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Genetics play major role in infectious disease susceptibility
Experts give insight into genetic connections and pathways of major infectious diseases, including tuberculosis and malaria.
SAN DIEGO — New genetics studies involving tuberculosis, malaria and other mycobacterial diseases may reveal the extent to which infectious disease risk is associated with genetic susceptibility. Unraveling the complex puzzle of host genetics vs. genetic pathways in organisms may provide information for more targeted interventions and vaccines, according to experts.
At the 45th Annual Meeting of the Infectious Diseases Society of America, Steven M. Holland, MD, clinical infectious diseases laboratory chief at the National Institute of Allergy and Infectious Diseases, used TB as an example of a disease that may be linked to a person’s genetic susceptibility. Holland said that although approximately 2 billion people worldwide are infected with TB, fewer than 0.15% die from the disease.
“There must be determinants, and obviously genetics is one of them,” Holland said. “There are complex, rare disorders that will continue to be diagnosed and will continue to show up at your clinic at unexpected times, and the rare diseases inform us about the common ones.”
“By looking at variability in genes, one can begin to get an understanding of how these different pathways are functioning in individuals with malaria,” said Douglas J. Perkins, PhD, director of the Laboratories of Parasitic and Viral Diseases at the University of Pittsburgh Graduate School of Public Health and the Centre for Global Health Research in western Kenya.
Both Holland and Perkins agreed that genetics must play a role in infectious disease morbidity and severity, although the fine points of genetics are complex and often confounded by many variables.
Disease susceptibility
In TB, as with other infectious diseases, both the genetic makeup of the microbe and the genetic make up of the human work together to create pathways and to regulate the success or failure of the microbe.
“There are important genetic contributions to TB, and they are largely the same as for nontuberculosis mycobacteria but are less pronounced as you would expect,” Holland said.
Mutations in interferon gamma receptor 1 lead to an inability to upregulate tumor necrosis factor and interleukin-12 and the inability to upregulate interferon gamma itself in response to interferon gamma stimulation.
“The consequences of this complete gamma deficiency are horrendous, and if you have a complete defect, you have a complete disaster,” Holland said.
Studying rare diseases can provide information of genetic pathways that increase genetic susceptibility to more common infectious diseases. For example, auto interferon antibody syndromes are most common in Asian women.
In 1966, scientists identified Job’s syndrome – later renamed extreme hyperimmunoglobulinemia E Syndrome (HIES) – characterized by genetic and developmental phenotype; the disease is seen in about one in 100,000 people.
Mutations cluster in two highly-conserved domains of signal transducer and activator of transcription 3, which results in dysregulated cytokine production and signaling. When the transcriptional array of cells from patients compared with controls is examined, patients had elevated levels of pro-inflammatory gene transcripts.
“Our hope is that with the identification of the gene that causes HIES, we can begin to understand what regulates susceptibility to infection in the skin, the lung and the teeth,” Holland said.
Susceptibility and malaria
Host variability in immune response genes and the relation to malaria susceptibility are the focus of Perkins’ and colleagues studies on severe malaria anemia in children located in Kisumu and Siaya, Kenya. Children in the study are enrolled when they are younger than 1 year of age at baseline and are followed for 36 months. A total of 22,000 genotypes in more than 800 children have been studied to date using a candidate gene approach.
“Our goal is to gain an understanding of the genetic and immunological basis of protective immunity for targeted interventions by identifying susceptible vs. protected individuals,” Perkins said.
Pharmacological and vaccine trials would be best served by the identification of novel targets for therapeutic interventions and the determination of reliable markers for measuring protection and pathogenesis.
Thus far, study results have pointed to genetics rather than infection levels as markers for progression to severe malarial anemia.
“What most people think about malaria is that the level of parasitemia is largely going to determine the amount of anemia you have, but this study has shown that when looking at children with uncomplicated malaria, they are doing well, but they are rare children,” Perkins said. “The level of parasitemia is higher, which indicates that it is not the level of infection per se, but how genetic variation conditions outcome.”
Perkins’s group found that macrophage migration inhibitory factor is highest in Gabonese children that have mild forms of malaria and lower in children that have more severe forms of disease. High levels of MIF in the Kenya cohort were associated with increased disease severity.
“Given the role of MIF, it clearly affects susceptibility,” Perkins said. “In a lot of these molecules, it is not the baseline expression but how it moves from baseline to the final level during disease that is conditioned by genetics.”
They have also concluded that children who are exposed to HIV and those that have HIV infections have much different immunological responses to malaria than children who have not been exposed or infected.
Each year, severe malaria anemia is responsible for the greatest malaria-associated morbidity and mortality and is attributed to more than 1.2 million worldwide deaths, mostly infants and young children. More than 50% of all severe malarial anemia deaths occur within 24 hours of hospital admission.
Malarial anemia is a heterogeneous syndrome that differs according to previous exposure, host genetic background, secondary infections including HIV and the interaction between the parasite, host genes and environmental factors.
Susceptibility to severe malaria differs among populations, similar to other infectious diseases.
In areas of holoendemic malaria transmission such as Siaya, nearly all children experience repeated infections prior to acquiring clinical immunity, but 10% to 15% develop severe malarial anemia.
In severe malaria, disease susceptibility results from the interactions between many genes at several loci. The genetic basis of severe malarial anemia is best defined through the examination of several panels of immune response genes and constructing haplotypes.
A confounder to studying anemia in children in this area is the prevalence of other anemia-causing infectious diseases and variables, such as HIV, bacteremia, hookworm and nutritional deficiencies.
To balance the study, the researchers used well-defined cohorts for the consideration of the additional variables and a candidate gene approach for the analysis of genetic markers for disease susceptibility.
The role of MIF promoter variation in severe malarial anemia susceptibility is a main area of study. Since MIF has a role in the control of inflammations and innate immune responses, and functional MIF polymorphisms can influence susceptibility to severe malaria. MIF is suppressed in children with severe malarial anemia, Perkins said.
“The most important part of this is that individuals with certain haplotypes have increased susceptibility to the disease,” Perkins said. – by Kirsten H. Ellis
For more information:
- Holland SM. Defects in gamma interferon pathways and susceptibility to infectious diseases. #614.
- Perkins DJ. Host variability in immune response genes and susceptibility to malaria. #615.
- Both presented at: the 45th Annual Meeting of the Infectious Diseases Society of America; Oct. 4-7, 2007; San Diego.