Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis.
OBJECTIVE
To examine the role of NRAMP1 in susceptibility to juvenile rheumatoid arthritis (JRA).


METHODS
DNA from 119 JRA patients (72 pauciarticular, 47 polyarticular) and 111 healthy controls from Latvia was genotyped for a functional repeat polymorphism in the promoter of NRAMP1 and a linked (<150 kb) microsatellite D2S1471. The findings were compared with those from HLA-DQ alleles typed previously. Chi-square analyses were performed using the Mantel-Haenszel test and stratification according to pure Latvian or pure Russian descent. Haplotype analysis was performed using the Associate program to implement the expectation-maximization algorithm based on the gene-counting technique.


RESULTS
Allele 3 at NRAMP1 conferred increased risk (odds ratios [ORs] 2.26, 2.31, and 2.19; P = 0.0006, 0.003, and 0.019) of disease in the JRA, pauciarticular, and polyarticular patient groups, respectively. Allele 2 conferred protection (OR 0.44, 0.43, and 0.46). Alleles at D2S1471 that conferred susceptibility (6 and 12) or protection (11) did so only when on a haplotype with alleles 3 or 2, respectively, at NRAMP1. Allele 3 at NRAMP1 was additive with HLA-DQ7 for susceptibility (OR 3.71, 3.71, and 4.02), and allele 2 at NRAMP1 was additive with HLA-DQ5 for protection (OR 0.19, 0.08, and 0.12).


CONCLUSIONS
The NRAMP1 allele conferring susceptibility to JRA drives high levels of NRAMP1 expression, while the allele associated with protection drives low levels. These 2 alleles are inversely associated with susceptibility to infectious disease, consistent with their maintenance in populations through balancing selection.
Sanjeevi
C B
CB
University of Cambridge School of Clinical Medicine, UK.
Miller
E N
EN
Dabadghao
P
P
Rumba
I
I
Shtauvere
A
A
Denisova
A
A
Clayton
D
D
Blackwell
J M
JM
D000293:Adolescent; D001171:Arthritis, Juvenile / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics*; D027682:Cation Transport Proteins; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000032:analysis; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007844:Latvia / Q000208:ethnology; D008565:Membrane Proteins / Q000235:genetics*; D018895:Microsatellite Repeats; D011110:Polymorphism, Genetic; D012426:Russia / Q000208:ethnology; D044465:White People / Q000235:genetics*; D000099173:Natural Resistance-associated Macrophage Protein 1
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D006683:HLA-DQ Antigens; D008565:Membrane Proteins; D000099173:Natural Resistance-associated Macrophage Protein 1; C410042:HLA-DQ5 antigen; C069546:HLA-DQ7 antigen