Common gene variants linked to sepsis and COVID-19 severity in African Americans
Researchers identify two pathways to target for disease protection

Date:
November 16, 2021
Source:
University of Pennsylvania School of Medicine
Summary:
Two genetic risk variants that are carried by nearly 40 percent
of Black individuals may exacerbate the severity of both sepsis
and COVID-19, researchers have found.



FULL STORY ==========================================================================
Two genetic risk variants that are carried by nearly 40 percent of Black individuals may exacerbate the severity of both sepsis and COVID-19, a
team of researchers from the University of Pennsylvania's Perelman School
of Medicine have found. The findings, published in Immunity,identify
two potential pathways to reduce the health disparities driven by these
gene mutations.


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"Our findings indicate that the APOL1risk variants could explain an
important racial disparity observed in sepsis incidence and severity among Black individuals. Furthermore, our work implies that the identification
of subjects with the high-risk APOL1 genotype might be important for
disease risk prediction and early intervention," said the study's lead
author, Katalin Susztak, MD, PhD, a professor of Renal-Electrolyte and Hypertension at Penn.

Each year, at least 1.7 million adults in the United States develop
a sepsis infection, resulting in nearly 270,000 deaths. In the U.S.,
patients of African ancestry have a 67 percent higher severe sepsis hospitalization rate and 20 percent increased likelihood of dying from
the condition compared to white individuals, even after adjusting for co-variates. Similarly, COVID-19 disproportionately affects African
Americans, with higher infection rates and more severe disease.

Two variants of the geneAPOL1 --G1 and G2 --are found almost exclusively
in people of West African descent. Carrying one risk allele imparts
resistance against African sleeping sickness, while having two risk
alleles significantly increases the risk of developing chronic kidney
disease, as well as HIV and COVID- induced glomerular disease, which
has been recently studied by the Susztak lab.

To determine whether the APOL1 risk variants could contribute to the
disparity in sepsis severity between Black and white patients, Penn
Medicine researchers analyzed data from the Million Veteran Program -- a national biobank that includes genomic data on more than 840,000 veterans.

The researchers assessed the association of the APOL1 risk variants with
sepsis incidence in 57,000 Black participants, finding that there was
a statistically significant correlation between the gene variants and
sepsis incidence in this population.

Similar to sepsis, COVID-19 is associated with severe inflammation,
renal failure, and severe vascular changes. The research team obtained
plasma samples from 74 COVID-19 patients admitted to the Hospital of
the University of Pennsylvania and found that there was again a link
between patients with the APOL1 variants and higher COVID-19 severity.

To test the strength of this correlation, the research team generated
new mouse models that carried the G2 risk alleles and compared them
to controls that did not carry the variants. The study showed that
mice expressing the risk alleles experienced vascular inflammation,
leakage, and more severe sepsis. Single cell sequencing and in vivo
experiments demonstrated expression of the risk-variant alleles also led
to mitochondria damage, leading to the cytosolic release of mitochondrial
DNA.

Finally, the research team tested whether these outcomes could be
prevented, finding that inhibiting two pathways (inflammasome and STING)
in genetically- altered mice protected against the defects induced
by the risk variants. There are several new promising drugs that are
being developed to target APOL1, and the Penn team's results indicate
that genetic studies could provide critical information for precision therapeutics in treating severe sepsis and COVID-19.

This work was supported by the National Institutes of Health (NIH
NIDDK R01DK076077, R01 DK087635, and R01 DK105821) and was performed in collaboration with the Penn COVID-MESSI team.

========================================================================== Story Source: Materials provided by University_of_Pennsylvania_School_of_Medicine. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Junnan Wu, Ziyuan Ma, Archana Raman, Pazit Beckerman, Poonam
Dhillon,
Dhanunjay Mukhi, Matthew Palmer, Hua Chang Chen, Cassiane Robinson
Cohen, Thomas Dunn, John Reilly, Nuala Meyer, Michael Shahaty,
Zoltan Arany, Gyo"rgy Hasko', Krzysztof Laudanski, Adriana
Hung, Katalin Susztak. APOL1 risk variants in individuals
of African genetic ancestry drive endothelial cell defects
that exacerbate sepsis. Immunity, 2021; 54 (11): 2632 DOI:
10.1016/j.immuni.2021.10.004 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211116175017.htm

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