Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis

Objective. To examine the role of NRAMP1 in susceptibility to juvenile rheu matoid arthritis (JRA), Methods. DNA from 119 JRA patients (72 pauciarticular, 47 polyarticular) an d 111 healthy controls from Latvia was genotyped for a functional repeat po lymorphism in the promoter of NRAMP1 and a linked (<150 kb) microsatellite DS1471. The findings were compared with those from HLA-DQ alleles typed pre viously, Chi-square analyses were performed using the Mantel-Haenszel test and stratification according to pure Latvian or pure Russian descent. Haplo type analysis was performed using the Associate program to implement the ex pectation-maximization algorithm based on the gene-counting technique. Results. Allele 3 at NRAMP1 conferred increased risk (odds ratios [ORs] 2.2 6, 2.31, and 2.19; P = 0.0006, 0.003, and 0.019) of disease in the JRA, pau ciarticular, and polyarticular patient groups, respectively, Allele 2 confe rred protection (OR 0.44, 0.43, and 0.46). Alleles at D2S1471 that conferre d susceptibility (6 and 12) or protection (11) did so only when on a haplot ype with alleles 3 or 2, respectively, at NRAMP1. Allele 3 at NRAMP1 was ad ditive with HLA-DQ7 for susceptibility (OR 3.71, 3.71, and 4.02), and allel e 2 at NRAMP1 was additive with HLA-DQ5 for protection (OR 0.19, 0.08, and 0.12). Conclusion. The NRAMP1 allele conferring susceptibility to JRA drives high levels of NRAMP1 expression, while the allele associated with protection dr ives low levels, These 2 alleles are inversely associated,vith susceptibili ty to infectious disease, consistent,with their maintenance in populations through balancing selection.