology, 38:11, (e185-e197), Online publication date: 1-Nov-2018. Thiriet M (2018) Cardiovascular Disease: An Introduction Vasculopathies, 10.1007/978-3-319-89315-0_1, (1-90), . September 2017Vol 37, Issue 9 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.117.309756PMID: 28835482 Originally publishedSeptember 1, 2017 Keywordsprevalencerisk factorskidney failure, chronicEditorialscardiovascular diseasesapolipoproteinsPDF download Advertisement