APOL1 and Cardiovascular Disease: A Story in Evolution

Observational 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 (ESRD) compared to 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 two separate genome wide association studies identified DNA variants in the APOL1 gene that were strongly associated with kidney disease in African Americans.^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.

APOL1 encodes for apolipoprotein L-I (apoL-I), a component of dense high-density lipoprotein (HDL3) particles.⁶ Circulating apoL-I has the ability to lyse the parasite Trypanosoma brucei, which is found only in sub-Saharan Africa.⁷ Over time, two subspecies of T. brucei, T. brucei gambiense and T. brucei rhodesiense, evolved resistance by producing a protein that binds and neutralizes apoL-I. Subsequently, two APOL1 variants (G1 and G2) emerged, producing apoL-I with decreased affinity for the trypanosome protein, conferring resistance to African sleeping sickness in carriers of these alleles.⁸ However, while being protected from one disease, African Americans with the APOL1 variant alleles have been shown to be at increased risk for renal disease, as well as a faster progression to ESRD.⁹ Individuals that are homozygous for either variant, or compound heterozygotes, have been found to have a 10–17 times higher odds for focal segmental glomerulosclerosis,^5,10 a 7 times higher odds for hypertension-associated ESRD,⁵ and 29–89 times higher odds for HIV-associated nephropathy.^10,11 Due to the initial natural selection, the prevalence of these variants in the population is significant: approximately 40% of African Americans carry one risk allele, while 10–15% carry two.^5,12,13 APOL1 is broadly expressed, including in the kidney and vasculature.¹⁴ While the mechanistic role of APOL1 variants in disease development has yet to be fully elucidated, recent work has demonstrated expression of APOL1 risk alleles as being causal for kidney disease development by altering podocyte function in mouse models.¹⁵

Beyond 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 at al.¹⁷ report on the association between the APOL1 risk alleles and CVD outcomes in the African American Study of Kidney Disease and Hypertension (AASK), a well-characterized cohort of individuals with CKD attributed to hypertension. The study’s authors compared the 160 AASK participants with two APOL1 risk alleles (“high-risk”) with the 533 who had either one 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 al. 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 (HR) 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 HR 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 al.¹⁸ demonstrated that among 1959 African American participants in the Jackson Heart Study, individuals with two APOL1 high risk alleles were at twice the risk of incident CVD when compared to 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 al.¹⁹ who showed that in over 6000 African Americans in the Cardiovascular Health Study, participants with high risk APOL1 genotypes had an 80% greater risk of incident myocardial infarction as compared to those with zero or only one 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 al. presented in this issue,¹⁷ a 2015 study of 2571 African American participants from the Systolic Blood Pressure Intervention Trial (SPRINT) failed to demonstrate an association between high-risk APOL1 genotypes and CVD, despite showing a strong association with CKD.²⁰ Similarly, investigators with the Atherosclerosis Risk in Communities (ARIC) Study found a strong association between the high risk APOL1 genotype and ESRD but failed to demonstrate any association with incident CVD in 3676 African American participants.²¹

The 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 1). The results reported by Chen et al.¹⁷ 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 “cardiovascular disease” 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 (EHR) 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 VA Million Veteran Program,²² 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 African American population.

Figure 1.

APOL1 risk genotypes are known to associate with CKD, dramatically increasing the risk of renal dysfunction. Although kidney disease in general leads to increased rates of 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.