Genes for Gaucher disease may have protected Jews from tuberculosis

Gaucher disease, a genetic disorder more common in Ashkenazi Jews, may offer protection against tuberculosis, according to a zebrafish study.

A genetic disorder called Gaucher’s disease, which is more common in some Jewish groups, may help protect people from TB, perhaps explaining why it persists.

When zebrafish are injected with the same mutations that lead to Gaucher disease, they are less susceptible to infection by the bacteria that causes tuberculosis.

Ashkenazi Jews, who make up about 8 out of 10 of all Jews, have a higher-than-average rate of Gaucher disease, the symptoms of which range from pain and fatigue to an enlarged liver and spleen.

This is caused by a malfunction of a type of immune cell called macrophages, whose job it is to engulf bacteria in internal compartments called lysosomes, where the microbes die. Unlike most bacteria, those that cause tuberculosis are called Mycobacterium tuberculosiscan survive inside lysosomes, allowing infection to spread to macrophages in the lungs.

There are several hundred mutations that cause Gaucher’s disease, but they all lead to the accumulation of fat in lysosomes. Lalita Ramakrishnan of the University of Cambridge and her colleagues investigated the effect of these mutations on zebrafish, which are sometimes used to study tuberculosis because they develop the same disease when infected. Mycobacteria marinea close relative of the human tuberculosis bacterium.

The team gave the fish the most common mutations that cause Gaucher disease in Ashkenazi Jews. As expected, fat accumulated in the lysosomes of their macrophages.

On two counts, the fish were less susceptible to infection. For example, in a test in which they were injected with a single bacterium, 42% of the mutated animals remained uninfected compared to 13% of fish without the mutations. “The host has a better chance of killing the bacteria,” Ramakrishnan says.

Further experiments showed that the type of fat that accumulates inside lysosomes is toxic to both human TB bacteria and the fish equivalent when grown in a dish. “The accumulation of this fat has detergent activity. This [disrupts] membranes of tuberculosis bacteria,” says Ramakrishnan.

Tuberculosis has been the leading cause of death in Europe over the past centuries, especially for those living in crowded conditions. Today, about 1 in 800 Ashkenazi Jews have Gaucher disease, but the figure could have been higher a few hundred years ago, when TB was more prevalent in Europe, Ramakrishnan says.

The variants that cause Gaucher disease in Ashkenazi Jews tend to result in a milder form of the disease than some other mutations, she says, supporting the idea that they may have been selected because they reduced people’s vulnerability to tuberculosis.

Mark Thomas of University College London says another explanation is that the Jewish population was previously small, and so a single person’s random mutation was inherited by many of their descendants. “There is strong evidence for the existence of small population bottlenecks in the Middle Ages, but this does not rule out the possibility [Gaucher mutations causing] some advantage in certain circumstances.