Identification of a genetic risk factor for systemic juvenile rheumatoid arthritis in the 5'-flanking region of the TNFalpha gene and HLA genes.
OBJECTIVE
To study polymorphisms in the 5'-flanking promoter/enhancer region of the tumor necrosis factor alpha (TNFalpha) gene and in the coding regions of HLA class I and class II genes, in order to better understand the genetic background of juvenile rheumatoid arthritis (JRA).


METHODS
One hundred eleven Japanese JRA patients (50 with systemic disease, 29 with pauciarticular disease, and 32 with polyarticular disease) and 575 healthy Japanese subjects were examined for the allele frequencies of the TNFalpha, HLA-A, and HLA class II (DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1) genes, by DNA typing using the polymerase chain reaction-sequence-specific oligonucleotide probe method.


RESULTS
The frequencies of the polymorphic allele at positions -1,031 (T to C substitution, termed -1,031C), -863 (C to A, termed -863A), and -857 (C to T, termed -857T) of the TNFalpha gene in patients with systemic JRA, but not in those with polyarticular or pauciarticular JRA, were significantly higher than in the healthy controls. The allele frequencies of DRB1*0405 and DQB1*0401 in systemic JRA, but not in the other JRA types, were significantly higher than in controls. Linkage analysis showed that the presence of both the TNFalpha -857T allele and DRB1*0405 yielded a significantly increased odds ratio (3.84), while the presence of only 1 of them did not yield a high odds ratio (0.87 and 1.58).


CONCLUSIONS
The -1,031C/-863A allele and the -857T allele of the TNFalpha gene, both of which are related to high production of tumor necrosis factor alpha, are associated with systemic JRA. The -857T allele may enhance the effect of the DRB1*0405/DQB1*0401 haplotype in predisposing to development of systemic JRA.
Date
Y
Y
Kurume University, Japan.
Seki
N
N
Kamizono
S
S
Higuchi
T
T
Hirata
T
T
Miyata
K
K
Ohkuni
M
M
Tatsuzawa
O
O
Yokota
S
S
Joo
K
K
Ueda
K
K
Sasazuki
T
T
Kimura
A
A
Itoh
K
K
Kato
H
H
D001171:Arthritis, Juvenile / Q000235:genetics*; D005809:Genes, Regulator / Q000235:genetics; D008040:Genetic Linkage; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000502:physiology; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D006680:HLA Antigens; D014409:Tumor Necrosis Factor-alpha