Frequency of NRAMP1 Gene Polymorphisms among Canadian First NationsPeoples Experiencing Endemic Tuberculosis

Objectives: The natural resistance-associated macrophage protein 1 (NRAMP1) regulates susceptibility to infectious and autoimmune diseases. NRAMP1 gene polymorphisms have been implicated in susceptibility to tuberculosis. The frequency of NRAMP1 gene polymorphisms was therefore evaluated in three Manitoba First Nations sub-groups (Dene, Cree, and Saulteaux) with differential but high rates of tuberculosis (636/100,000, 496/100,000, and 0/100,000 respectively). Methods: Venous blood samples were collected from 281 study participants from three First Nations sub-groups (Dene (N=108), Cree (N=41), Saulteaux (N=49)), and a non-indigenous Canadian-born (European-descent) group (N=83). Genomic DNA was extracted and four single nucleotide polymorphisms in the NRAMP1 gene (5′ (GT)n, -274 (C/T), Intron 4 (469+14 G/C), D543N (G/A)) were genotyped using restriction fragment length polymorphism. NRAMP1 SNP allele frequencies were counted and compared between studied sub-groups. Results: The Dene sub-group had significantly different allele frequencies of NRAMP1 (5′(GT)n, -274 (C/T), Intron 4(G/C), D543N (G/A)) compared to the European-descent group. The NRAMP1 allele frequencies at D543N (G/A) and Intron 4(G/C) differed significantly between the Cree and the European-descent group while the allele frequencies of the Saulteaux were not significantly different from the European-descent group. Two sub-groups (Dene and Cree) had higher frequency of NRAMP1 D543N (A) allele, which is associated with tuberculosis in other populations. Conclusion: High, but differential rates of tuberculosis among the First Nation sub-groups in Manitoba are related to social determinants of health (i.e. poverty, racism, inadequate housing) but other potential risk factors such as gene polymorphisms associated with tuberculosis have only recently come under investigation. NRAMP1 allele frequencies were found to be different comparing the Dene, Cree and Saulteaux and their role in tuberculosis susceptibility/resistance needs further investigation.