Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility

Abstract

A polymorphism in the promoter of human NRAMP1 encodes a Z-DNA forming dinucleotide repeat with four alleles: (1) t(gt)₅ac(gt)₅ac(gt)₁₁g; (2) t(gt)₅ac(gt)₅ ac(gt)₁₀g; (3) t(gt)₅ac(gt)₅ac(gt)₉g; and (4) t(gt)₅ac(gt)₉g. Alleles 1 and 4 are rare (gene frequencies ∼0.001); alleles 2 and 3 occur at gene frequencies ∼0.20−0.25 and ∼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 expression. In the absence of exogenous stimuli, alleles 1, 2, and 4 are poor promoters; allele 3 drives high expression, indicating that the repeat itself has endogenous enhancer activity. All four alleles show a similar percentage enhancement of reporter gene expression in the presence of interferon-γ, consistent with the multiple interferon-γ response elements both 5′ and 3′ of the Z-DNA forming repeat. However, while the addition of bacterial lipopolysaccharide (LPS) has no effect on alleles 1 and 4, it causes significant reduction in expression driven by allele 2 and enhances expression driven by allele 3, suggesting that the juxtaposition of LPS related response elements (NFκB, AP-1, NF-IL6) may be differentially affected by the two commonly occurring alleles. These results are consistent with the hypothesis that chronic hyperactivation of macrophages associated with allele 3 is functionally linked to autoimmune disease susceptibility, while the poor level of NRAMP1 expression promoted by allele 2 contributes to infectious disease susceptibility. Conversely, allele 3 protects against infectious disease and allele 2 against autoimmune disease. Hence, alleles that are detrimental in relation to autoimmune disease susceptibility may be maintained in the population because they improve survival to reproductive age following infectious disease challenge.