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An international research team has used a novel approach to identify genetic factors that appear to influence susceptibility to cholera, a disease that affects from 3 to 5 million people each year and causes more than 100,000 deaths. The findings indicate the importance of pathways involved in regulating water loss in intestinal cells and highlight the innate immune system’s key role in the body’s response to the bacteria that causes cholera.
The work involved investigators from Harvard Medical School and Massachusetts General Hospital; the Broad Institute; and the International Center for Diarrhoeal Disease Research, Bangladesh.
“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,” said Regina LaRocque, an assistant professor of medicine at Mass General and a co-senior author of the report published in Science Translational Medicine. “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.”
People contract cholera by consuming water or food contaminated with the bacteria Vibrio cholerae, which releases a toxic protein upon reaching the small intestine. This toxin binds to the intestinal surface, causing severe diarrhea and sometimes death from dehydration. Cholera or cholera-like illnesses have been reported in the Ganges Delta for centuries, and most recent global outbreaks of the disease originated in that region.
A potential fingerprint of cholera’s genetic impact could be the relative rarity in the region of people with blood type O, which confers an increased risk of severe cholera symptoms. The persistence of cholera in the Ganges Delta would be expected to exert an evolutionary force on the population, since individuals with gene variants that reduce their susceptibility to the disease would be more likely to survive and pass those variants along to their children.
To search for genomic regions that affect cholera susceptibility, the team employed a new two-step approach. The first step, developed by the Broad team, used a method called Composite of Multiple Signals (CMS) to scan the genomes of 126 individuals from the Ganges Delta for patterns that signal a long-term increase in the prevalence of particular DNA segments, indicating the effects of natural selection. That scan identified 305 regions under selective pressure, many of which are involved in two important biologic functions. One is regulation of the passage of water through intestinal cells via structures called potassium channels and the other is a signaling pathway involved in both the innate immune system and the maintenance of the intestinal lining.
The second step directly tested the potential impact of these selected regions on cholera susceptibility by comparing the genomes of 105 cholera patients from the region with the genomes of 167 individuals who did not contract the disease, despite being exposed to it in their homes. That comparison found that the genomic region most strongly associated with cholera susceptibility in this population was one that the CMS scan indicated was under strong selection pressure. Genes in this region relate to an innate immune signaling pathway. LaRocque’s team had previously shown this pathway to be activated by exposure to cholera toxin, and the current study identified the potential involvement of several additional genes in that pathway
“Understanding the basic biology of a disease is fundamental to making clinically relevant advances in treatment,” said LaRocque. “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.”
Support for the study includes National Institutes of Health grants TW007409, AI058935, AI079198 and NIH Innovator Award DP2-OD006514-01; grants from the Howard Hughes Medical Institute, the American Cancer Society and the Packard Foundation; and an MGH Claflin Distinguished Scholar Award.
Adapted from a Mass General news release.