Inhibitor IkappaBalpha promoter functional polymorphisms in patients with rheumatoid arthritis.
BACKGROUND
Rheumatoid arthritis (RA) is a chronic inflammation disease that may involve extra-articular organs in addition to joints. Many proinflammatory cytokines are involved in the inflammatory process of RA. IkappaBalpha conjugates with NF-kappaB and is a key player in regulation of the inflammatory process. We carried out experiments to define the effect of different promoter polymorphisms on the transcriptional activities of IkappaBalpha promoter and the development of RA.


METHODS
Different IkappaBalpha promoter reporters were constructed and were examined in human mononuclear cells, THP-1 cells. One hundred forty patients and 115 healthy controls were recruited from the Kaohsiung Medical University Hospital.


RESULTS
The activities of IkappaBalpha promoter constructs with -826C, -550A, -519T, and -826T, -550A, -519T genotypes were expressed at one half the activity level of other constructs. Promoter constructs containing the sites -550A/T and -519T had a reduced risk of rheumatoid arthritis. The odds ratio of -826C/T genotype was significantly associated with an increase of risk in causing rheumatoid arthritis, whereas -826T/T genotype was associated only with a slightly increased risk of RA, but without statistical significance (odds ratio = 1.2; 95% confidence interval, 0.4-3.8).


CONCLUSIONS
The increase of T allele was associated with a significant increased risk and the tendency to the pathogenesis of RA. The association between IkappaBalpha promoter polymorphisms and disease severity of rheumatoid arthritis is partly due to different transcriptional activities of IkappaBalpha promoter and the activation of NF-kappaB.
Li
Ruei-Nian
RN
Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan.
Hung
Yu-Hung
YH
Lin
Chia-Hui
CH
Chen
Yen-Hsu
YH
Yen
Jen-Hsien
JH
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D002460:Cell Line; D003001:Cloning, Molecular; D018450:Disease Progression; D017930:Genes, Reporter / Q000235:genetics; D005838:Genotype; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012306:Risk; D015533:Transcriptional Activation / Q000235:genetics
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha