Evidence for a functional repeat polymorphism in the promoter of the humanNRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility

A polymorphism in the promoter of human NRAMP1 encodes a Z-DNA forming dinu cleotide repeat with four alleles: (1) t(gt)(5)ac(gt)(5)ac(gt)(11)g; (2) t( gt)(5)ac(gt)(5) ac(gt)(10)g; (3) t(gt)(5)ac(gt)(5)ac(gt)(9)g; and (4) t(gt) (5)ac(gt)(9)g. Alleles 1 and 4 are rare (gene frequencies similar to 0.001) ; alleles 2 and 3 occur at gene frequencies similar to 0.20-0.25 and simila r to 0.75-0.80, respectively. Here, luciferase reporter gene constructs are used to show that the four alleles differ in their ability to drive gene e xpression. In the absence of exogenous stimuli, alleles 1, 2, and 4 are poo r promoters; allele 3 drives high expression, indicating that the repeat it self has endogenous enhancer activity. All four alleles show a similar perc entage enhancement of reporter gene expression in the presence of interfero n-gamma, consistent with the multiple interferon-gamma response elements bo th 5' and 3' of the Z-DNA forming repeat. However, while the addition of ba cterial lipopolysaccharide (LPS) has no effect on alleles 1 and 4, it cause s significant reduction in expression driven by allele 2 and enhances expre ssion driven by allele 3, suggesting that the juxtaposition of LPS related response elements (NF kappa B, AP-1, NF-IL6) may be differentially affected by the two commonly occurring alleles. These results are consistent with t he hypothesis that chronic hyperactivation of macrophages associated with a llele 3 is functionally linked to autoimmune disease susceptibility, while the poor level of NRAMP1 expression promoted by allele 2 contributes to inf ectious disease susceptibility. Conversely, allele 3 protects against infec tious disease and allele 2 against autoimmune disease. Hence, alleles that are detrimental in relation to autoimmune disease susceptibility may be mai ntained in the population because they improve survival to reproductive age following infectious disease challenge.