The pros and cons of the Black Death-fighting gene variant

The same genetics that helped some of our ancestors fight the plague are still likely to be at work in our bodies today, potentially providing some of the population with extra protection against respiratory diseases such as COVID-19. But there is a trade-off, as this same variation is also linked to increased autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.

Previous studies have revealed that survivors of the Black Death, the devastating bubonic plague pandemic in the Middle Ages, were more likely to carry certain variants (alleles) in a gene called ERAP2 than those who didn’t survive. In new research published in The American Journal of Human Genetics, UK researchers reveal that the same variants are present in humans today and providing similar protection against not only bubonic plagues but also other infections including pneumonia and COVID-19. However, the same genetic make-up is likely to be linked with increases in various autoimmune diseases.

“This gene essentially chops up proteins for the immune system,” said lead author Dr Fergus Hamilton, from the University of Bristol. “Although we don’t know the exact mechanism influencing disease risk, carriers of alleles that provide more protection against respiratory disease seem to have an increased risk of autoimmune disease. It is potentially a great example of a phenomenon termed ‘balancing selection’ — where the same allele has different effect on different diseases.”

Hamilton and colleagues looked at infection, autoimmune disease and parental longevity across participants in three large contemporary genetic studies (UK Biobank, FinnGen and GenOMICC). They used an analytical technique known as Mendelian randomisation to find associations between variation in the ERAP2 gene and risk of autoimmune disease and infection. Their findings point to antagonistic effects across these two groups of diseases driven by pressures likely to be more or less present in different human eras.

“This is a theoretical story of balance — relating to historical and contemporary disease profiles — which reflects our past and is rarely seen in real human examples,” said Professor Nicholas Timpson, also from the University of Bristol.

Identifying links between genetics and susceptibility to disease can pave the way for potential treatments. However, it also highlights potential challenges: therapeutics to target ERAP2 are currently being developed to target Crohn’s disease and cancer, so it is important to consider potential effects on the risk of infection from these agents.

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