Using a new approach, scientists have identified genetic factors that may explain why some people are more susceptible to cholera and others less so. They searched the genomes of people who live in a region where cholera has been endemic for centuries and found signs of possible natural selection pressure in parts of DNA linked to water regulation and immune function.
The international team, whose members include investigators from Massachusetts General Hospital (MGH), the Broad Institute of MIT and Harvard in the US, and the International Centre for Diarrhoeal Disease Research in Bangladesh, write about their work in a recent online issue of Science Translational Medicine.
Cholera affects 3 to 5 million people globally each year and kills more than 100,000.
The Ganges River Delta is home to a population that has known cholera, or cholera-like illness, for centuries, and most of the recent global outbreaks of the disease, which is caused by a strain of the bacterium Vibrio cholerae, have originated there.
The bacterium enters the body through contaminated water or food. When it reaches the small intestine, it releases a toxic protein that binds to the gut lining, causing severe diarrhea and risk of death from dehydration.
The researchers suggest that the relative rarity of blood type O among dwellers of the Ganges Delta could be a potential “fingerprint” of the genetic impact of the disease. Individuals of blood type O are more susceptible to severe cholera.
They wondered if the persistence of cholera in the region has exerted an evolutionary or “natural selection” pressure on the population: people with gene variants that help them withstand the infection would be more likely to survive into adulthood, have children, and pass those variants on to future generations.
Co-senior author Regina LaRocque, from MGH’s Division of Infectious Diseases, says in a statement:
“We sought to understand cholera by studying the genetics of a population that has been affected by the disease for centuries – people in the Ganges River Delta of Bangladesh.”
The study consists of two parts. In the first part, the team used a method called Composite of Multiple Signals (CMS) to scan the genomes of 126 people from the Ganges Delta. They looked for patterns that might indicate certain DNA segments have increased under pressure of natural selection.
They located 305 potential regions, including many that deal with two functions relevant to how the body responds to cholera.
One function is to do with regulation of water passing through the cells of the gut. The affected genes code for potassium channels that control a process involving the discharge of chloride, which leads to the large amounts of water that feature in severe diarrhea.
The other function affects a signaling pathway that is involved in both the innate immune system and maintaining the lining of the gut.
In the second part of the study, the team compared the genomes of two groups of people from the Ganges Delta. One group was 105 patients who contracted cholera, and the other group was 167 people who did not contract it, despite being in contact with people who had the disease in their homes.
They found that the segment of DNA most strongly linked with cholera susceptibility was one of the areas the CMS scan had earlier proposed as being under selective pressure from the pathogen.
The genes in this part of the genome are involved in a signaling pathway of the innate immune system. In an earlier study, the team had already shown this same pathway was activated by the cholera toxin. This latest study has pointed out a few more genes in that pathway.
The researchers say more work now needs to be done to find out how the immune system responds to cholera, and they hope this will lead to improved vaccines.
People with blood type O are less protected by current vaccines against cholera.
“Understanding the basic biology of a disease is fundamental to making clinically relevant advances in treatment. Our laboratory is now working on further studies of the innate immune response to cholera, and we believe this work will be highly relevant to developing improved vaccines,” says LaRocque.
The team suggests their new approach could also be used to identify genetic factors that affect susceptibility and resistance in other diseases.
LaRocque says this study is just the beginning:
“Our findings are just a first step, but they demonstrate how combining ancient history with the current impact of an infectious disease can be a powerful way of identifying human genes that are important to disease outcome.”
Grants from the National Institutes of Health (NIH), the Howard Hughes Medical Institute, the American Cancer Society and the Packard Foundation, plus an MGH Claflin Distinguished Scholar Award helped finance the study.
In 2011, scientists reported finding a link between cholera outbreaks and rises in river flow. The Ganges was one of the rivers they studied.
Written by Catharine Paddock PhD