Polymorphisms in the gene that encodes interleukin (IL-12) and their clinical associations with the different clinical outcomes of malaria in populations of the middle Rio Negro region, Amazonas

Malaria is a complex disease with biological, genetic, social and environmental determinants influencing the clinical spectrum of the disease. Human genetic factors contribute to the variability of malaria phenotypes and, therefore, should help in determining some of the mechanisms involved in susceptibility to infection by Plasmodium spp. The pathogenesis of malaria is complex and the clinical presentation is characterized by a wide spectrum ranging from asymptomatic forms to severe disease, which can even lead to death. However, the factors that cause an individual to be asymptomatic are still unknown. The clinical and epidemiological variability of malaria seems to be associated with genetic factors. The genetic basis of malaria resistance and susceptibility is complex on several levels. Several genetic polymorphisms, particularly in genes related to the immune response, have been associated with susceptibility and resistance to malaria. The clinical course of malaria appears to be influenced by the overall production balance (and profiles) of pro-inflammatory and anti-inflammatory cytokines. Interindividual differences in cytokine profiles appear to be, in part, due to allelic polymorphisms in the regulatory regions of these genes, so that polymorphisms in their genes have been associated with protection and/or susceptibility to infection.

It is proposed to sequence the promoter region of the IL-12 gene in 300 individuals living in the municipality of Barcelos in order to identify SNPs and haplotypes and their allelic frequencies. Individuals will be divided into the following groups: 1) with asymptomatic infection, 2) with clinical malaria, 3) not infected, but with a previous history of malaria, and 4) who have never had malaria. After the analysis and identification of SNPs and haplotypes, clinical association studies will be carried out, evaluating possible roles of these SNPs as “genetic markers” of susceptibility and/or resistance. The choice of the IL-12 cytokine was based on previous studies that report it as the main mediator of the natural immune response to intracellular microorganisms, such as in malaria, and as the essential inducer of the acquired immune response. Previous studies have shown that the increase in IL-12 levels represents a reliable parameter to predict the progression of malaria. Several polymorphisms have already been identified in this gene, and its associations with malaria have already been validated in other populations. The research team hopes to clarify the relevance of the highly polymorphic characteristic of this gene and its association with susceptibility to malaria in the population of the Rio Negro. Detailed analysis of these SNPs will contribute to a better understanding of the role of this cytokine in the pathophysiology of acute malaria and which host factors would be associated with the development of asymptomatic infection. This work is part of a larger project to study candidate genes associated with susceptibility and resistance to malaria that is being developed by our group in populations of the Middle Rio Negro region, state of Amazonas.

Project details

Basic Science

Jun 2021

Brazil