Analysis of the NRAMP1 gene implicated in iron transport: association with multiple sclerosis and age effects

Multiple sclerosis (MS) is believed to be an autoimmune process occurring in genetically susceptible individuals after an appropriate environmental exposure. We have exploited the homogeneous Afrikaner population of European ancestry to investigate the likelihood that iron dysregulation, in association with infectious and/or autoimmune disease susceptibility, may underlie the MS phenotype in a subgroup of patients. The functional Z-DNA forming repeat polymorphism of the natural resistance-associated macrophage protein-1 (NRAMP1) gene was analyzed in 104 patients diagnosed with MS and 522 Caucasian controls. A family-based control group consisting of 32 parental alleles not transmitted to MS offspring was additionally studied to exclude the likelihood of population substructures. Statistically significant differences in allelic distribution were observed between the patient and control samples drawn from the same population (P < 0.01). Evidence is furthermore provided that alleles considered to be detrimental in relation to autoimmune disease susceptibility may be maintained in the population as a consequence of improved survival to reproductive age following infectious disease challenge. Although it remains to be determined whether the disease phenotype in MS patients with allele 5 of the NRAMP1 promoter polymorphism is directly related to dysregulation of iron or modified susceptibility to viral infection and/or autoimmunity, a combination of these processes most likely underlies the disease phenotype in these patients. In view of the emerging role of polymorphic variants in complex diseases and minimizing of possible confounding factors in this association study, we conclude that allelic variation in the NRAMP1 promoter may contribute significantly to MS susceptibility in the South African Caucasian population.