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. Author manuscript; available in PMC: 2015 Feb 28.
Published in final edited form as: Circ Res. 2013 Dec 30;114(5):845–850. doi: 10.1161/CIRCRESAHA.114.302347

Increased Burden of Cardiovascular Disease in Carriers of APOL1 Genetic Variants

Kaoru Ito 1,2, Alexander G Bick 1,2, Jason Flannick 2,3, David J Friedman 4,5, Giulio Genovese 2,4, Michael G Parfenov 1, Steven R DePalma 1, Namrata Gupta 2, Stacey B Gabriel 2, Herman A Taylor Jr 6,7, Ervin R Fox 6, Christopher Newton-Cheh 2,3,8, Sekar Kathiresan 2,3,8, Joel N Hirschhorn 1,2,9, David M Altshuler 2,3, Martin R Pollak 2,4, James G Wilson 10, J G Seidman 1,2, Christine Seidman 1,2,11
PMCID: PMC3982584  NIHMSID: NIHMS559962  PMID: 24379297

Abstract

Rationale

Two distinct alleles in the gene encoding apolipoprotein L1 (APOL1), a major component of HDL, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease (CKD). Approximately 14% of African-Americans carry two APOL1 risk alleles, accounting for the high CKD burden in this population.

Objective

We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African-Americans.

Methods and Results

We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and CKD were confirmed (p=2.4 × 10−6). Among JHS participants with two APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without vs. 37/280 events among participants with two risk alleles; odds ratio (OR): 2.17, p=9.4 × 10−4). We replicated this novel association of APOL1 genotype with CVD in Women’s Health Initiative (WHI) participants (66/292 events among participants without vs. 37/101 events among participants with two risk alleles; OR: 1.98, p=8.37 × 10−3; JHS and WHI combined, p=8.5 × 10−5; OR: 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and CKD.

Conclusions

APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with two APOL1 risk alleles may benefit from intensive interventions to reduce CVD.

Keywords: Genetics, risk factors, epidemiology, chronic kidney disease, atherosclerosis, genetic association, cardiovascular genomics, race, ethnicity

INTRODUCTION

Individuals of African American descent are at four-fold greater risk of developing chronic kidney disease (CKD), three-fold increased risk of stroke, and two-fold greater risk of dying from coronary disease than individuals of European descent. These hazards are independent of traditional disease risk factors and sociologic disparities (e.g. income and education).1–3 Moreover, CKD conveys greater risk for cardiovascular disease (CVD) in African Americans than individuals of European decent (HR: 1.76 vs. 1.13 respectively), even after adjusting for known risk factors.4

Previous genome-wide association studies for CKD in African Americans identified two alleles (termed G1 and G2) in apolipoprotein L1 (APOL1) that significantly increased the burden of renal disease.5–7 The APOL1 G1 allele consists of two missense mutations (p.S342G, p.I384M); the G2 allele is a 2 amino acid deletion (residues 388 and 389). Both G1 and G2 APOL1 alleles enhance lysis of Trypanosoma brucei rhodesiense, conveying resistance to African sleeping sickness.6 Positive selection for this protection against African sleeping sickness explains the high frequency of G1 and G2 alleles in individuals with African ancestry and their complete absence in individuals of European American ancestry. A recent analysis of the burden of APOL1 risk alleles among 1825 African American participants in the Dallas Heart Study showed that 1.7% individuals with CKD had one or no APOL1 risk alleles, whilst 6.7% of individuals with CKD had two risk alleles, suggesting a recessive model of disease pathogenesis.8 As approximately 36% of African Americans carry either the G1 or G2 allele and 14% carry two APOL1 risk alleles,5, 6 the increased burden of CKD in African Americans is largely explained by APOL1 genotypes. Mechanisms by which APOL1 alleles increase CKD risk are still unknown.

As CKD confers greater risk for cardiovascular disease on African Americans than individuals of European descent, we hypothesized that APOL1 alleles G1 and G2 contribute to the increased CVD risk observed in African Americans. This hypothesis seemed biologically plausible as APOL1 is a major apolipoprotein component of dense high-density lipoprotein (HDL3) particles that plays a central role in cholesterol transport and attenuate LDL oxidation.9 HDL levels are associated with CVD risk, but whether this relationship reflects concomitant abnormalities in other lipid levels (particularly LDL)10, 11 or pleiotropic HDL functions (e.g., cholesterol efflux, insulin secretion)12, 13 remains controversial.

In this study we defined the allelic spectrum of the APOL1 gene in 1959 unrelated individuals from the Jackson Heart Study Cohort and assessed the association of common and rare alleles with CKD and CVD. We replicated results using exome sequence data from 749 African ancestry participants from the Women’s Health Initiative (WHI) cohort (Figure 1).

Figure 1.

Figure 1

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Cardiovascular disease (CVD) and/or chronic kidney disease (CKD) in 2708 individuals with APOL1 genotypes. Associations were initially performed in 1959 random participants in the Jackson Heart Study (JHS) who were fully sequenced for the APOL1 gene. Replication of the CVD association was performed 749 African American participants in the Women’s Health Initiative (WHI) with exome sequence data.

METHODS

Study subjects

APOL1 was sequenced in African Americans enrolled in the Jackson Heart Study (JHS; dbGaP Study Accession phs000286.v3.p1). The JHS is a large, community-based, observational study whose participants were recruited from urban and rural areas of the Jackson, Mississippi metropolitan statistical area.14 Further details are provided in Online Methods. These studies were performed using protocols approved by the JHS, institutional ethics committees, and with informed consent from all participants.

Replication studies were performed by analyses of African American participants from the Women’s Health Initiative (WHI) clinical trial (dbGaP Study Accession phs000200.v1.p1). The WHI recruited and followed 161,808 postmenopausal women aged 50 to 79 years at 40 clinical centers across the United States from 1993 to 1998.15 The WHI eligibility criteria included the ability to complete study visits with expected survival and local residency for at least 3 years. Enrollment criteria excluded individuals with advanced kidney disease. These studies were performed using protocols approved by the WHI, institutional ethics committees, and with informed consent from all participants.

CVD risk factors, including age, gender, BMI, diabetes status, hypertension status, smoking status, and renal function was assessed in all study participants. In JHS participants clinical histories of stroke, cardiac surgery and arterial catheterization, cardiac computerized tomography (CT) with Agatston coronary artery calcium scores were assessed. In WHI participants we assessed stroke and adjudicated cardiovascular event free survival. Further details are provided in Online Methods.

Genotype ascertainment

Coding exons of the APOL1 gene were sequenced using a custom hybrid capture array as previously described16 and detailed in the Online Methods for JHS participants. WHI samples were exome sequenced as part of the NHLBI Grand Opportunity Exome Sequencing Project as previously described.17 All JHS and WHI samples were also genotyped on the Affymetrix Genome-Wide Human SNP Array 6.0. We computed concordance of sequence genotypes with these SNP array genotypes using the PLINK software package.18 Principal component analysis was performed using PLINK and EIGENSTRAT (Online Figure I).19 These analyses verified that all individuals were unrelated and were of African ancestry. Quality control showed high (>96%) concordance between sequence and SNP array genotypes for the same individuals.

Statistical comparison of variant carrier phenotypes

We assessed association between and variant carrier status using the Fisher exact test, logistic regression adjusted for covariates, and cox proportional hazard models as specified. Statistical analysis was conducted with the R software package.

RESULTS

DNA sequence analysis of the APOL1 gene in 1959 JHS subjects identified 32 non-synonymous sequence variants. Twenty-one were rare variants with minor allele frequency (MAF) <1%, including one frame-shift and one nonsense mutation (Online Table I). Ten of these variants were not found in public databases. Previously identified APOL1 alleles, rs73885319 (p.S342G), rs60910145 (p.I384M), that together are denoted G1, and rs71785313 (deletion of p.N388 and p.Y389; denoted G2) had MAF of 23%, 22% and 14% respectively. We also identified 16 individuals with an allele consisting of p.S342G without p.I384M, unlike the G1 allele, which we designated G1a. Among 284 JHS participants with two APOL1 risk alleles, 40% were G1 homozygotes, 14% were G2 (rs71785313) homozygotes, and 46% were compound G1/G2 heterozygotes.

There were no significant differences in the baseline distribution of age, gender, smoking status, body-mass index, type 2 diabetes prevalence, hypertension prevalence, total cholesterol and LDL-cholesterol among JHS participants with or without APOL1 risk alleles (Table 1, Online Table II). Previously reported associations between the common APOL1 G1 and G2 risk alleles and CKD were replicated among JHS subjects.6, 20, 21 36% of JHS participants with two risk alleles had CKD compared to 18% of individuals with no risk alleles (p=2.4 × 10−6 and Online Table III). The association between CKD and these APOL1 genotypes was robust to adjusting for age, gender, BMI, diabetes status, hypertension covariates LDL-C, HDL-C, and PCA vectors 1 and 2 to account for African American population admixture (Online Table IV). These APOL1 risk alleles were also associated with earlier onset kidney disease and dialysis with a cox-proportional hazard model (p=0.005 and p=0.04 respectively, Online Figure II).

Table 1.

Baseline cohort characteristics stratified by genotype

JHS (n=1959) WHI (n=749)
Genotype Ref/Ref One risk allele Two risk alleles Ref/Ref One risk allele Two risk alleles
n 783 892 284 302 344 103
Age 56.9 (11.1) 56.3 (11.6) 57.4 (12.1) 61.1 (6.99) 60.9 (6.85) 60.3 (7.20)
Female (%) 62.8 62.2 62.7 100 100 100
Smoking (%) 12.8 14.1 10.9 11.7 13.7 8.1
BMI (kg/m2) 31.5 (7.2) 32 (7.2) 32 (6.9) 34.25 (9.87) 34.2 (9.50) 35.4 (9.92)
Diabetes (%) 23.6 24.9 28.1 19.9 23.5 25.2
Hypertension (%) 69.8 68 67.5 57.6 56.7 69.7*
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The single risk allele group consists of G1/Ref, G1a/Ref and G2/Ref genotypes. The two-risk allele group consists of G1/G1, G1a/G2, G1/G2, G1/G1a and G2/G2 genotypes.

*

p<0.05 compared to Ref/Ref genotype. Standard deviation for continuous variables indicated in parentheses. P-value calculated by fisher exact test for dichotomous variables and by t-test in continuous variables. Differences were not significant after correction for multiple comparisons.

We next considered whether APOL1 G1 and G2 alleles were associated with increased risk of cardiovascular disease, defined as a composite endpoint of myocardial infarction, stroke, or therapeutic surgical or endovascular interventions. JHS subjects with two APOL1 risk alleles had a two-fold increased risk in these CVD events compared to individuals with no risk alleles (OR: 2.17, p=9.4×10−4; Table 2). Increased risk for these events was robust in a cox-proportional hazard model adjusted for traditional CVD risk factors (age, gender, BMI, diabetes status, hypertension status, smoking status, LDL-C, and HDL-C), including CKD (p=0.029, Figure 2a). Sub-stratification of events revealed a two-fold increased risk for stroke (p=0.02) and cardiovascular surgery (p=0.015) as well as an eight-fold increased risk for endovascular catheterization (p=0.006, Online Table V).

Table 2.

CVD disease incidence stratified by genotype in JHS and WHI participants.

Genotype JHS WHI
Ref/Ref G1/G1 G2/G2 Two risk alleles Ref/Ref Two risk alleles
Ntotal 763 107 37 280 292 101
NCVD (NMI) 50 (13) 13 (6) 8 (4) 37 (10) 66 (5) 37 (2)
p-value 0.045 3.40E-03 9.40E-04 8.37E-3
OR (95%CI) 1.97 (0.95–3.85) 3.92 (1.47–9.39) 2.17 (1.34–3.48) 1.98 (1.17–3.31)
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Numbers of individuals with cardiovascular disease (NCVD) and myocardial infarction (NMI) are shown.

P-values and odds ratio (OR) calculated using a Fisher’s exact test in comparison to Ref/Ref genotype.

Figure 2.

Figure 2

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Major adverse cardiac event (MACE) free survival Kaplan-Meier curves stratified by genotype (Ref/Ref, no APOL1 risk alleles versus two risk alleles) for (a) JHS and (b) WHI. P-value and hazard ratios calculated by multivariable cox-proportional hazards model adjusted for gender, BMI, smoking, LDL-C (JHS), HDL-C (JHS), diabetes, hypertension and CKD.

To better establish CVD risk among individuals carrying APOL1 risk alleles, we performed replication analyses in African American participants in the Women’s Health Initiative (WHI), a randomized control trial of postmenopausal hormone therapy in healthy women. WHI enrollment excluded individuals with existing medical conditions, such as CKD, or individuals with a predicted survival of less than three years. The frequency of African American WHI participants with two APOL1 risk alleles was comparable to the frequency in JHS participants (p=0.6) and was in Hardy–Weinberg equilibrium. There was less CKD based on eGFR and dialysis status in WHI (Online Table VI) compared to JHS participants that we attribute to the WHI enrollment exclusion criteria. However, we observed an association in WHI participants with two APOL1 risk alleles and eGFR (p=0.04) and hemoglobin (p=0.01), findings that may suggest subclinical renal impairment (Online Table VII).

After controlling for age, BMI, diabetes status and hypertension, WHI participants with two APOL1 risk alleles had a two-fold increased risk of major adverse cardiovascular event (p=8.4 × 10−3) within two and a half years after trial enrollment compared to those who did not have two risk alleles (Table 2, Figure 2b and Online Table VIII). Importantly, CKD incidence in these individuals was not statistically discernable from baseline (Online Table VI), an observation that likely reflected trial exclusion criteria (e.g., significant renal disease and conditions that cause CKD). These findings suggest that individuals with APOL1 risk genotypes, even those without clinically significant kidney disease, have significantly increased risk for CVD.

To further elucidate the pathophysiology underlying this increased cardiovascular risk, we considered a diverse set of intermediate cardiovascular phenotypes in the JHS and WHI studies including type 2 diabetes status, hypertension status, measures of left ventricular geometry or function (left ventricular hypertrophy and left ventricular dilatation studied as dichotomous phenotypes or quantitative phenotypes), hematocrit, blood glucose levels, cholesterol, and LDL-C (Online Tables II, VII, Online Figure III). APOL1 risk alleles were not associated with any of these intermediate phenotypes. Notably, we observed no association between APOL1 risk allele status and the inflammatory marker C-reactive protein (p=0.87) in JHS participants after controlling for body mass index, gender, age, diabetes, hypertension, smoking status and renal function. Additionally, among JHS participants who had cardiac CT imaging, APOL1 risk allele status was associated with decreased Agatston scores (a measurement of coronary artery calcium22) in the left main coronary artery (β: −6.04, p=0.019). This association remained even when individuals with CKD were removed from the dataset (β: −6.2, p=0.024). Hence, the risk conferred by APOL1 may not be captured by conventional cardiovascular risk factors.

We also sought to determine whether the two APOL1 risk alleles conferred distinct CKD and/or CVD phenotypes. The risk for CKD and albuminuria in G2/G2 individuals was reduced compared with G1/G1 individuals (Online Table III). Moreover, G1 homozygote carrier status was associated with reduced hematocrit (p<0.005, coefficient: −1.04) while G2 homozygotes had no association with hematocrit (p=0.5, coefficient −0.4), findings that imply allele differences may result in different degrees of kidney function impairment (Online Table II). In contrast, individuals with a G2/G2 risk were at higher risk for stroke (Online Table V) and had decreased total-cholesterol and HDL-C, while G1/G1 individuals were not associated with these phenotypes (Online Table II).

A robust evaluation of rare and often unique APOL1 variants (Online Table I) was hampered by small numbers, which reduced overall power to detect an effect. Fourteen individuals had a single rare APOL1 variant unaccompanied by the more common risk alleles and 12 individuals had a single rare APOL1 variant in combination with one common risk allele. Three individuals had a single rare APOL1 variant in combination with two risk alleles while one individual had multiple rare APOL1 variants with two risk alleles. The risk conferred by single rare variant either with or without a single APOL1 risk allele did not significantly influence CKD, CVD or other phenotypes and the outcomes described above (Online Table IX).

DISCUSSION

Two major APOL1 alleles G1 and G2 that substantially increase the burden of renal disease and dialysis-dependent CKD also increase the risk for CVD in African Americans (JHS and WHI combined, p=8.5 × 10−5). We demonstrate that APOL1 risk alleles impact CVD among participants in the JHS, an unselected community-based cohort. Importantly, we show in an unrelated cohort that the association of APOL1 alleles and CVD risk is independent of renal disease. These data support epidemiological evidence4 that the differential burden of CVD in African Americans is based on ancestry that is unexplained by physiological risk factors.

Understanding APOL1 biology will be critical to elucidating the mechanisms by which APOL1 risk alleles promote CVD. Notably our analyses uncovered distinct CVD phenotypes among individuals with either common APOL1 risk alleles. For example, in comparison to G1/G1, individuals with G2/G2 alleles had lower risk for CKD but higher risk for stroke, decreased total-cholesterol, and HDL-C, (Online Tables II and V). We hypothesize that the G1 allele, which contains missense residues and the G2 allele, which deletes amino acids in the C-terminal domain may convey distinct biological interactions that may incite distinct molecular processes and account for divergent phenotypes.

Atherosclerotic disease contributed to an increased CVD burden among APOL1 risk allele carriers in the JHS and WHI participants (Online Figure III). As inflammation and immunity play crucial roles in atherosclerosis,23 we speculate that APOL1 impacts atherosclerosis through these pathways. We found no association between C-reactive protein levels and APOL1 risk alleles after controlling for multiple parameters; as such the CVD risk conferred by APOL1 variants may be mediated through other distinct mechanisms. APOL1 risk allele status was also associated with decreased Agatston scores. While the precise connection between Agatston scores and cardiovascular events remains to be defined, higher Agatston scores are correlated with increased stable atherosclerotic plaque.24 In contrast, atherosclerotic cardiovascular disease is thought to stem from unstable atherosclerotic plaque.25, 26 Whether and how APOL1 participates in atherosclerotic plaque formation and stability remains to be determined.

APOL1 also has specific functions (formation of anionic pores in the parasite lysosomal membranes, causing lysis) in innate immune responses to Trypanosoma brucei brucei6 that may also be relevant to removal of pro-atherosclerotic cells. For example, inefficient removal of macrophage-derived foam cells from vascular beds promotes the accumulation of cellular debris and extracellular lipids that contributes to the formation of necrotic plaques.27 In addition, as a component of HDL, APOL1 might also participate in anti-inflammatory actions that HDL has on endothelial cells, leukocytes, and vascular smooth muscles.13 Notably, the abundance of APOL1 in dense HDL3 particles strongly correlates with the capacity of HDL to attenuate LDL oxidation.9

The substantial morbidity and mortality associated with CKD and CVD, alone and in combination,28 underscores the importance of identifying and treating high-risk individuals. Recent guidelines29 recommend screening kidney transplantation candidates for CVD based on the presence of multiple risk factors (diabetes, previous cardiovascular disease, dialysis for >1 year, left ventricular hypertrophy, aged >60 years, smoking, hypertension, and dyslipidemia). Our conclusion that APOL1 risk alleles are associated with accelerated CVD, as well as with CKD, indicates that incorporation of analyses of these variants in African American patients may provide important information to improve their clinical care.

Supplementary Material

302347R2 Online Data Supplement

Novelty and Significance.

What Is Known?

  • African Americans have greater risk for developing chronic kidney disease (CKD) and cardiovascular disease (CVD) than Americans of European ancestry.

  • Genome wide association studies identified two risk alleles (G1 and G2) in Apolipoprotein L1 (APOL1) that significantly increased the burden of CKD in African Americans.

What New Information Does This Article Contribute?

  • The APOL1 risk alleles G1 and G2 also significantly increase the burden of CVD in African Americans.

  • The increased CVD risk conveyed by APOL1 alleles is independent of CKD and traditional risk factors for atherosclerosis.

Two risk alleles in APOL1, which convey resistance to sleeping sickness and are found among individuals of African but not European ancestry, account for a substantial burden of CKD found in African Americans. As African Americans also have higher risks of CVD than individuals of European descent, we asked whether the two APOL1 risk alleles were associated with increased risk for atherosclerosis in two separate cohorts. Among 1959 randomly selected African American participants from the Jackson Heart Study with two risk alleles, we observed increased risk for atherosclerotic CVD events that was independent of CKD and traditional atherosclerotic risk factors. We replicated this novel and independent association of APOL1 alleles and atherosclerotic CVD in 749 participants in the Women’s Health Initiative. The substantial morbidity and mortality associated with CKD and CVD, alone and in combination, underscores the importance of identifying and treating high-risk individuals. We suggest that ascertaining APOL1 risk allele status in African Americans may provide important information to guide treatments that reduce the risk of CVD.

Acknowledgments

We gratefully acknowledge the contribution of Jackson Heart Study and Women’s Health Initiative study participants as well as the JHS and WHI investigators and staff for enabling this research.

SOURCES OF FUNDING

This work was supported by grants from the National Human Genome Research Institute (Medical Sequencing Program grant U54 HG003067, to the Broad Institute PI, Lander), the National Heart, Lung and Blood Institute (HL080494-05 to C.E.S. and J.G.S.), the National Institute on Minority health and Health Disparities (R01MD007092 to M.R.P.) and the Howard Hughes Medical Institute (to C.E.S). K.I. was supported by Banyu Fellowship Program and Uehara Research Fellowship Program. A.G.B. is supported by NIH Medical Scientist Training Program fellowship 5T32GM007753-33. The Jackson Heart Study is supported by contracts N01-HC-95170, N01-HC-95171, and N01-HC-95172 from the National Heart, Lung, and Blood Institute, the National Institute for Minority Health and Health Disparities, and additional support from the National Institute of Biomedical Imaging and Bioengineering. The WHI Sequencing Project is funded by the NHLBI (HL-102924) as well as the National Institutes of Health (NIH), U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The WHI exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO).

Nonstandard Abbreviations and Acronyms

APOL1

apolipoprotein L1

CKD

chronic kidney disease

CT

computerized tomography

CVD

cardiovascular disease

G1

APOL1 allele that consists of two missense mutations (p.S342G, p.I384M)

G2

APOL1 allele that contains a 2 amino acid deletion (residues 388 and 289)

HDL-C

high density lipoprotein cholesterol

JHS

Jackson Heart Study

LDL-C

low density lipoprotein cholesterol

MI

myocardial infarction

PCA

Principal component analysis

WHI

Women’s Health Initiative

Footnotes

DISCLOSURES

The authors have no competing financial interests.

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302347R2 Online Data Supplement
NIHMS559962-supplement-302347R2_Online_Data_Supplement.pdf (6.6MB, pdf)

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