Research Roundup: Genetic Variants Associated with Severe COVID-19 and More

Genetic sequence

Specific comorbidities and conditions have been associated with severe COVID-19, including diabetes, obesity, and, of course, older age. But researchers have now identified 16 new genetic variants associated with severe COVID-19. For that and more research stories, continue reading.

16 Genetic Variants Associated with Severe COVID-19

Investigators with the University of Edinburgh analyzed the genomes of 57,000 people, part of the GenOMICC consortium, a global collaboration to study genetics in critical diseases. They identified 16 new genetic variants associated with severe COVID-19 and sequenced the genomes of 7,491 patients from 224 intensive care units in the U.K. That DNA was compared with 48,400 other people who did not have COVID-19. They were participants in Genomics England’s 100,000 Genomes Project and another 1,630 people who had mild COVID-19. The findings are published in Nature.

“Our latest findings point to specific molecular targets in critical COVID-19,” said Professor Kenneth Baillie, the project’s chief investigator and a Consultant in Critical Care Medicine at the University of Edinburgh. “These results explain why some people develop life-threatening COVID-19, while others get no symptoms at all. But more importantly, this gives us a deep understanding of the process of disease and is a big step forward in finding more effective treatments.”

In addition to the 16 new gene variations, they confirmed seven other genetic variations that were already linked with severe COVID-19. Part of their findings was a single gene variant that can disrupt interferon alpha-10, a key messenger molecule in immune system signaling. This variant alone was enough to increase a patient’s severe disease risk. Another variation is Factor 8, which is important to blood clotting, and was connected to critical COVID-19.

Nanoparticle decreases Scleroderma Skin and Lung Scarring

Researchers with Michigan Medicine – University of Michigan identified a unique macrophage, a type of immune cell, that plays a significant role in the chronic inflammation and scarring seen in the lungs and skin of scleroderma patients. The macrophage, dubbed MARCO+, was isolated in people with the disease, which is rare and affects about 70,000 people in the U.S. They then, working with laboratory mice, injected the animals with biodegradable PLG (lactic-co-glycolic acid) nanoparticles that targeted MARCO+ inflammatory cells. This appeared to prevent the skin and lung fibrosis in the mice associated with the disease. The team theorizes that the MARCO+ cells are activated in scleroderma, circulate in the bloodstream, move to tissues, and cause scar formation.

A Predictive Model for Rheumatoid Arthritis

Scientists from Tokyo Medical and Dental University developed a genomic model to predict the progression of rheumatoid arthritis. They utilized data from a genome-wide association study (GWAS) of R.A. susceptibility. They then developed a polygenic risk score (PRS) and tested it to predict radiographic progression in people with rheumatoid arthritis. Earlier studies identified specific genetic factors for R.A. progression, including anti-citrullinated protein antibodies (ACPAs) and variants in the human leukocyte antigen (HLA) region of the chromosome that regulates the immune system. Those are useful but not considered robust. Their new analysis found that patients with a higher PRS had a higher risk of severe progression, particularly in people who were younger at the onset.

microRNAs Unique to Human Beings

Student researchers at John Jay College of Criminal Justice identified human microRNA genes that are not found in any other primate species. They believe they may have had a significant role in the evolution of human beings. They found at least three families of microRNA genes on chromosome 21. They leveraged genome alignment tools and compared the most recent versions of human and chimpanzee genomes, working to find genetic elements unique to humans. 

On chromosome 21, they found a large region of unique DNA called 21p11, which harbors several orphan microRNA genes. The long arm of human chromosome 21 matches up well with other ape species, but the short arm aligns poorly. The microRNAs in that region, specifically miR3648 and miR6724, probably evolved since the chimpanzee and human lineages split — probably in the last seven million years.

Organs Age at Different Rates

You’re only as old as you feel, right? Well, maybe. But new research out of the Beijing Genomics Institute and China National GeneBank in Shenzhen, China, found that different organs and systems have different ages from a biological perspective. 

Using biomarkers, statistical modeling, and other tools, they analyzed the aging in 4,066 volunteers who supplied blood and stool samples, facial skin images, and to undergo physical fitness examinations. They were between the ages of 20 and 45 years. They measured 403 features: 74 metabolomic features, 34 clinical biomarkers, 10 electroencephalography features, 16 facial skin features, and 210 gut microbiome features. They then classified them into nine categories, including cardiovascular-related, renal-related, liver-related, sex hormone, facial skin, nutrition and metabolism, immune system, physical fitness-related and gut microbiome features. They found that the biological ages of different organs and bodily systems had diverse correlations. They also examined single nucleotide polymorphisms (SNPs) and identified certain genetic changes associated with aging-related pathways.

FDA-Approved Drug Halts RAS-Based Tumor Growth

Researchers with the University of California, San Francisco used an FDA-approved drug to stop tumor growth in cancers driven by mutations in the RAS gene. RAS mutations are typically difficult to treat and make up about one in four cancer deaths. They found that cancer cells require a reactive form of iron called ferrous iron. They then modified an anticancer drug to work only on these iron-rich cells, allowing other cells to function normally. They focused their research on RAS-mutated pancreatic and gastrointestinal cancers. Cobimetinib and similar drugs are effective at blocking the excessive growth stimulated by RAS mutations and do the same thing in non-cancer tissue, which causes serious side effects that lead many patients to discontinue treatment. They modified cobimetinib to have a small molecule that senses ferrous iron, which essentially shuts cobimetinib off until it meets up with ferrous iron in the cancer cells.

“By removing toxicity from the equation, you’re talking not just about one new drug, but 10 new combinations that you can now think about exploring in the clinic,” said Adam Renslo, a pharmaceutical chemist at UCSF and co-author of the study. “That would be the home run for this approach.”

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