ktsimage; John Abbott
ktsimage; John Abbott

Heritage and Health Discrepancies

by Jackie Swift

One of the notable aspects of the COVID-19 pandemic is the discrepancy in health outcomes between people of different racial and social backgrounds. In the United States, for instance, African Americans are 3.7 times more likely to be hospitalized with COVID-19 symptoms compared to white Americans, according to the Centers for Disease Control and Prevention. They are also 2.8 times more likely to die from the virus.

Melissa B. Davis, Surgery, Weill Cornell Medicine, homed in on these disparities early in the pandemic. In particular, she was struck by a key symptom in patients of all backgrounds with severe COVID-19: Their bodies may produce a sudden, massive, uncontrolled release of inflammatory signaling molecules called cytokines—producing what’s known as a cytokine storm, which often causes death. “I immediately thought about how Black people with West African heritage may have more critical inflammatory reactions because they carry a special gene mutation that affects their ability to clear inflammatory chemokines from circulation in the bloodstream,” she says.

Duffy-Null Mutation, Severe COVID-19 Linked?

The gene mutation, known as Duffy null, affects the Duffy Antigen Receptor for Chemokines (DARC) gene. “It was fixed in African populations prior to the slave trade because it conveyed resistance to some forms of malaria, which is an ongoing endemic problem in West Africa,” Davis explains. “People descended from enslaved Africans are known to commonly carry this mutation. The DARC gene plays a regulatory role of the immune system response systemically, and Duffy null modifies this regulation, removing expression of DARC on red blood cells. This effectively increases the longevity of inflammatory chemokines during infections. Knowing this, I wondered how much more it would impact a population that is overexposed for COVID anyway.”

Davis is currently working with colleagues at Weill Cornell Medicine’s Clinical Translational Science Center and the Caryl and Israel Englander Institute for Precision Medicine to assess whether there are biological determinants associated with more severe COVID-19, even in the context of social determinants already known to impact health outcomes overall. The researchers have been modeling clinical risk factors such as obesity, heart disease, and hypertension to determine the impact they have on the severity of COVID-19 outcomes and patient mortality.

“When we break that analysis down within race groups, we find that some factors actually are less significant in impacting outcomes in the Black population compared to the Hispanic and white populations,” Davis says.

One reason for this could be that although risk factors like diabetes or obesity influence a worse outcome generally, other yet-unmeasured variables in the African American population are compounded with these known factors, and these interactions could be driving a worse outcome for certain groups of patients, Davis says. Her theory is that the Duffy-null mutation is one of those variables, and she is continuing to pursue this line of research.

Ancestry’s Role in Triple Negative Breast Cancer

The Duffy-null mutation is familiar to Davis because she has been investigating it for some time as part of her research on an aggressive subtype of cancer known as triple negative breast cancer (TNBC). This type of breast cancer is characterized by the lack of expression of three hormone receptors— estrogen, progesterone, and Human Epidermal Growth Factor Receptor 2 (HER2). Typically, in other types of breast cancers, one or more of these receptors are positive, thus allowing for treatment by drugs that target the steroid pathway to block the signal that causes the tumor to grow and metastasize. TNBC, however, has no targeted therapy, and treatment still consists of the same interventions of 30 years ago: systemic chemotherapy, radiation, and surgery.

Davis became intrigued by TNBC during her postdoctoral work at the University of Chicago where she collaborated on a University of Chicago Hospital study comparing breast cancer patients from the more affluent North Side, who tended to be white, with patients from the poorer South Side, who tended to be Black. The researchers found that even when they controlled for socioeconomic differences, there were differences in survival rates between the two groups, as well as differences in tumor characteristics. Black women were much more likely to have the aggressive, hard-to-treat TNBC, and they were more likely to die from it.

“In every country where there is data available ... we find triple negative breast cancer is more frequent in the component of the population that may be of African descent.”

“That was enlightening to me in two ways,” Davis says. “First, it showed that there could be biological differences driving differences in survival rates. It isn’t always that poorer women aren’t coming to the hospital in time; it’s that once they get there, the treatment options for the type of tumors that they have are less effective than treatments for other tumor types. And second, while poverty and disadvantaged health care are always contributors to survival, these social factors preventing access to care and driving disparities in cancer survival weren’t an issue in this study because both groups of patients were coming to the same hospital, seeing the same doctors, and getting the same treatments for the same types of diagnoses.”

Following that train of thought, Davis continued to investigate TNBC. She moved on to the Henry Ford Health Systems in Detroit and teamed up with a colleague, Lisa A. Newman, now chief of breast surgery at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center. Davis and Newman noticed that women of West African ancestry had higher rates of TNBC, combined with prevalence of Duffy-null mutation. The Davis lab has since discovered that these women also have a tumor immune profile with high inflammation and unique immune responses compared to women without the mutation.

Pursuing Oncologic Anthropology

Both researchers eventually joined Weill Cornell Medicine where they co-lead the International Center for the Study of Breast Cancer Subtypes (ICSBCS) and continue to collaborate, especially on a type of research they call oncologic anthropology. “In every country where there is data available for subtypes of breast cancer, we find TNBC is more frequent in the component of the population that may be of African descent,” Davis says. “Recently we discovered that the DARC Duffy-null mutation is actually associated with a higher risk specifically for that type of cancer, and the DARC gene is driving a unique immune response in tumors. Now my work is about characterizing that difference in the immune response to see whether there is a potential for targeted therapy.”

Davis was drawn to study cancer risk and genetic ancestry as a way to make health outcomes better in her own family and in Black communities generally. “As a first-generation PhD, I believed my best career path was either to be a medical doctor or a lawyer, and I chose medicine,” she says. “But as I started down that career path, I began to see that I didn’t have to be a medical doctor to make a difference. I saw the world behind the clinical world—this network of scientists, of researchers, who were really influencing medicine. I decided that if I could influence that stream of information as a researcher, then maybe my findings would eventually trickle down into communities by changing how medical professionals approached treatment.”