09:29 AM

APOL1 High-Risk Genotype in SLE: A Genes in Context Story

At this year’s American College of Rheumatology (ACR) annual meeting, HSS rheumatologist Ashira D. Blazer, MD, MSCI, delivered the Edmond L. Dubois, MD Memorial Lectureship. This lectureship is presented annually at the ACR meeting and features an outstanding investigator in the area of lupus research.

Dr. Blazer specializes in the treatment of rheumatic diseases including undifferentiated connective tissue disease, Sjogren’s syndrome, inflammatory arthritis, and systemic lupus erythematous (SLE), particularly in patients of African ancestry. As a physician-scientist, she studies the interplay between genetic signatures commonly found in African ancestry backgrounds, environmental and social stressors, and SLE pathogenesis. Here, she talks about the subject of her lecture and her broader research.

In my experience, any rheumatologist who takes care of people with lupus has observed disparities in outcomes for African American patients compared to others. This is especially true when it comes to lupus nephritis, the type of kidney damage associated with lupus. The bulk of this disparity is related to access to care and the social determinants of health. For a subgroup of African Americans, however, aggressive kidney disease may be due to genetic risk.

Thanks to research looking at the connections between African American genomes and disease, we are beginning to answer some of those questions. Investigators have found that about 13% of people of recent African descent carry two copies of a particular version, or variant, of the gene Apolipoprotein L1, or APOL1. One copy of the variant protects against Trypanosoma brucei, the parasite that causes African sleeping sickness. This evolutionary advantage helps explain why the variant is so common. But having two copies is associated with a much higher risk of kidney disease, as well as cardiovascular disease.

Interestingly, about 80% of people with high-risk APOL1 genes don’t go on to develop end-stage kidney disease. It takes a “second hit,” usually chronic infection or chronic inflammation, to send people with this mutation down the path toward having these severe kidney problems. By studying the how the inflammation seen in lupus patients interacts with these APOL1 variants and leads to severe disease, we hope to develop ways to modify the factors that trigger that risk.

Part of my research is focused on clinical observations in patients who carry these APOL1 variants. When a lupus patient has protein in their urine, is it due only to lupus nephritis or is it a combination of autoimmune activity and the APOL1 phenotype? These differences could affect how patients are treated and which medications they are given, including the amount of steroids we use. By learning more about these clinical differences, we hope to ultimately reduce the number of lupus patients who end up on dialysis. And it’s very exciting to bring precision medicine to a patient population that is largely underserved.

The other part of my research is focused on understanding which immune pathways are active when the APOL1 variant is most highly expressed and whether the combination of APOL1 and immune activity is really producing these severe disease symptoms. We look at how the APOL1 gene is expressed in different cell types and how that affects the cell damage that we see. One thing I’ve been studying is how these variants affect mitochondria and their ability to produce energy for the cell. I’ve also been looking at how the variants affect autophagy, which is one way that cells recycle their damaged parts. Studying autophagy could explain not only the relationship between APOL1 and inflammation, but potentially how APOL1 causes cellular injury in people who carry the variants.

The field of rheumatology is in a golden age right now. We have all these new biologic drugs that can specifically modulate different pathways. It’s possible that by identifying the essential immune stimulus, we’ll be able to find ways to decrease the likelihood that someone with lupus suffers kidney injury — preventing the poor outcomes seen in so many of these patients. We may also be able to develop small molecules that could directly impact the protein product of APOL1.

I’m studying the connections between these gene variants and lupus outcomes not only in patients who are treated at HSS; but I’m also working with collaborators at two teaching hospitals in Africa, the University of Ghana and Lagos State University in Nigeria. These large patient populations help us to study the cellular damage caused by the APOL1 variant and why patients who have it are more likely to develop global damage to their kidneys. Studying patients who are being treated in resource-limited countries also helps us understand the interplay between lupus, social determinants of health, and genetic risk; and how these factors that contribute to poorer kidney outcomes

The findings about APO1 explain a reason why African American lupus patients with this particular genetic background don’t do as well, but we know there are many socioeconomic and societal factors that also influence the different in outcomes. Ultimately, we want to find ways to promote better health for all people with lupus, whether they carry these variants or not.