Genomic Approaches to Dissect Human Host-pathogen Interactions in the Amazonian Rainforest
Overview
- Phase
- Not Applicable
- Intervention
- Not specified
- Conditions
- Host-Pathogen Interactions
- Sponsor
- Universidad Peruana Cayetano Heredia
- Enrollment
- 300
- Primary Endpoint
- Genes showing different transcriptional profiles and methylation pattern according environment, genetic ancestry and past viral exposure
- Status
- Not yet recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
This observational study, aims to characterize with a multi-omic approach, the impact of host genetics and the pathogenic environment on immune response variation in Native Amazonians in comparison with Mestizo Amazonian, a severely underrepresented population in genomic studies.
Various samples will be taken from the participants, including blood, urine, saliva, etc. From the blood sample, peripheral blood mononuclear cells will be obtained and will give us information about the differences between immune response variation of Amazonian population. From the other samples we will be able to obtain additional information on the risk factors related to the difference in the immune response of the participants.
Detailed Description
The Amazon rainforest is characterized by adverse climatic conditions and a great diversity of pathogenic microorganisms that, consequently, would generate a selective pressure on the human immune response with a high impact on mortality. Some of the best characterized examples of human genetic adaptation have been related to infections; for example, the alleles causing sickle cell anemia, thalassemia and malaria. In addition, the introduction of infectious diseases from the "old world" during Spanish colonization in the 15th century and the urbanization of the last few centuries in the Amazon has also generated rapid adaptation that could drive variation in immune response. However, the evolutionary mechanisms that contributed to the adaptation of human defense against the aforementioned phenomena and events in this region are poorly understood. For this reason, studying these human genetic mechanisms in native populations would allow us to identify new genes that would be associated with resistance to infections, and also to explore the signs of rapid adaptation to the environment to which Amazonian populations have been exposed throughout their history. We propose to study the variation of the immune system in Amazonian populations, studying together the degree of diversity with different approaches: genomic, epi-genomic and transcriptomic of the host and viral exposome, taking into consideration sociodemographic characteristics and comorbidities, which may shape the immune response. This study will provide new insights into variants in the human genome that affect the immune response, thereby increasing our understanding of the etiology and susceptibility to immune-related diseases, mainly tropical infectious diseases. Because human genetic studies are underrepresented in Native American populations, the knowledge gained would reduce the existing inequality in health knowledge between Native and non-Native populations.
Investigators
Eligibility Criteria
Inclusion Criteria
- •People over 18 years of age who agree to participate in the study and sign the informed consent
- •People whose parents and grandparents were born in the Peruvian Amazon.
- •For volunteers from native communities, whose parents and grandparents belong to the same native community.
Exclusion Criteria
- •People who do not wish to have 40 mL of blood taken
- •People who are passing through a febrile illness (fever during the last 5 days to the date of enrollment).
- •Pregnant women
- •People over 65 years old
- •Breastfeeding women.
Outcomes
Primary Outcomes
Genes showing different transcriptional profiles and methylation pattern according environment, genetic ancestry and past viral exposure
Time Frame: Baseline
We will measure genome-wide expression profiles in peripheral blood mononuclear cells after stimulation for 6 hours with: (i) dengue virus, a major public health burden in the region, (ii) gardiquimod, an imidazoquinoxaline compound that activates toll like receptor 7/toll like receptor 8, able to sense viruses and intracellular pathogens; and (iii) lipopolysaccharide, a toll like receptor 4 agonist, to obtain a general view of responses to viruses and bacteria. Gene expression profiles will be measured using RNA-seq.
Genetic and epigenetic diversity of amazonian population
Time Frame: Baseline
Using saliva from participants as source of DNA, we will perform whole-genome sequencing (WGS) at 8-10xcoverage.
Impact of microbial exposures on immune response
Time Frame: Baseline
The viral exposome will be characterized in the 300 donors using a new tool call "VirScan", which identifies antibodies against \>600 pathogens and allergens, including viruses (\>1,200 viral strains) that are highly prevalent in the Amazonian, such as dengue, hepatitis B/C/D, or Mayaro virus.
Genetic variants associated wit transcriptional response to immune activation and DNA methylation variation
Time Frame: Baseline
We will assess the host genetic factors controlling transcriptional responses and methylated DNA levels by mapping expression and methylation quantitative trait loci (eQTL and methylated eQTLs, respectively).
Secondary Outcomes
- Demographic and admixture history of amazonian population(Baseline)
- Natural selection role in shaping immune response variation in Amazonians(Baseline)