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APOL1 variant gene may explain lupus outcome disparities between black, white patients

HILTON HEAD, S.C. — A variant of the apolipoprotein L gene could help explain why patients of African ancestry with lupus typically experience worse disease-related outcomes compared with white patients, according to Ashira Blazer, MD, a rheumatologist and assistant professor at the NYU School of Medicine.

“I studied the genetic underpinnings of differences in outcomes in African American lupus patients, and recently there have been these gene polymorphisms in the apolipoprotein L1, or the APOL1 gene, that have been shown to associate with both worse outcomes with regard to kidney disease and cardiovascular disease,” Blazer told Healio Rheumatology.

Part of Blazer’s research included collecting samples and data from patients of African descent with lupus, located at NYU as well as in Nigeria and Ghana, she said. According to Blazer, the gene was associated with worsened outcomes related to kidney disease, increased hypertension and worsened cardiovascular outcomes.

“Because APOL1 is a part of the immune system, its expression is contingent upon immune activation, so a number of inflammatory stimuli increase expression of the gene, and that causes the protein to accumulate in cells, including endothelial cells and macrophages,” Blazer said. “What we found is that that protein is supposed to help the cell deal with stress, so under an adverse condition, such as low oxygen or an inflammatory insult, the APOL1 gene is expressed and the protein is supposed to initiate autophagy, which allows the cells to digest old protein and organelles for energy so that it can make it through that stress.”

APOL1 also has a domain that is pore-forming, and a variant of the gene “has this pore-forming at a lower threshold of expression.”

“So what you end up getting is disruption in mitochondria and lysosomes, which leads to poorer energy and mobility for the cell, and also leads to a defect in the later stages of autophagy, meaning that the cell cannot complete this maintenance process,” Blazer said. “And so, cells that are expressing too much variant APOL1 end up dying under adverse host conditions earlier than cells that don’t. Now, we know in lupus there is this undulating inflammatory insult, so a number of cells are in direct contact with the cytokine storm, including blood vessels, including macrophages, and we have shown that these cells, in these conditions, do express too much APOL1, and that the variant cells end up carrying these defects.”

Disclosure: Blazer reports no relevant financial disclosures.

HILTON HEAD, S.C. — A variant of the apolipoprotein L gene could help explain why patients of African ancestry with lupus typically experience worse disease-related outcomes compared with white patients, according to Ashira Blazer, MD, a rheumatologist and assistant professor at the NYU School of Medicine.

“I studied the genetic underpinnings of differences in outcomes in African American lupus patients, and recently there have been these gene polymorphisms in the apolipoprotein L1, or the APOL1 gene, that have been shown to associate with both worse outcomes with regard to kidney disease and cardiovascular disease,” Blazer told Healio Rheumatology.

Part of Blazer’s research included collecting samples and data from patients of African descent with lupus, located at NYU as well as in Nigeria and Ghana, she said. According to Blazer, the gene was associated with worsened outcomes related to kidney disease, increased hypertension and worsened cardiovascular outcomes.

“Because APOL1 is a part of the immune system, its expression is contingent upon immune activation, so a number of inflammatory stimuli increase expression of the gene, and that causes the protein to accumulate in cells, including endothelial cells and macrophages,” Blazer said. “What we found is that that protein is supposed to help the cell deal with stress, so under an adverse condition, such as low oxygen or an inflammatory insult, the APOL1 gene is expressed and the protein is supposed to initiate autophagy, which allows the cells to digest old protein and organelles for energy so that it can make it through that stress.”

APOL1 also has a domain that is pore-forming, and a variant of the gene “has this pore-forming at a lower threshold of expression.”

“So what you end up getting is disruption in mitochondria and lysosomes, which leads to poorer energy and mobility for the cell, and also leads to a defect in the later stages of autophagy, meaning that the cell cannot complete this maintenance process,” Blazer said. “And so, cells that are expressing too much variant APOL1 end up dying under adverse host conditions earlier than cells that don’t. Now, we know in lupus there is this undulating inflammatory insult, so a number of cells are in direct contact with the cytokine storm, including blood vessels, including macrophages, and we have shown that these cells, in these conditions, do express too much APOL1, and that the variant cells end up carrying these defects.”

Disclosure: Blazer reports no relevant financial disclosures.

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