Extended reports
Association of polymorphism in glutathione S-transferase loci
with susceptibility and outcome in rheumatoid arthritis: comparison
with the shared epitope
a Staffordshire
Rheumatology Centre, The Haywood, High Lane, Burslem, Stoke on Trent,
Staffordshire ST6 7AG, b ARC Epidemiology
Research Unit, Manchester University, Manchester, c Department of Mathematics, Keele University,
Staffordshire, d Clinical
Biochemistry Research Laboratory, School of Postgraduate Medicine,
Keele University, North Staffordshire Hospital, Stoke on Trent,
Staffordshire
Correspondence to: Dr D L Mattey.
Accepted for publication 31 December 1998
OBJECTIVE
To determine
whether glutathione S-transferase GSTM1, GSTM3, GSTT1, and GSTP1
genotypes influence susceptibility or outcome in rheumatoid arthritis (RA).
METHODS277 RA
patients were compared with 577 controls to examine any associations
between GST genotypes and susceptibility to RA. The effect of genotypes
on outcome (Larsen and functional scores) and time integrated acute
phase responses (erythrocyte sedimentation rate and C reactive protein)
was assessed in 122 patients with disease duration of 5-10 years. GST
and HLA-DRB1 genotypes were determined using polymerase chain reaction
based assays. Data were analysed using multiple regression analysis
with correction for age, sex, disease duration, and the DRB1 associated
shared epitope (SE) and rheumatoid factor (RF) positivity where appropriate.
RESULTSThe
GSTM1*A/*B genotype was less common in RA
cases (3 of 276) than in controls (22 of 591) (exact p=0.047), though
significance was lost when adjustment was made for multiple
comparisons. The Larsen score was higher (p=0.039) in the GSTM1 null
patients (89.9) than those with other GSTM1 genotypes (74.7), and this
was independent of the SE. Again, correction for multiple testing
resulted in loss of significance. The difference in Larsen scores
between patients homozygous or negative for the SE (87.9 v 74.3) was similar to that between GSTM1
null and non-null patients. No associations between GSTM3 or GSTT1
genotypes and disease markers were identified although the association
between GSTP1*B/*B and Larsen score
approached significance (p=0.096).
CONCLUSIONIt is
proposed that certain GSTs may influence susceptibility and
radiological progression in RA and that this is independent of the
effect of the HLA-DRB1 associated SE. The mechanism for this effect is
presumed to be because of differences in the ability of various GST
enzymes to utilise the cytotoxic products of oxidant stress. Although
significance was lost after correction for multiple testing, the data
indicate that further studies may be of value in RA to determine the
influence of the GST and other genes involved in cellular protection
against oxidative stress.
© 1999 by Annals of the Rheumatic Diseases
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