This research investigated immunogenetic variability and explored how genetics and the unique histories of First Nations may contribute to differential resistance and/or susceptibility to tuberculosis. With the support of First Nations communities, DNA samples were collected from Dene, Saulteaux, Cree and Caucasian cohorts within Manitoba. Single nucleotide polymorphisms (SNPs) in the cytokines promoter region of IL-12 (rs3212227) and in genes encoding the TLR2 (rs5743708)and TLR4 (rs4986790&4986791) were typed using PCR-RFLP analysis. Compared with the Caucasian and Saulteaux populations, the Dene and Cree were found to have a significantly higher frequency of SNPs associated with IL-12 low expression, while variation within TLRs was not statistically significant. The lower production of IL-12 has been associated with a down-regulated Th1 immune response, which is essential for the containment of Mycobacterium tuberculosis. First Nations have unique cultural, political and historical identities and the contemporary immunogenetic profiles are likely a reflection of these histories.