November 10-15

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ACR Convergence 2023

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Home // Investigator demonstrates selective advantage for gene mutations that cause rheumatic disease

Investigator demonstrates selective advantage for gene mutations that cause rheumatic disease


5 minutes

Daniel L. Kastner, MD, PhD
Daniel L. Kastner, MD, PhD

Through the process of natural selection, a vast number of beneficial human genetic variants have evolved with regard to infectious diseases. These variants have helped the human race survive, but they could also be the cause of autoimmune and autoinflammatory diseases.

Rheumatologists can hear the latest research examining how natural selection has helped protect humans from infections such as malaria while simultaneously putting some individuals at risk for other, sometimes fatal, diseases in the session Natural Selection in Human Genetics: Consequences for Rheumatic Disease from 1:00 – 2:00 pm Tuesday in Room S100bc.

Investigator Daniel L. Kastner, MD, PhD, Scientific Director of the National Human Genome Research Institute, Bethesda, MD, said the relationship between sickle cell anemia and malaria is a good example of the type of genetic double-edged swords he’s uncovering with his research.

“We know that sickle cell anemia is caused by a specific mutation in the gene encoding beta globin,” he said. “We know carriers of the mutation are protected from malaria, but those individuals with two copies have sickle cell anemia, which is potentially fatal.”

As part of his discussion, Dr. Kastner will explain basic population genetics to show why nature would select a gene variant that is potentially fatal. Hint: It comes down to math.

If the carrier frequency of a particular mutated gene is 20 percent of a population, the allele frequency is one half of the carrier frequency, which is 10 percent or one in 10. Thus the odds of an individual having two copies of the variant is the square of the allele frequency, which is one in 100, or 1 percent.

“The overall benefit to the population of protection against a particular infectious disease outweighs the negative affect of having a small number of people prone to a potentially fatal illness,” Dr. Kastner said.

Given the way natural selection works in the example of the sickle cell gene mutation and malaria, Dr. Kastner and others have been researching autoimmune and autoinflammatory diseases to see if there’s a genetic variant behind them that has evolved as protection against an infectious disease.

One of the diseases he’s long been interested in is familial Mediterranean fever (FMF). Patients with familial Mediterranean fever have recurrent episodes of fever with arthritis, severe abdominal pain, or pleurisy. At least some patients develop systemic amyloidosis, which can be fatal.

“In FMF, there is a very high carrier frequency of mutations for FMF in the Mediterranean population — just as there is a high carrier frequency for sickle cell mutations in sub-Saharan Africa, where malaria is endemic,” Dr. Kastner said.

Dr. Kastner’s research group discovered the gene for FMF in 1997. Based on that discovery and the identification of mutations in the gene, they confirmed there are certain mutations that cause FMF that are common among Jewish, Arab, Turkish, Greek, Italian, and Armenian populations in the Mediterranean basin and Middle East. In places, the carrier frequency is as high as one in five—or 20 percent.

However, Dr. Kastner said, there were multiple mutations discovered for FMF, unlike the situation with sickle cell anemia and malaria, where one mutation is responsible.

“For familial Mediterranean fever, there are three or four mutations common in Mediterranean populations,” he said. “It’s not a coincidence. Multiple mutations have been selected. It didn’t just happen once.”

Until recently, Dr. Kastner and other researchers were perplexed about what drove the high carrier frequency of FMF in these populations. The reason a mutation on that gene would be a selective advantage was unknown.

A breakthrough came in 2014 when a group from China published a paper in Nature demonstrating that when bacterial toxins inactivate RhoA, a key molecule in host defense, they indirectly trigger the FMF gene product pyrin to activate interleukin-1, a potent inflammatory cytokine.

“RhoA is vital to white blood cell migration, phagocytosis, and degranulation—all of which are important to our response to infectious disease,” Dr. Kastner said. “So we finally knew that the function of the FMF gene in normal—non-mutated—physiology is to ‘sense’ and respond to bacterial toxins that inactivate RhoA. Because RhoA is important for all of these processes for host defense, the bacteria evolved toxins that would inactivate this thing that is so important.

“It’s like the bacteria found an Achilles heel. The mammalian host, in turn, has evolved this pyrin inflammasome system, which leads to the activation of IL-1 beta, which has an anti-bacterial effect. So you have RhoA, which is important for host defense in the first place. Bacteria evolve toxins to inactivate RhoA, and we, in turn, have evolved pyrin and the pyrin inflammasome to produce more IL-1 to counter the bacteria. It’s a cat-and-mouse game.”

However, none of this revealed a particular infectious disease that may have been the reason for the natural selection of FMF mutations. To solve that mystery, Dr. Kastner’s group has done a series of experiments looking at bacteria to see if there is some increased survival value conferred by having mutations in the FMF gene.

“What we found was a back-and-forth relationship between humans and one particular bacterium—Yersinia pestis. The organism that is the causative agent of the bubonic plague,” Dr. Kastner said.

In his talk, he will describe this relationship between the toxins produced by Yersinia pestis and the pyrin inflammasome associated with the FMF gene mutation.

“You have a situation in which individuals who have the mutation in the pyrin protein associated with FMF can still produce IL-1 beta in response to bubonic plague, even though most people cannot,” he said.

He will also share details from experiments with mouse models to confirm this link between familial Mediterranean fever and bubonic plague.

“We have mice that are wild type or have various FMF mutations, and we can expose those to various laboratory strains of plague,” Dr. Kastner said. “What we see is that the wild type mice without the mutation all die. However, the mice with FMF-associated mutations are protected from the lethal effects of plague. Not 100 percent, but there’s a significant survival advantage in the mice with the mutations. We think that’s good evidence that FMF-associated pyrin mutations confer a selective advantage against the plague.”