The unlikely link between the Black Death and RA

By Jules Murtha | Medically reviewed by Anita Chandrasekaran, MD, MPH

Published September 12, 2023

Key Takeaways

A recent study revealed that survivors of the Black Death pandemic were more likely to carry genes that enabled their immune systems to effectively fight off the infection caused by the bacterium Yersinia pestis.
Researchers found that people who live with autoimmune diseases, including RA, are more likely to carry the same genes that prevented death from the Black Plague.
Scientists believe it’s unlikely that the COVID-19 pandemic will lead to long-term genetic alterations among the general public, namely due to the fact that the majority of those who died of COVID-19 were older.

Most people can confidently say that the only pandemic they lived through was the COVID-19 pandemic, which is well-known for taking millions of lives across the globe.

But many pandemics preceded COVID-19, including the Black Death (aka bubonic plague), the impact of which led to rapid genetic alterations that may be linked with the development of autoimmune diseases like rheumatoid arthritis (RA) in humans today, according to a 2022 study published by Nature.^[]

So, how could a beneficial gene that protected so many people from the Black Death become a genetic disadvantage over time? And will the COVID-19 pandemic yield similar genetic changes?

The potential genetic link

The Black Death pandemic wiped out 30% to 50% of the Afro-Eurasian population in the mid-1300s.

In order to identify how this pandemic may have influenced human genetics, researchers used 206 ancient DNA extracts to characterize genetic variation in immune-related genes, according to the Nature study. These extracts originated from two separate European populations pre- and post-plague, as well as during.

Within the London dataset alone, researchers identified 245 highly differentiated variants. Of these, 4 were replicated in an independent cohort in Denmark. According to the Nature authors, these variants “represent the strongest candidates for positive selection.”

“The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages,” they wrote.

They estimate that, when compared with individuals homozygous for the deleterious variant, those homozygous for rs2549794 had a nearly 40% higher likelihood of surviving the bubonic plague.

Furthermore, the study results suggest a direct correlation between the genetic alteration caused by the Black Death and modern day susceptibility to autoimmune and chronic inflammatory diseases.

“We show that ERAP2 is transcriptionally responsive to stimulation with a large array of pathogens, supporting its key role in the regulation of immune responses,” the authors wrote. “Therefore, selection imposed by Y. pestis on ERAP2 probably affects the immune response to other pathogens or disease traits.”

For example, one top-candidate loci, rs11571319 near CTLA4, is linked with an increased risk of both RA and systemic lupus erythematosus.

Thus, a once-protective gene to those fighting the bubonic plague is a seemingly disadvantageous gene today for those at risk of autoimmune diseases like RA.

The authors elaborate on the clinical significance of these findings, and how they might inform future research: “To date, most of the evidence for an association between autoimmune risk alleles and adaptation to past infectious diseases remains indirect, primarily because the aetiological agents driving selection remain hidden,” the authors wrote. “Our ancient genomic and functional analyses suggest that Y. pestis has been one such agent, representing empirical evidence connecting the selective force of past pandemics to present-day susceptibility to disease.”

Will COVID-19 play a role in future genetic alterations?

If you’re wondering whether the survivors of COVID-19 will pass on genes that could pave the way for autoimmune disease among our descendants, we have good news for you: It’s highly unlikely.

For one, the age of those who died from COVID-19 very much differed from those who died of the Black Death.

“Even though COVID-19 has killed millions of people worldwide, most of its victims were older,” wrote Robert Shmerling, MD, in a article published by Harvard Health Publishing.^[] “Selective pressure is most powerful when applied to a population before the age of reproduction.”

Research also shows that those who have a higher likelihood of developing a severe case of COVID-19 may carry genes that could potentially reduce their risk of a certain autoimmune diseases.

One 2022 study published by PLOS Genetics looks at the genetic material shared between existing medical conditions and COVID-19 severity.^[]

Using genotype-phenotype data from the Veterans Affairs Million Veteran Program and genome-wide association summary data from the Host Genetics Initiative, researchers conducted a Phenome-Wide Association Study of genetic variants linked with severe illness or hospitalization due to acute COVID-19.

Researchers said the risk alleles revealed that type 2 diabetes, ischemic heart disease, and deep venous thrombosis are just a few conditions associated with risk factors for severe COVID-19.

When it comes to autoimmune diseases, however, the opposite seems true.

“[W]e observed that variants associated with severe COVID-19 had an opposite association, or reduced odds with autoimmune inflammatory conditions, such as psoriasis, psoriatic arthritis, RA, and inflammatory lung conditions,” the authors wrote. The reason why is currently unclear.

Overall, the biggest takeaway from the Nature study is that genetic changes caused by pandemics that occurred hundreds of years ago have the potential to inform future susceptibility to certain diseases—a lesson worth filing away for the future.

What this means for you

Unlike other human genetic changes that can take a few hundred years, those caused by the Black Plague came to fruition rather quickly. Unfortunately, what was once a genetic benefit for those fighting the infection caused by Yersinia pestis now seemingly creates the conditions for the development of RA. COVID-19, on the other hand, is unlikely to cause dramatic changes in human genetics due to the fact that most of its victims were well beyond the age of reproduction.