Your genes likely determine your risk of diarrhoea

Uncovering the genetic causes of disease has long been a major goal and promise in biomedical research. Genes encode proteins that perform specific roles in how an organism functions, and disruption of their function through genetic changes or mutations often leads to disruption of physiology — what we think of as disease. While many diseases, including Huntington’s disease, sickle cell anemia, and muscular dystrophy, have been successfully pinpointed to arise from mutations in single genes, most diseases are shaped by variation across multiple genes, as well as the organism’s environment.
Genomic studies have not only revealed complex genetic bases of diseases like Alzheimer’s disease, Type 1 diabetes, and asthma, but also of susceptibility to many infectious diseases. A series of recent studies conducted in Bangladesh by icddr,b and collaborators have made major contributions to our understanding of how the host genome — the genetic makeup of the infected individual — can shape whether and how severely an individual is affected by many diarrhoeal diseases.

Introducing GWAS

Studies investigating genetic variation underlying a disease or trait commonly use a method known as GWAS (genome-wide association studies), which looks for mutations or genetic variants that are at significantly different frequencies between cases — for instance, individuals who have diarrhoea — and controls. If a particular variant increases susceptibility to diarrhoea, it should be more common in individuals with diarrhoea than in controls who do not. Conversely, if individuals with no diarrhoea are considered the cases, one may identify variants associated with protection from diarrhoea by comparing to control individuals with diarrhoea.
Globally, diarrhoea is the second leading cause of death among children under five, killing 525,000 children under five every year. Several diarrhoeal pathogens remain endemic in Bangladesh, including rotavirus, Shigella, and Vibrio cholerae. Recent GWAS studies by icddr,b and collaborators have taken advantage of three birth cohorts to identify genetic variants that possibly protect against or increase susceptibility to many of these pathogens. In each birth cohort, infants were enrolled within one week after birth and then evaluated for different illnesses including diarrhoea for at least a year via weekly visits. The cohorts — Dhaka Birth Cohort (DBC), the “Performance of Rotavirus and Oral Polio Vaccines in Developing Countries” cohort (PROVIDE), and Cryptosporidiosis Birth Cohort — provide genome-wide data on the enrolled infants, as well as stool or clinical samples collected at regular intervals for surveillance, or during diarrhoeal episodes. The stool samples allow identification of specific pathogens associated with diarrhoea cases.

icddr,b helps identify genetic variants associated with risk of diarrhoeal diseases

The most recent such study, published in the Journal of Infectious Diseases in March 2023, investigated whether genetic variation among infants influenced the frequency or duration of diarrhoea over the first year of life. The authors compared infants who had no diarrhoea over the period to those with at least six episodes and with at least 25 days with diarrhoea and identified three protective variants — two each for frequency and duration, with one shared between them. The variants occur near or within genes or genomic regions known to be involved in intestinal inflammation and controlling intestinal blood flow and secretions.
These findings add to other recent discoveries by the same group, revealing unique genetic variants and biological pathways involved in different diarrhoeal diseases. For instance, in a 2021 study on Shigella-associated diarrhoea, they reported four risk-associated variants in genomic regions linked to the modulation of bacterial secretion systems that are important for invasion of host cells by bacteria. A 2018 study identified variants in and near a gene called CREM, that increase risk of diarrhoea resulting from Entamoeba histolytica infection. CREM is involved in intestinal inflammation and mediates susceptibility to intestinal bowel disease (IBD), a chronic inflammatory disease — suggesting shared pathological mechanisms of the two diseases. A. Findings like these — also reported for Campylobacter- and Cryptosporidium-associated diarrhoea — thus provide insight into biological mechanisms underlying susceptibility to different infectious diseases, generating novel hypotheses to test and possibly allowing the development of novel therapeutics against the diseases.

Why do these variants exist?

Why might there be such variation in the population in the response to diarrhoeal pathogens? One possibility is that certain pathogens have exerted strong selection on endemic human populations to favor the spread of variants that provide some protection against the pathogens. That appears to the case for cholera, as shown in icddr,b’s first foray into work in this area in 2013. The study identified several variants associated with susceptibility to symptomatic cholera in or near genes involved in immune sensing and activation of inflammation, and show through evolutionary analyses that many of these genes have undergone strong past selection in the Bangladeshi population. Similar discoveries have recently been made for tuberculosis in Europeans and Chagas diseases in indigenous Amazons.
It is also possible that some of the diarrhoeal disease-associated variants may be playing in a role in other pathways that respond to different, possibly unrelated selection pressures, and their involvement in diarrhoea simply occurs by chance. Regardless of why they occur, identification of risk-associated loci for diarrhoeal and other infectious diseases will be key in identifying and accommodating high-risk patients.
“Most people have probably noticed individual variability in the outcomes of infection by the same pathogen,” said Dr. Rashidul Haque, a Senior Scientist at icddr,b involved in all of the recent GWAS studies described, apart from the 2013 cholera study. “How an individual fares depends not only on the strain of the pathogen, but on the individual’s own genome as well. Our hope is that the discovery of risk variants will eventually allow more personalized approaches to healthcare, such as priority care for individuals who are more susceptible to severe symptoms or outcomes.”