For example, tumour necrosis factor polymorphisms have been associated with susceptibility to malaria and other infections; chemokine receptor polymorphisms with susceptibility to HIV; natural resistance-associated macrophage protein 1 with tuberculosis; and mannose binding lectin polymorphisms with meningococcal disease.
Several important candidate genes like human leucocyte antigen/alleles and non-human leucocyte antigen genes, such as cytokines and their receptors, chemokines and their receptors, pattern recognition receptors (including toll-like receptors, mannose binding lectin and the dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin), solute carrier family 11A member 1 (formerly known as natural resistance-associated macrophage protein 1) and purinergic P2X7 receptor gene polymorphisms, have been associated with differential susceptibility to TB in various ethnic populations.
In the present study, we scanned the regulatory and coding region of Nuclear LIM Interactor-Interacting Factor gene (NLI-IF), which is physically close to the tuberculosis-associated gene NRAMP1.
Among the subjects, D543NNRAMP1 polymorphism, history of contact with TB patients, and not having a clear BCG scar on the upper arm tended to be significantly association with active TB.
We then examine the putative role of iron-related host genes by focussing on two candidate genes, haptoglobin and NRAMP1, for which there are common polymorphic variants in humans with strong evidence of functionally distinct biochemical phenotypes that would be predicted to influence the course of HIV and TB infections.
To test this, we determined the frequency of an allele (SLC11A11729 + 55del4) associated with natural resistance to intracellular pathogens such as tuberculosis and leprosy.
These results indicate that variant alleles in the Nramp1 gene are associated with increased mycobacterial replication rather than susceptibility for tuberculosis and may thus confer increased risk of severe disease.
The (GT)n promoter alleles 2 and 3 (rs534448891), which alter SLC11A1 expression, were significantly associated with tuberculosis (OR=1.47 (1.30-1.66), OR=0.76 (0.65-0.89), respectively) and infectious disease (OR=1.25 (1.10-1.42), OR=0.83 (0.74-0.93), respectively).
These findings suggest that the 5'(GT)n polymorphism of NRAMP1 modifies TB susceptibility in this Caucasian population, and could possibly be related to the site of infection among HIV-negative individuals and HIV-coinfected TB.
The 469 + 14 G/C (INT4), 1465 - 85 G/A, and C274T polymorphisms of NRAMP1 and the A/C polymorphism of IL12 3'-UTR were analyzed in ethnic Russians with (N = 58) or without (N = 127) tuberculosis (TB) from Tomsk.
Similarly, no significant differences were observed between NRAMP1 polymorphisms and rheumatoid factor positivity and erosive disease in RA and localization of TB.
On the basis of linkage disequilibrium pattern, three genetic markers from SLC11A1 and one from the nearby IL8RB locus were selected and examined for association with TB susceptibility.
The present study describes both an assay for human NRAMP1 functional activity and concomitant evidence for reduced NRAMP1 function in the common genetic variant shown to be associated with tuberculosis susceptibility in pediatric patients.
Through comparative genomics, we have identified the homologous human NRAMP1 gene, alleles of which are now being used for tests of linkage with TB and leprosy.
This finding, together with the emerging information on almost total sequence homology between the murine and human Nramp genes suggests that this gene may be responsible for the phenotype of resistance or susceptibility to tuberculosis.
Multiple host iron status biomarkers, Haptoglobin and solute carrier family 11, member 1 (SLC11A1) genotypes were modeled to characterize how indicators of host iron metabolism were associated with TB susceptibility.
Polymorphisms in the NRAMP1 gene, VDR gene, HLA-DRB1 gene, and HLA-DQB1 gene are statistically associated with susceptibility to TB in the Chinese Kazakh population.
Many genes involved in tuberculosis susceptibility (e.g., NRAMP1 (SLC11A1), IFNG, NOS2A, VDR, ISG15, TACO, TLR1, TLR, IL18R1, chemokines, PADI, DUSP14, MBL, and MASP-2) have been subjected to epigenetic modification.
The present study describes both an assay for human NRAMP1 functional activity and concomitant evidence for reduced NRAMP1 function in the common genetic variant shown to be associated with tuberculosis susceptibility in pediatric patients.