Susceptibility for and clinical manifestations of rheumatoid arthritis are associated with polymorphisms of the TNF-alpha, IL-1beta, and IL-1Ra genes.
OBJECTIVE
To analyze the association of genetic polymorphisms of pro-inflammatory cytokines with rheumatoid arthritis (RA) in comparison with healthy controls from Northern Sweden and the potential contribution of these genetic variants for disease severity and development of cardiovascular complications.


METHODS
Polymerase chain reaction amplification was used for analysis of TaqI restriction fragment length polymorphism (RFLP) of interleukin-1 beta (IL-1beta), variable tandem repeat polymorphism of IL-I receptor antagonist (IL-1Ra) gene and NcoI RFLP at position -308 of tumor necrosis factor-alpha (TNF-alpha) gene. One hundred and fifty-four patients with RA, 42 men and 112 women, were consecutively recruited into the study through the Department of Rheumatology.


RESULTS
The allele A1 of TNF-alpha was more common in the patient group (p < 0.01; OR = 1.62). Patients having the genotype A1A2 seemed to develop more severe disease compared with patients with A1A1 genotype: they were younger at disease onset (p < 0.05), had a higher accumulated disease activity (p < 0.05) and worse functional class (p < 0.05). Patients with genotype A2A2 of IL- 1beta had higher accumulated disease activity score than patients with A1A1 and A1A2 (p < 0.05). The allelic combination Al IL-1beta/A2 IL-1Ra was less prevalent in RA patients who developed cardiovascular complications (p < 0.005; OR = 0.20).


CONCLUSIONS
The Al allele of TNF-alpha associates with RA. Genotypes A1A2 of TNF-alpha and A2A2 of IL-1beta are associated with more severe disease. The allelic combination A1IL-1beta/A2 IL-1Ra is less often present in RA patients who developed cardiovascular complications.
Cvetkovic
Jasmina Trifunovic
JT
Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Wallberg-Jonsson
Solveig
S
Stegmayr
Birgitta
B
Rantapaa-Dahlqvist
Solbritt
S
Lefvert
Ann Kari
AK
D000328:Adult; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D002561:Cerebrovascular Disorders / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D004247:DNA / Q000032:analysis; D015252:Deoxyribonucleases, Type II Site-Specific; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012795:Sialoglycoproteins / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D015252:Deoxyribonucleases, Type II Site-Specific; C027046:TCGA-specific type II deoxyribonucleases