Genetic basis of cholera resistance found

Believe it or not, there is a hereditary component that determines whether a person is susceptibility to cholera or not. At least in the case of those of Bengali ethnicity in Dhaka, Bangladesh, there appears sufficient proof to say so.

According to a paper published today (July 4, 2013) in Science Translational Medicine , this population has resistance to infection caused by Vibrio cholerae , the bacterium that causes cholera, and is hence less susceptible.

According to the paper, cholera has an ancient origin, high prevalence, and high fatality rate in the Ganges River Delta region. So high is the prevalence that by age 15, more than half the population shows evidence of cholera infection. At 5-10 per cent, the mortality rate is high even today; it was once more than 50 per cent.

The three factors — ancient origin, high prevalence and high mortality — turned out to be the prime drivers in inducing a strong selection pressure. While many died, those who had genetic resistance to cholera survived the bacteria’s onslaught. These people in turn passed on the useful, protective genes to their children. Over the years, a large number of people in the population inherited the protective genes.

Many studies have found that in a household, the first-degree relatives of cholera patients have “three-fold higher risk” than those who are unrelated. Also, people living in Dhaka have the “lowest prevalence” of O blood group, and hence reduced risk of severe cholera.

While the virulence of the bacterium is well known, what makes individuals susceptible to the infection is unknown. So the team led by Dr. Elinor K. Karlsson from Harvard University looked for genomic regions that were associated with cholera susceptibility.

Whole-genome scans of 42 families (126 individuals) of Bengali ethnicity living in Dhaka were done. 305 genomic regions were found to be under selective pressure. It was narrowed down to 12 regions.

To test the genomic regions for association with cholera susceptibility, the authors compared the genomes of 105 cholera patients with that of 167 healthy people. “Our natural selection tests find regions of the genome that are under selection, but don’t tell us why they were selected — which is why we went on to do the gene enrichment analysis and comparison of cholera patients and healthy people,” Dr. Karlsson explained in an email to this Correspondent.

The findings strongly supported their hypothesis — the regions with the “strongest association” to cholera showed the most natural selection in the genome. Changes to genes in these regions provided resistance to cholera.

It contains five genes. “We still need to find the precise mutations that change the response to cholera,” she noted. The findings were reconfirmed when the whole genome of 124 people who had severe cholera was compared with that of 72 parents.

They found that natural selection had picked up many genes encoding for key pathways associated with cholera infection.

Why infection persists

But despite the positive selection to resist the infection, why do people still come down with cholera? “Clearly, cholera is still a health concern in Bangladesh and India,” Dr. Karlsson noted. “First of all, many people may still not have inherited the resistance mutations. In addition, we don’t know yet how big an effect they have.

“In evolutionary terms, even being a little bit less susceptible to a dangerous and quite common disease like cholera would have been very beneficial. We expect that people with the selected mutations are more resistant to cholera, and perhaps get less sick when they are infected, but they still might not be completely protected.”

This study has great implications. The same approach can be used in the case of other infectious diseases like TB and malaria that have been around for a very long time.

Published in The Hindu on July 4, 2013