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Story of Discovery—APOL1 Gene Variants: Unraveling the Genetic Basis of Elevated Risk for Kidney Disease in African Americans

African Americans have higher rates of end-stage renal disease (ESRD) than European Americans, but for many years the reasons for this health disparity were largely unknown. In 2008, researchers reported that genetic variations on chromosome 22, later revealed to be in the APOL1 gene, were linked to a greater incidence of non-diabetic kidney disease among African Americans. The identification of APOL1 kidney disease risk variants, which are found primarily in African Americans, is arguably the most important discovery about the pathogenesis of chronic kidney disease over the past several decades, and these variants are among the only known genetic factors contributing to the well-appreciated health disparities in kidney diseases. In the years since the initial groundbreaking discovery of APOL1 risk variants, numerous NIDDK-supported studies have shed light on their important roles in disease risk and the underlying mechanisms of APOL1 protein function, creating new research avenues to improve health in populations at risk.

The Heavy Burden of Kidney Disease in Some Populations

Early-stage kidney disease often has no symptoms. Left unchecked, however, it can silently progress to kidney failure, a condition in which the kidneys are no longer able to filter waste and excess fluids from the blood. Millions of U.S. adults are estimated to have chronic kidney disease (CKD), and despite recent advances in preserving kidney function in individuals with early-stage kidney disease, serious health complications are common.

The two most common causes of kidney failure are diabetes and hypertension (high blood pressure), which account for a majority of new cases. Both conditions are more frequent in minority populations, and African Americans bear an especially heavy burden of kidney disease. African Americans are more likely to develop diabetic kidney disease and kidney failure than Whites. One cause is a form of kidney disease called focal segmental glomerulosclerosis (FSGS), in which the glomeruli—the tiny filtering units of the kidneys—are damaged and scarred. Most FSGS arises from unknown causes and is termed “idiopathic” FSGS. African Americans are significantly more likely to develop idiopathic FSGS compared to individuals of other racial backgrounds. The health disparity increases dramatically with HIV infection: African Americans are far more likely than Whites to develop FSGS related to infection with HIV, the virus that causes AIDS. These rather striking disparities represent a serious public health problem, not only because of the kidney disease itself, but also because people who have even mild- to moderately-severe kidney disease typically have high blood pressure and other risk factors for serious complications such as cardiovascular disease.

What accounts for this dramatically increased risk of severe kidney disease in African Americans? Scientists and physicians have long known that kidney disease tends to run in families and to cluster in racial/ethnic groups. These observations indicate that kidney disease is likely to have a genetic component. It is also almost certain that environmental and other factors also play a role in disease susceptibility and outcomes. However, studies that have attempted to identify genes that confer susceptibility to kidney disease and kidney failure had not generally been successful.

Moreover, it is not clear that all forms of kidney disease originate from a common starting point or progress through a shared pathway. For example, while patients with diabetes or those with hypertension are at increased risk of developing kidney disease and kidney failure, not all patients at risk go on to develop kidney disease. In addition, it is not clear that the underlying disease mechanisms which initiate injury and facilitate progression in diabetic and hypertensive kidney disease are the same. If, in fact, these two conditions cause kidney disease through different pathways, then treatment strategies for people whose kidney disease is a consequence of diabetes could be very different from those for people whose kidney disease is attributed to hypertension. Because of these considerations, it has been especially important to identify the genetic contribution to disease development and progression and characterize the biological pathways that lead to diminished kidney function.

A Foundational Discovery

In 2008, members of the NIDDK-supported Family Investigation of Nephropathy and Diabetes (FIND) Consortium, along with scientists in the NIDDK’s Intramural Research Program, reported that genetic variations on chromosome 22 were linked to greater incidence of non-diabetic kidney disease among African Americans. Initially, attention focused on the region surrounding the MYH9 gene. Further analyses revealed that much of the increased risk of kidney disease is actually due to two variations in the adjacent APOL1 gene, which encodes the protein apolipoprotein L1 (also designated as APOL1 protein,) a component of so-called “good” cholesterol that is found circulating in the blood and in kidney cells. Two specific variants of this gene, termed G1 and G2, have been shown to account for nearly all of the excess risk of kidney failure in African Americans arising from causes other than diabetes—a major breakthrough in understanding the increased burden of the disease. The low-risk APOL1 genetic variant is termed G0.

NIH Scientists Identify Critical Associations Between APOL1 Variants and Kidney Diseases

Soon after this association was reported, scientists found that African Americans with two copies of APOL1 high-risk variants are at increased risk of developing kidney disease, particularly FSGS and kidney disease related to infection with HIV. This finding comes from collaborative research led by scientists in NIDDK and NCI’s intramural research programs. Investigators in the United States and Europe were also part of the research team. The scientists studied patients with kidney disease who came to the NIH Clinical Center or other collaborating medical centers and provided blood samples for genetic studies.

Human cells typically have two copies of each gene—one inherited from each parent. African Americans with no normal copies of the APOL1 gene, but instead two kidney disease risk variant copies, have about a 4 percent lifetime risk of developing FSGS. Those who develop this disease tend to do so at younger ages than other FSGS patients, with 70 percent diagnosed between ages 15 and 39, compared to 42 percent in that age group for people with one or no APOL1 high-risk variants. FSGS patients with two APOL1 high-risk variants respond as well to steroid treatments, the therapy with the best chance of inducing a partial or complete remission of the disease, as people without the variants. However, the scientists found that the disease progresses more rapidly to kidney failure in patients with two APOL1 variants. Among African Americans who are HIV-positive, but not receiving anti-viral therapy, possessing two APOL1 variants raises the risk of developing HIV-associated kidney disease to 50 percent. (Anti-viral therapy appears fairly effective at preventing HIV-associated kidney disease.)

The persistence of APOL1 variants in people of African descent may be partly explained by the ability of the APOL1 protein to destroy certain parasites. Although the normal APOL1 protein can destroy the parasite Trypanosoma brucei brucei (T. b. brucei), it is unable to destroy two related parasites, T. b. rhodensiense and T. b. gambiense. These parasites cause African sleeping sickness, a hematologic and neurological disease, spread by the tsetse fly, that kills thousands of people in sub-Saharan Africa each year. However, people with at least one copy of the G1 or G2 variants are protected against infection because they are able to destroy T. b. rhodensiense and T. b. gambiense. These two APOL1 variants appear to have evolved relatively recently—in the past 10,000 years or so. Their relatively recent appearance and high frequency in chromosomes in individuals of African descent suggest that the variants may support protection against parasitic infection.

It should be noted that most people with two APOL1 variants do not develop kidney disease. Indeed, the much higher risk of kidney disease in patients with HIV suggested that a second triggering event, or “hit,” either with a virus or another factor, contributes to kidney injury in people who have two high-risk APOL1 variants. Nevertheless, the observed increased risks of FSGS and HIV-associated kidney disease were the strongest effects yet discovered for common variants in a complex disease.

A New Understanding of Kidney Disease Progression and Treatment

The link between APOL1 gene variants and kidney disease risk led scientists in different studies to seek associations between these variants and measures of kidney disease severity. One NIDDK-supported study examined biosamples from participants in the African American Study of Kidney Disease and Hypertension (AASK). The AASK study enrolled African American patients with mild kidney disease due to hypertension and found that an angiotensin-converting enzyme inhibitor was better than two other drug options at slowing kidney disease progression. The investigators asked whether APOL1 and other gene variants were associated with an increased risk of worsening kidney disease in 700 AASK participants. They analyzed archived DNA samples and found that the presence of the G1 variant was associated with a faster decline of kidney function compared to study participants without this variant. Another NIDDK-supported study examined over 400 African Americans with kidney failure and asked whether the presence of one or two copies of either APOL1 variant was associated with a younger age at which the participants began hemodialysis, a therapy used to cleanse the blood of waste products and excess fluids and salts when the kidneys no longer function. The researchers found that African Americans with two copies of the G1 variant began hemodialysis at a significantly younger age (approximately 49 years old), than those with one copy of the variant (about 56 years old). People with two normal copies of the APOL1 gene began hemodialysis at around 62 years of age.

APOL1 Gene Variants and Cardiovascular Disease

Because hypertension is a leading cause of kidney failure, researchers have also sought to determine the relationship between the APOL1 variants and cardiovascular disease. Scientists analyzed data from people enrolled in AASK and the Chronic Renal Insufficiency Cohort (CRIC) Study. The CRIC study, also supported by the NIDDK, is one of the largest and longest ongoing studies of CKD epidemiology in the United States; it is examining the health of both White and African American people with CKD, about half of whom also have diabetes. In their analysis, the researchers found a correlation between the presence of high-risk variants of the APOL1 gene and an increased risk of CKD progression among African Americans. This effect was seen regardless of whether patients maintained good blood pressure control or had diabetes. In a separate study, over 2,500 African American volunteers in the Systolic Blood Pressure Intervention Trial (SPRINT) clinical study agreed to undergo genetic testing to allow researchers to examine their APOL1 status as it related to their kidney function and risk of developing cardiovascular disease. SPRINT was led by the National Heart, Lung, and Blood Institute (NHLBI), and co-sponsored by the NIDDK and other NIH institutes. In the genetics study, which also was supported by the NIDDK and other NIH Institutes, researchers found that SPRINT study participants with two risk variants of the APOL1 gene were more likely to have mild kidney disease than people with a single risk variant or none. However, they were not more likely to have cardiovascular disease. More recently, scientists supported by the NIDDK analyzed data from multiple independent studies, overall including over 5,000 African American study participants, to explore whether APOL1 variants affect the age of hypertension onset. They found that in young African Americans (20-29 years old), high-risk APOL1 variants were linked to higher blood pressure levels and younger age of hypertension diagnosis than low-risk variants. Another NIDDK-supported research team asked whether APOL1 gene variants were linked to differences in blood pressure trajectories over time. The scientists analyzed data from NHLBI’s Coronary Artery Risk Development in Young Adults (CARDIA) Study, which began in 1986 and has been examining the development and determinants of cardiovascular disease and its risk factors by following study participants for 25 years. The scientists found that while blood pressure levels over the years rose to higher levels in African Americans than in Whites, blood pressure trajectories in those with high-risk APOL1 variants did not appear to be different than in people with the low-risk variants.

Cellular and Molecular Mechanisms of APOL1 Protein Function

Great strides have been made over the past few years in defining various aspects of the genetic risk of kidney disease associated with APOL1 variants in some populations. In addition, understanding the mechanisms of APOL1 protein action in the kidney that underlie disease risk could inform clinical decisions and the development of new therapeutic strategies for people with high-risk variants. To begin exploring these mechanisms, one important experimental challenge had to be overcome by scientists—the APOL1 gene is only found in humans and some primates. Thus, researchers needed to develop innovative strategies for investigating APOL1 protein function in animal models and other laboratory systems. Recent reports have shed light on the proteins and pathways that mediate APOL1 action in the kidney.

In one study, NIDDK-supported researchers genetically engineered mice to produce the human APOL1 G0, G1, or G2 variants in specialized cells in the kidney, called podocytes, that wrap around the glomerulus and are key components of the filtration apparatus. Mice that produced the G0 variant appeared normal, but those with a high-risk G1 or G2 variant exhibited hallmarks of human kidney disease (e.g., high levels of protein in the urine, physical injury to podocytes). These results in mice lend strong support to the hypothesis that these human APOL1 variants cause kidney disease. Another team of scientists supported by the NIDDK used the Drosophila melanogaster fruit fly system to investigate cellular and molecular mechanisms of APOL1 activity. The researchers engineered flies to produce human APOL1 G0 or G1 variants in their nephrocytes, which are cells in Drosophila that have a similar function as human podocytes. Both variants over time led to increased protein uptake by nephrocytes and impaired acidification of critical cellular compartments. These cellular changes over time were accompanied by decreased function, increased size, and premature death of nephrocytes. In each experiment, the results were much more severe in flies with the G1 variant than in those with the G0 variant. Together, these findings suggest that APOL1 variants are causative agents of kidney disease, and point to cellular toxicity as a potential mechanism for decline in kidney function.

High levels in the blood of a protein called suPAR are associated with decline in kidney function and progression to CKD. Because many people with the high-risk G1 and G2 APOL1 variants do not develop kidney disease, an NIDDK-supported research team explored whether blood suPAR levels can help predict whether African Americans with these genetic variants will experience declining kidney function. The scientists analyzed data from the Emory Cardiovascular Biobank (EmCAB) and the AASK trial, which together included almost 1,100 African American participants. The scientists found that in people with high-risk APOL1 variants, kidney function was likely to decline more rapidly over time in those with elevated plasma suPAR levels than those with lower suPAR. To gain additional insights, the researchers studied APOL1 variants and suPAR in mice. Female mice engineered to express either the G1 or G2 variant showed evidence of kidney damage, but mice with the G0 variant appeared normal. However, when suPAR was genetically deleted from mice, the kidney damage caused by the G2 variant was gone. Taken together, these findings suggest that high levels of suPAR may be necessary for the kidney function decline observed in some people with APOL1 G1 and G2 variants, and thus may serve as a useful predictor of kidney disease. (For more details about this study, please see the advance earlier in this chapter).

Looking Forward

A clear picture is emerging that links APOL1 gene variants to kidney diseases under a range of conditions that need further study, such as HIV-associated nephropathy, pediatric kidney disease, sickle cell nephropathy, and kidney transplantation. The NIDDK continues to support research at multiple levels to understand these relationships in African Americans and other populations. For example, the NIDDK held a conference in June 2015 on APOL1 and kidney disease to assess gaps in knowledge, including the function of the APOL1 protein and its role in kidney transplantation. The conference developed new ideas regarding how APOL1 gene variants lead to disease susceptibility, what kidney and cardiovascular outcomes are associated with these variants, which additional genetic variants or environmental factors play a role in differences in disease symptoms, and the possible role of determining whether patients have APOL1 gene variants in guiding treatment as well as preventive strategies for patients.

Additionally, in 2016 the NIDDK, the National Institute on Minority Health and Health Disparities, and the National Institute of Allergy and Infectious Diseases began the APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) initiative. This initiative aims to determine the impact of APOL1 genetic variants as risk factors in U.S. kidney transplant recipients who received kidneys from African American donors. The consortium will examine the rate of change of kidney function in recipients, and rates of acute rejection of the kidney transplant, graft failure, and return to maintenance dialysis in the recipients, who received kidneys from patients of African descent, in the presence and absence of the APOL1 genetic variants. Outcomes in kidney donors, including vital and renal functional status, will also be assessed.

These seminal studies, as well as many others over the past several years, have revealed the importance of APOL1 in understanding some key differences in kidney disease risk across populations. Unraveling the molecular mechanisms by which APOL1 variants contribute to kidney injury could provide key insights into the causes and possible treatments for kidney disease in African Americans. Moving forward, clinicians may be able to make more informed choices about when to start screening for kidney disease and how to choose an appropriate therapy by identifying which patients have these gene variants and are therefore at increased risk of developing kidney disease and progressing to kidney failure.