Association of tumor necrosis factor microsatellite polymorphisms with HLA-DRB1*04-bearing haplotypes in rheumatoid arthritis patients.
OBJECTIVE
To investigate 1) tumor necrosis factor (TNF) microsatellite allele frequencies in rheumatoid arthritis (RA), and 2) associations between TNF microsatellites and RA-associated HLA specificities in order to build up extended HLA haplotypes.


METHODS
Eighty-five caucasoid patients with RA and 109 healthy caucasoid controls were typed for TNF microsatellites a-d using fluorescent-labeled primers and semiautomated genotyping. A further 56 RA patients who were selected for having certain HLA-DRB1 types were also typed for these TNF microsatellites. Linkage disequilibria between TNF and HLA alleles were calculated, and extended haplotypes were established.


RESULTS
The TNFa6 allele frequency was significantly increased in the RA patients compared with the controls (P = 0.0019, odds ratio [OR] 2.5, 95% confidence interval [95% CI] 1.3-4.6), an increase that was further evident in patients who were HLA-DRB1*0401 homozygous (P = 0.0003, OR 7.3, 95% CI 2.2-24.4). This increase was found to be due to association with HLA-DRB1*0401. No TNF microsatellite allele was found to be associated with HLA-DRB1*0404. Three HLA extended haplotypes were identified in the RA group: 1) HLA-DRB1*0401;TNFd4;TNFa6;TNFb5;HLA-B44; HLA-Cw5;HLA-A2, 2) HLA-DRB1*0301;TNFd2; TNFa2;TNFb3;HLA-B8;HLA-Cw7;HLA-A1, and 3) TNFd5;TNFc2;TNFa2;TNFb1;HLA-B62;HLA-Cw3.


CONCLUSIONS
TNF microsatellites found to be associated with RA do not appear to be independent of class II HLA associations.
Hajeer
A H
AH
University of Manchester, UK.
Worthington
J
J
Silman
A J
AJ
Ollier
W E
WE
D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D005787:Gene Frequency; D008040:Genetic Linkage; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; C553505:HLA-DRB1*04:01 antigen; D014409:Tumor Necrosis Factor-alpha