Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Influence of TNF-, MMP-3, TIMP-3 and HLA Class II Genes Polymorphisms in the Rheumatoid Arthritis Articular Damage.

Alarcon5,  Renata T., Fernandes5,  Artur R. C., Pinheiro3,  Geraldo R. C., Usnayo3,  Magali J. G., Porto4,  Luis C. M., Cardoso-Oliveira3,  Juliana, Fabricio-Silva3,  Gustavo M.

Universidade de Sao Paulo, Sao Paulo, SP, Brazil
Universidade Estadual de Campinas, Campinas, SP, Brazil
Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RF, Brazil
Universidade Federal de Sao Paulo - UNIFESP, Sao Paulo, SP, Brazil


The recent availability of drugs that may alter the course of rheumatoid arthritis (RA) has emphasized the need for predictors of disease outcome in order to assign patients to appropriate treatment. HLA-DRB1 and extra-HLA genes are implicated in the predisposition and progression of RA and polymorphism in some of those may serve as modulators of disease severity. TNF-alpha, matrix metalloproteinase-3 (MMP3) and tissue inhibitor of metalloproteinases-3 (TIMP-3) are integrated in the pathway of joint destruction in RA. Genetic studies of patients with RA can supply data that contribute to define more precisely the groups of patients with good and bad disease progression.


To evaluate possible associations between cumulative articular damage and polymorphisms in HLA-DRB1, TNF-alpha (-308G/A), MMP3 (-1171 5A/6A) and TIMP3 (-899T/A, -915A/G and -1296T/C) genes in a sample of Brazilian patients with RA.


We selected 440 RA patients from three university centers in southeast Brazil (São Paulo, Rio de Janeiro, and Campinas). DNA was obtained from peripheral leukocytes. The regions of interest for TNF-alpha, MMP-3 and TIMP-3 were amplified by PCR. Amplicons were digested with appropriate restriction enzymes and the resulting fragments were resolved in agarose gel electrophoresis (RFLP). HLA-DRB1 alleles were determined by PCR using sequence-specific oligonucleotide probes (PCR/SSO) and DRB1*04 alleles by PCR sequence-specific primers (PCR/SSP). Sharp's index was scored in hands and feet X-rays by an experienced blinded radiologist. Derivative Sharp scores were developed according to the mathematical division of hands/feet scores (Sharp-h/f), fingers/wrists scores (Sharp-f/w), and erosion/space narrowing scores (Sharp-e/sn).


There was no ethnic association except for a higher prevalence of MMP3 allele 6A in blacks (83.3%) compared to other races (60%) (p<0.001). There was no association between the studied polymorphisms and total Sharp score. However, patients with predominant feet damage (Sharp-h/f < 1.67) had higher frequency of TIMP3 –1296T (72.6% vs 52.6%, p=0.001) and TIMP3 –915A (71.4% vs 55.5%, p=0.009) alleles as compared with those with predominant hand damage. Predominance of space narrowing (Sharp-e/sn <1.67) was associated with -899 TIMP3 allele A (7.8% vs 0.5%, p=0.007). Sharp-f/w score was not associated with polymorphism in the studied genes. The derived Sharp scores were not associated with HLA-DRB1, weight, height, and BMI.


TIMP-3 polymorphism was significantly associated with the preferential topography of joint destruction and with the predominant type of radiographic changes (erosion versus space narrowing) in rheumatoid arthritis.

To cite this abstract, please use the following information:
Alarcon, Renata T., Fernandes, Artur R. C., Pinheiro, Geraldo R. C., Usnayo, Magali J. G., Porto, Luis C. M., Cardoso-Oliveira, Juliana, et al; Influence of TNF-, MMP-3, TIMP-3 and HLA Class II Genes Polymorphisms in the Rheumatoid Arthritis Articular Damage. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :356
DOI: 10.1002/art.28125

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