Analysis of MHC region genetics in Finnish patients with juvenile idiopathic arthritis: evidence for different locus-specific effects in polyarticular vs pauciarticular subsets and a shared DRB1 epitope.
This study used Finnish juvenile idiopathic arthritis (JIA) probands with pauciarticular and rheumatoid factor (RF) negative polyarticular subtypes of JIA to further define the genetic susceptibility to JIA. We examined 16 markers spanning an 18 cM region of chromosome 6 encompassing the MHC and surrounding genomic region in a set of 235 Finnish JIA nuclear families and 639 Finnish control individuals. Analysis by case/control association and transmission disequilibrium test (TDT) methods each demonstrated strong evidence for a susceptibility locus near the D6S2447 microsatellite (P<10(-6) for both methods) that is flanked by DQB1 and DRB1. Analysis of the DRB1 locus suggested that DRB1*0801 and DRB1*1101 rather than DQA1 or other HLA alleles may be responsible for conferring susceptibility to disease. These findings are consistent with the most compelling results of previous reports on HLA associations and suggest a JIA DRB1 shared epitope encompassing critical amino-acid residues in the third hypervariable region of this molecule. Most importantly, in pauciarticular patients, the strong association does not extend to proximal markers as it does in polyarticular patients (P<0.00001). Analysis strongly suggests that the difference is because of additional JIA susceptibility loci within the MHC being present in polyarticular RF negative patients.
Runstadler
J A
JA
Rowe Program in Human Genetics and Molecular Medicine, Department of Biological Chemistry, University of California, Davis, USA. jarunstadler@ucdavis.edu
Säilä
H
H
Savolainen
A
A
Leirisalo-Repo
M
M
Aho
K
K
Tuomilehto-Wolf
E
E
Tuomilehto
J
J
Seldin
M F
MF
D017668:Age of Onset; D001171:Arthritis, Juvenile / Q000235:genetics*; D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005387:Finland; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008285:Major Histocompatibility Complex / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D017422:Sequence Analysis, DNA
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains