Some people with COVID-19 experience the disease more severely than others. Previous research has identified certain variants in specific human genes that are associated with a person experiencing more severe COVID-19. Some of these variants may also be associated with other medical conditions that may already be well understood; identifying these shared variants could improve understanding of COVID-19 and illuminate potential new paths for treatment.

To identify shared variants, Verma and colleagues used an unprecedented dataset of genotypic information linked to electronic health record data (EHR) for more than 650,000 U.S. veterans. They conducted a type of analysis known as a phenome-wide association study (PheWAS) to examine links between variants often found in Veterans who experienced severe COVID-19 and variants associated with a broad selection of medical conditions.

The analysis revealed that certain variants associated with COVID-19 are also associated with known risk factors for COVID-19. Particularly strong links were found for variants associated with venous embolism and thrombosis, as well as type 2 diabetes and ischemic heart disease — two known COVID-19 risk factors.

The analysis also found genetic links between severe COVID-19 and neutropenia for Veterans of African and Hispanic ancestry; these links did not appear for those of European ancestry.

Among respiratory conditions, idiopathic pulmonary fibrosis and chronic alveolar lung disease shared genetic links with severe COVID-19, but other respiratory infections and chronic obstructive pulmonary disease (COPD) did not. Some variants associated with severe COVID-19 were also associated with reduced risk of autoimmune conditions, such as psoriasis and lupus. These findings highlight the need to carefully weigh various aspects of the immune system when developing new treatments.

Despite some limitations of the PheWAS method, these findings could help deepen understanding of COVID-19 and guide development of new treatments.

Verma concludes, “The study demonstrates the value and impact of large biobanks linking genetic variations with EHR data in public health response to the current and future pandemics. MVP is one of the most diverse cohorts in the US. We had a unique opportunity to scan thousands of conditions documented before the COVID-19 pandemic. We gained insights into the genetic architecture of COVID-19 risk factors and disease complication.”

“One thing that stood out to us was the high number of immune-mediated conditions that shared genetic architecture with severe manifestations of COVID-19,” coauthor Katherine Liao adds. “The nature of the associations brought to light how the SARS-CoV2 virus pushes on a pressure point in the human immune system and its constant balancing act of fighting infection while maintaining enough control so that it does not also become an autoimmune process, attacking self.”

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The Centers for Disease Control estimates that the bacterium causes approximately 500,000 infections in the United States annually, with severe diarrhea and colitis (inflammation of the colon) as characteristic symptoms.

The researchers’ findings are published in the April 27, 2022 online issue of PNAS.

C. difficile is the most dominant cause of hospital-associated infections, in part from the use of antibiotics, which can kill enough healthy bacteria to allow C. difficile to grow unchecked. Infections are particularly dangerous in older persons. One in 11 people over the age of 65 who are diagnosed with a hospital-associated case of C. difficile die within one month, reports the CDC.

“C. diff is persistent and pervasive,” said senior author Jonathan M. Monk, PhD, a research scientist in the Systems Biology Research Group at UC San Diego, directed by Bernhard O. Palsson, PhD, professor of bioengineering and an adjunct professor in the UC San Diego School of Medicine. “It doesn’t cause typical diarrhea. Most people do recover, but some become seriously ill, require hospitalization and some die from complications like kidney failure or sepsis.”

To better understand the genetic features of C. difficile — and thus develop models that can identify and predict its complex and constant evolution — researchers used whole-genome sequencing, high-throughput phenotypic screening and metabolic modeling of 451 bacterial strains.

This data was used to construct a “pangenome” or entire set of genes representative of all known C. difficile strains, from which they identified 9,924 distinct gene clusters, of which 2,899 were considered to be core (found in all strains) while 7,025 were “accessory” (present in some strains but missing in others).

Using a new typing method, they categorized 176 genetically distinct groups of strains.

“Typing by accessory genome allows for the discovery of newly acquired genes in genomes of pathogens that may otherwise go unnoticed with standard typing methods,” said co-author Jennifer K. Spinler, PhD, an instructor in pathology and immunology at the Baylor College of Medicine. “This could be critical in understanding what drives an outbreak and how to fight its spread.”

Thirty-five strains representing the overall set were experimentally profiled with 95 different nutrient sources, revealing 26 distinct growth profiles. The team then built 451 strain-specific genome scale models of metabolism to computationally produce phenotype diversity in 28,864 unique conditions. The models were able to correctly predict growth in 76 percent of measured cases.

“One of the strengths of the presented work is the cohesion of distinct biological data types into comprehensive systems biology frameworks that enable analysis at scale,” said first author Charles J. Norsigian, PhD, a data scientist in the Systems Biology Research Group. “By interpreting strains of C. difficile in a population context, we were able to bring to light pertinent strain features regarding nutrient niche, virulence factors, and antimicrobial resistance determinants that might have otherwise gone undetected.”

Co-authors include: Bernhard O. Palsson, UC San Diego; Heather A. Danhof, Colleen K. Brand, Firas S. Midani, Robert A. Britton and Tor C. Savidge, Baylor College of Medicine; and Jared T. Broddrick and Jennifer K. Spinier, NASA Ames Research Center.

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“Despite the common experience of swallowing medications orally, there is a huge number of therapies that are not available orally,” says Khatcher Margossian, the lead author of the study and a candidate for a dual M.D./Ph.D. from Rush Medical College and the UMass Amherst Department of Polymer Science and Engineering, respectively. This is because there are many drugs that can’t withstand the stomach’s harshly acidic environment. Two ways around this problem are to either inject or implant medications; but in both cases, the pain, fear and potential side effects can limit a patient’s willingness to undergo treatment or to stick with the treatment plan through its full course. And even those drugs that are strong enough to withstand the stomach’s acid and make it through to the small intestine, where they can be absorbed into the bloodstream, often do not make it through entirely intact. “The doses of oral medications are usually larger than what our body really needs,” explains Murugappan Muthukumar, the Wilmer D. Barrett Professor in Polymer Science and Engineering at UMass Amherst and the study’s senior author. “This is because some of the medication decomposes in the stomach.”

“If there were some way to protect this precious therapeutic cargo,” says Margossian, “we could expand the library of medications that we can deliver orally.” Figuring out how to protect the precious cargo is exactly what Margossian, Muthukumar, and their colleagues have done.

The study, recently published in Nature Communications, details a new class of material, called a pZC, which forms through a process known as “complex coacervation.” In their system, two types of charged polymers, a polyzwitterion and a polyelectrolyte, associate to form a protective droplet inside of which medications can travel. The trick that the pZC has to perform is that it not only needs to be tough enough to withstand the highly acidic stomach environment, it also has to disassemble in the much gentler, neutral conditions of the small intestine.

Paradoxically, the key to the group’s success was not to strengthen the bonds between the polyzwitterion and polyelectrolyte but to weaken them. “Weakening the association between the two materials,” says Muthukumar, “allows us to control precisely when they come apart. If the bonds are too strong, then there’s no room to play.”

The group’s research is driven by the real-life needs of medical practitioners. Not only will these materials allow clinicians to more efficiently deliver the right dosages of drugs, but they will vastly increase the number of medications that can be taken orally. “This is a foundational technology that can alter how we treat disease,” says Margossian. “We hope that our work will make its way into clinicians’ hands and help them save lives.”

This research was supported by the National Science Foundation and the Air Force Office of Scientific Research.

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Scientists have known that mutations to three cardiac transcription factors — GATA4, NKX2-5 and TBX5 — lead to a range of congenital heart disease states. Researchers have thought that an inability of these mutated genes to “turn on” cardiac genes is what led to heart disease.

Now, the lab of Frank Conlon, PhD, professor of biology and genetics at the University of North Carolina at Chapel Hill, discovered there’s more to the story. It involves non-cardiac genes, as well as answering a question researchers have struggled with for years.

Aside from the aforementioned transcription factors, past research showed that a protein complex subunit called CHD4 seems to play a major role in congenital heart disease. Deleting it causes embryonic death in animal models. Mutations to it cause major problems with proteins involved in skeletal and muscle development.

Turns out, CHD4 is essential for numerous developmental events, such as ensuring proper timing of the switch from stem cell lineages to differentiated cell types — that is, the moment when stem cells turn into, say, heart cells or leg muscle cells. CDH4 also is essential for maintaining cell differentiation — keeping heart cells healthy heart cells. And CDH4 is a player in activating cellular processes to deal with DNA damage.

Yet, CHD4 cannot bind DNA. It needs to be brought to a specific location, or genetic loci, of a cardiac gene to do its things. So, scientists could not answer the key question of how CHD4 played its role in cardiac disease.

Conlon’s lab, in collaboration with colleagues at UNC-Chapel Hill, Princeton, and Boston Children’s Hospital, shows that GATA4, NKX2-5 and TBX5 interact with CHD4 inside the embryonic heart, recruiting it for action, and that’s how CHD4 plays its role in heart health and disease.

These findings, published in the journal Genes & Development, imply that heart disease states are not only due to loss of cardiac gene expression, but that these genes’ recruitment of CHD4 can lead to a misexpression of non-cardiac genes, leading in the end to faulty heart development.

To put this implication to the test, Conlon and his collaborators removed the binding site for Nkx2-5 in the skeletal muscle gene Acta1 in mice and, independently, the GATA4 binding site in the smooth muscle gene Myh11.

“In both instances, the mutation led to the inappropriate expression of the non-cardiac genes in the heart in a dominant manner,” said Conlon, a member of the UNC McAllister Heart Institute. “This provides a mechanism for the prevalence of congenital heart disease in humans with just one mutated copy of Nkx2-5, Gata4 or Tbx5.”

Other authors include, co-first authors Zachary L. Robbe and Wei Shi in the Conlon lab; Lauren K. Wasson, Angel P. Scialdone, Caralynn M. Wilczewski1, Austin J. Hepperla, and Ian J. Davis at UNC-Chapel Hill; Brynn N. Akerberg and William T. Pu at Boston Children’s Hospital; and Ileana M. Cristea and Xinlei Sheng at Princeton University.

This work was supported by grants from the NIH/NHLBI (R01HL156424) to Frank Conlon, and (R01HD089275) to Frank Conlon and and Ileana Cristae, and (NIH-2UM1HL098166) to William Pu.