Analysis of the NRAMP1 gene implicated in iron transport: Association withmultiple sclerosis and age effects

Multiple sclerosis (MS) is believed to be an autoimmune process occurring i n genetically susceptible individuals after an appropriate environmental ex posure, We have exploited the homogeneous Afrikaner population of European ancestry to investigate the likelihood that iron dysregulation, in associat ion with infectious and/or autoimmune disease susceptibility, may underlie the MS phenotype in a subgroup of patients. The functional Z-DNA forming re peat polymorphism of the natural resistance-associated macrophage protein-1 (NRAMP1) gene was analyzed in 104 patients diagnosed with MS and 522 Cauca sian controls, A family-based control group consisting of 32 parental allel es not transmitted to MS offspring was additionally studied to exclude the likelihood of population substructures, Statistically significant differenc es in allelic distribution were observed between the patient and control sa mples drawn from the same population (P < 0.01), Evidence is furthermore pr ovided 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 chal lenge, Although it remains to be determined whether the disease phenotype i n MS patients with allele 5 of the NRAMP1 promoter polymorphism is directly related to dysregulation of iron or modified susceptibility to viral infec tion and/or autoimmunity, a combination of these processes most likely unde rlies the disease phenotype: in these patients. fn view of the emerging rol e of polymorphic variants in complex diseases and minimizing of possible co nfounding factors in this association study, we conclude that allelic varia tion in the NRAMP1 promoter may contribute significantly to MS susceptibili ty in the South African Caucasian population. <(c)> 2001 Academic Press.