Association of SLC11A1 (NRAMP1) with persistent oligoarticular and polyarticular rheumatoid factor-negative juvenile idiopathic arthritis in Finnish patients: haplotype analysis in Finnish families.
OBJECTIVE
The SLC11A1 (formerly called NRAMP1) gene is important in natural resistance to a variety of intracellular infections mediated by macrophages and has been proposed as a candidate gene for autoimmune disease susceptibility. The aim of this study was to examine susceptibility in Finnish patients with persistent oligoarticular and polyarticular rheumatoid factor (RF)-negative juvenile idiopathic arthritis (JIA) due to the presence of the SLC11A1 locus on chromosome 2.


METHODS
A total of 234 Finnish JIA nuclear families and 639 elderly Finnish controls without a history of JIA were evaluated for association with JIA at 3 intragenic single-nucleotide polymorphisms: an intragenic insertion/deletion, a promoter microsatellite (NRAMP1), and a 3' microsatellite (D2S1471).


RESULTS
Analysis of marker haplotypes demonstrated a strong association of Finnish JIA with 6-marker, 4-marker, and 2-marker haplotypes. Most impressively, 1 of the 6-marker haplotypes showed an odds ratio (OR) of 4.0 (95% confidence interval [95% CI] 2.6-6.2) in all JIA patients, 3.5 (95% CI 1.9-6.5) in those with persistent oligoarticular JIA, and 4.1 (95% CI 2.5-6.7) in those with polyarticular RF-negative JIA. Stratification of the haplotype data suggested that susceptibility to JIA in the haplotype spanning the SLC11A1 locus is independent (P < 0.01) of an association with a DRB1 JIA shared epitope (DRB1*JIASE) that includes well-characterized strong susceptibility to DRB1*08 and *11 alleles. This SLC11A1 haplotype also had an additive effect with DRB1*JIASE in those with polyarticular, but not those with persistent oligoarticular, disease (P = 0.06, OR 2.9 [95% CI 0.9-9.2] versus P = 0.5, OR 1.6 [95% CI 0.4-6.0]).


CONCLUSIONS
Taken together, these data provide support for the existence of a locus at or near SLC11A1 that is a strong susceptibility factor for JIA in Finnish patients.
Runstadler
Jonathan A
JA
Davis Rowe Program in Human Genetics, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
Säilä
Hanna
H
Savolainen
Anneli
A
Leirisalo-Repo
Marjatta
M
Aho
Kimmo
K
Tuomilehto-Wolf
Eva
E
Tuomilehto
Jaakko
J
Seldin
Michael F
MF
D000293:Adolescent; D000368:Aged; D001171:Arthritis, Juvenile / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002889:Chromosomes, Human, Pair 2; D000939:Epitopes; D005260:Female; D005387:Finland; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D012217:Rheumatoid Factor / Q000097:blood*; D000099173:Natural Resistance-associated Macrophage Protein 1
D027682:Cation Transport Proteins; D000939:Epitopes; D005819:Genetic Markers; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D012217:Rheumatoid Factor; D000099173:Natural Resistance-associated Macrophage Protein 1