Tumor necrosis factor alpha 5'-flanking region, tumor necrosis factor receptor II, and HLA-DRB1 polymorphisms in Japanese patients with rheumatoid arthritis.
OBJECTIVE
New polymorphisms affecting transcriptional activity were recently reported within the 5'-flanking region of the tumor necrosis factor alpha gene (TNFalpha). In addition, genome-wide linkage screening indicated 1p36 as one of the candidate chromosomal regions where the TNF receptor II gene (TNFR2) is located. In the present study, HLA-DRB1, TNFalpha promoter, and TNFR2 genotypes were determined to examine whether these polymorphisms are associated with rheumatoid arthritis (RA), either independently or in combination.


METHODS
Genotypes of HLA-DRB1, TNFalpha upstream promoter, and TNFR2 codon 196 were determined in 545 Japanese patients with RA and 265 healthy controls. Association of these genes with susceptibility to RA was analyzed both independently and after stratification by one of the genotypes.


RESULTS
As expected, the HLA-DRB1 shared epitope was strongly associated with RA. In addition, a significant negative association of DRB1*1405 and 1302 was observed. Furthermore, DRB1*1405 was suggested to possess a protective role for the development of RA in DRB1*0405-positive individuals. A significant increase in TNFalpha-U02 in RA was detected, which was not independent of DRB1*0405. A significant association was not observed between TNFR2-196M/R polymorphism and RA.


CONCLUSIONS
Among the 3 genes examined in this study, HLA-DRB1 was considered to be most strongly associated with RA.
Shibue
T
T
University of Tokyo, Japan.
Tsuchiya
N
N
Komata
T
T
Matsushita
M
M
Shiota
M
M
Ohashi
J
J
Wakui
M
M
Matsuta
K
K
Tokunaga
K
K
D015703:Antigens, CD / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D005260:Female; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry* / Q000235:genetics*
D015703:Antigens, CD; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha