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. 2019 Sep 17;140(12):1031-1040.
doi: 10.1161/CIRCULATIONAHA.118.036589. Epub 2019 Jul 24.

Association of APOL1 Risk Alleles With Cardiovascular Disease in Blacks in the Million Veteran Program

Alexander G Bick  1   2   3 , Elvis Akwo  4   5 , Cassianne Robinson-Cohen  4   5 , Kyung Lee  6 , Julie Lynch  6   7   8 , Themistocles L Assimes  9   10 , Scott DuVall  8 , Todd Edwards  4   5 , Huaying Fang  9   10 , S Matthew Freiberg  4   5 , Ayush Giri  4   5 , Jennifer E Huffman  1 , Jie Huang  1 , Leland Hull  1   6 , Rachel L Kember  11   12 , Derek Klarin  1   2   3 , Jennifer S Lee  9   10 , Michael Levin  11   12 , Donald R Miller  6   13 , Pradeep Natarajan  2   3 , Danish Saleheen  11   12 , Qing Shao  6 , Yan V Sun  14   15 , Hua Tang  9   10 , Otis Wilson  4 , Kyong-Mi Chang  11   12 , Kelly Cho  1 , John Concato  16 , J Michael Gaziano  1   17 , Sekar Kathiresan  2   3   17 , Christopher J O'Donnell  1   17 , Daniel J Rader  11 , Philip S Tsao  9   10 , Peter W Wilson  14   15 , Adriana M Hung  4   5 , Scott M Damrauer  11   12 ; VA Million Veteran Program
Affiliations

Association of APOL1 Risk Alleles With Cardiovascular Disease in Blacks in the Million Veteran Program

Alexander G Bick et al. Circulation. .

Abstract

Background: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (APOL1) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program.

Methods: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association.

Results: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; P=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; P=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; P=0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets.

Conclusions: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

Keywords: apolipoprotein L1; cardiovascular diseases; genetics; renal insufficiency, chronic.

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Conflict of interest statement

Conflict of Interest Disclosures

None

Figures

Figure 1.
Figure 1.. Association of APOL1 and incident CAD, Stroke and PAD.
Kaplan Meier plots depicting disease free survival amongst individuals free of kidney disease at baseline over the 12.5 year follow up period stratified by APOL1 2 risk allele status. Data is censored at last VA clinical encounter or upon developing chronic kidney disease. Inset plots displays the same data on an expanded y-axis. Risk-sum tables for each phenotype are displayed below the x axis. CAD, coronary artery disease; PAD, peripheral artery disease.
Figure 2.
Figure 2.. Association of APOL1 and incident CAD, Stroke and PAD.
Forest plot representing hazard ratios of disease-free survival stratified by APOL1 risk allele carrier status in fully adjusted Cox proportional hazard models. CAD, coronary artery disease; PAD, peripheral artery disease.
Figure 3.
Figure 3.. Cumulative incidence function estimates from competing risks modeling of CAD and CKD/ESRD outcomes.
Test for equality across APOL1 risk allele groups CAD: p=0.56. CKD/ESRD p=5.1 × 10−4. CAD, coronary artery disease; PAD, peripheral artery disease; ESRD, end-stage renal disease
Figure 4.
Figure 4.. Cardiovascular phenome-wide association of APOL1 two risk allele status in individuals free of kidney disease.
Phenome-wide association did not identify any significant cardiovascular disease associations with APOL1. Dashed horizontal line represents experiment wide significant p-value adjusted for 115 cardiovascular phenotypes (p<4 × 10−4). Each triangle represents a subset of CVD disease as defined by ICD-9 codes, colored by cardiovascular disease category.
See this image and copyright information in PMC

References

    1. Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Jordan LC, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, O’Flaherty M, Pandey A, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Spartano NL, Stokes A, Tirschwell DL, Tsao CW, Turakhia MP, VanWagner LB, Wilkins JT, Wong SS, Virani SS. Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation. 2019; 139:e56–e528. - PubMed
    1. Safford MM, Brown TM, Muntner PM, Durant RW, Glasser S, Halanych JH, Shikany JM, Prineas RJ, Samdarshi T, Bittner VA, Lewis CE, Gamboa C, Cushman M, Howard V, Howard G. Association of Race and Sex With Risk of Incident Acute Coronary Heart Disease Events. JAMA. 2012; 308:1768. - PMC - PubMed
    1. Tarver-Carr ME, Powe NR, Eberhardt MS, LaVeist TA, Kington RS, Coresh J, Brancati FL. Excess risk of chronic kidney disease among African-American versus white subjects in the United States: a population-based study of potential explanatory factors. J Am Soc Nephrol. 2002;13:2363–70. - PubMed
    1. 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;15:1307–15. - PubMed
    1. Ito K, Bick AG, Flannick J, Friedman DJ, Genovese G, Parfenov MG, Depalma SR, Gupta N, Gabriel SB, Taylor HA, Fox ER, Newton-Cheh C, Kathiresan S, Hirschhorn JN, Altshuler DM, Pollak MR, Wilson JG, Seidman JG, Seidman C. Increased burden of cardiovascular disease in carriers of APOL1 genetic variants. Circ Res. 2014;114:845–850. - PMC - PubMed

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