David Friedman, MD, is a nephrologist at Beth Israel Deaconess Medical Center and an assistant professor at Harvard Medical School. His laboratory studies the genetics of chronic kidney disease. In addition to working on the genetics and biology of APOL1, he also studies Mesoamerican Nephropathy, a chronic kidney disease epidemic in Central America.

This is an invited commentary summarizing the recent advances made in understanding the molecular mechanisms of how APOL1 enhances ESRD risk in multiple kidney diseases particular in African Americans.

When it emerged as the major African American kidney disease gene in 2010, few nephrologists had ever heard of ApolipoproteinL1. APOL1 wasn’t one of the usual suspects when candidate kidney disease genes were rounded up for a renal genetics symposium. Many in the world of renal genetics thought that it couldn’t be right. After dozens of replications, investigators are now puzzling over what APOL1 does and why the high risk African variants cause kidney disease.

APOL1 isn’t a typical disease gene. While Mendelian mutations are very powerful but quite rare, and polymorphisms that contribute to common complex diseases tend to be common but confer small differences in disease risk, the APOL1 kidney risk variants display an unusual combination of high frequency and strong effect size. This combination is explained by the evolutionary benefit of a single APOL1 risk allele, likely due at least in part to the enhanced ability of risk variants to protect against one type of African sleeping sickness. Only when two risk alleles are present, one inherited from each parent, does the very large increase in kidney disease risk occur. While we know a lot about APOL1 biology in trypanosome killing, we know much less about what APOL1 does in the human kidney.

Given the large impact of APOL1 risk variants on kidney disease, many groups are trying to understand its function in health and in disease. Here are some of the big questions that APOL1 researchers are interested in understanding:

1. Is APOL1-kidney disease a loss-of-function or a gain-of-function disease? APOL1-kidney disease is inherited in a recessive fashion, meaning that you need two risk alleles for increased risk of disease. Typically, recessive diseases are explained by loss-of-function variants (think of cystic fibrosis or phenylketonuria), so a good first guess is that the APOL1 mutations prevent APOL1 from working normally. Several pieces of data argue against this assumption. First, only humans and a few primate species even have a functional APOL1 gene (chimps have lost the gene!), suggesting that it is dispensable in most mammals. Second, researchers have identified at least one human completely null for APOL1, and he has normal kidney function well into middle age. In addition, several groups have shown that overexpressing APOL1 variants can be quite destructive to cells or tissues, offering some evidence for gain-of-function toxicity. Another viewpoint is that APOL1, as an innate immunity molecule, is only necessary for kidney health in the setting of certain unidentified environmental triggers.
2. Is it the circulating form of APOL1 generated in the liver or the protein produced by the kidney cells themselves that is central to the disease process? APOL1 is made in large quantities in the liver and circulates bound to dense HDL particles at relatively high concentrations. APOL1 can also be found in meaningful quantities in podocytes, renal vasculature, and proximal tubules (ref, ref). Renal transplant data indicate that the risk travels with the donor kidney’s APOL1 genotype, not with the host APOL1 genotype, suggestively linking the APOL1 expressed in kidney cells with development of disease (ref, ref, ref). However, filtration and reuptake of circulating APOL1 occurs and may contribute to disease or alter its manifestations.
3. Why do some people with the APOL1 high risk genotype develop disease while others do not? Are there additional genetic factors? What environmental factors other than HIV might be important here? Is enhanced expression of APOL1, a gene dramatically stimulated by inflammatory factors, an important element in disease onset? Theories related to interactions with other genetic variants, non-HIV viruses, and activation of inflammatory pathways have been proposed, but figuring out which people with the APOL1 high risk genotype will develop disease is no easier today than it was 5 years ago when APOL1’s role in kidney disease surfaced.

The protean clinical phenotypes caused by APOL1 risk variants (hypertension-associated ESRD, FSGS, HIVAN, etc.) suggest that a variety of cell types, triggers, and mechanisms may be involved in disease pathogenesis. As we work on these fundamental questions, several major obstacles come to mind. For example, since most mammals have no APOL1 gene, animal model systems must be built from scratch and their relevance to the human biology must be established. It is uncertain whether a gene that arose 70 million years after the human and rodent lineages split will behave in rodent kidneys in ways that are truly informative, or whether the disease processes that progress over decades in some forms of APOL1 kidney disease can be compressed into weeks or months in healthy young mice. Another vexing impediment is that APOL1 protein is extremely difficult to produce and purify, limiting even our most basic understanding of its 3D structure, an essential part of drug discovery. We are betting that advances in sequencing techniques, proteomics, microscopy, and other technologies will help overcome a wide array of obstacles and ultimately lead to molecular therapies for APOL1 kidney disease.

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