Health research with Manitoba First Nations. An investigation of gene variants affecting the Th17 immune pathway and the P2RX7 receptor.
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Date
2016
Authors
Semple, Catlin
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Abstract
Introduction: Canadian First Nations experience a significantly higher rate of Mycobacterium tuberculosis (MTB) infection than non-Indigenous Canadians. Th17 cells are a subset of CD4+ T cells that are distinguished by their production of Interleukin-17A (IL-17A), an important cytokine for defense against mycobacteria. IL-17 is a primary contributor to the formation and stabilization of the lung granuloma, a biological containment vessel to protect the host from tuberculosis (TB). Past research with First Nations people has identified single nucleotide polymorphisms (SNPs) in the Th1 and Th2 immune pathways may affect their disease risk. However, SNPs in key Th17 related genes and the P2RX7 gene have not been explored in First Nations despite their important role against infectious diseases.
Hypothesis: This research hypothesizes that distinct First Nations groups (Dene, Cree and Saulteaux) will have a different frequencies of SNPs in the key Th17 immunity related genes (IL-17A, IL-17AR, IL-23R, and IFN-γR) and the P2RX7 gene, as compared to a non-Indigenous Canadian group.
Methods: SNP profiles (IL-17A rs2275913, IL-17RA rs4819554, IL-23R rs10889677, IFN-γR rs2234711 and P2RX7 rs3751143) were identified through literature research and the NCBI database was used for identifying gene motifs, primer locations and Restriction Enzyme cut sites. Polymerase Chain Reaction and Restriction Fragment Length Polymorphism analysis was performed on and visualized on agarose gel to determine specific allele frequencies. Four different Manitoba First Nations communities; the Northern Dene (Dene 1 N=69. Dene 2 N=52), Central Cree (N=46), and Southern Saulteaux (N=56), participated in this research and their SNP profiles were compared to a non-Indigenous Canadian cohort (N=99).
Results: Allele frequencies for IL-17A were statistically different for every First Nation community when compared to the non-Indigenous cohort (Dene 1 p=0.0043, Dene 2 p=0.0000, Cree p=0.0001, Saulteaux p=0.0000). Allele frequencies for IL-17RA were statistically different for every First Nation community except Saulteaux when compared to the non-Indigenous cohort (Dene 1 p=0.0000, Dene 2 p=0.0028, Cree p=0.0000). Allele frequencies for IL-23R were statistically different for Dene 1 and Saulteaux community when compared to the non-Indigenous cohort (Dene 1 p=0.0002, Saulteaux p=0.0000). Allele frequencies for IFN-R were statistically different for Cree community when compared to the non-Indigenous cohort (Cree p=0.0026). Allele frequencies for P2RX7 were statistically different for both Dene communities when compared to the non-Indigenous cohort (Dene 1 p=0.0000, Dene 2 p=0.0000).
Conclusions: An effective Th17 response is required to bring Th1 cells to infected tissues and to balance inflammatory responses. Functional SNPs may compromise an appropriate immune response and contribute to disease. This study demonstrate that the non-Indigenous population maintained a significantly different genetic profile when compared to the First Nations populations.
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Keywords
First Nations, Indigenous, Interleukin-17, Genetics, P2RX7, IFN-gamma receptor, Interleukin-23 receptor, Immunogenetics, Tuberculosis, Knowledge translation, Interleukin-17 receptor