Association of polymorphism in glutathione S-transferase loci with susceptibility and outcome in rheumatoid arthritis: comparison with the shared epitope
Dl. Mattey et al., Association of polymorphism in glutathione S-transferase loci with susceptibility and outcome in rheumatoid arthritis: comparison with the shared epitope, ANN RHEUM D, 58(3), 1999, pp. 164-168
Objective-To determine whether glutathione S-transferase GSTM1, GSTM3, GSTT
1, and GSTP1 genotypes influence susceptibility or outcome in rheumatoid ar
thritis (RA).
Methods-277 RA patients were compared with 577 controls to examine any asso
ciations between GST genotypes and susceptibility to RA. The effect of geno
types on outcome (Larsen and functional scores) and time integrated acute p
hase responses (erythrocyte sedimentation rate and C reactive protein) was
assessed in 122 patients with disease duration of 5-10 years. GST and HLA-D
RB1 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.
Results-The 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 gen
otypes (74.7), and this was independent of the SE. Again, correction for mu
ltiple testing resulted in loss of significance. The difference in Larsen s
cores 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 b
etween GSTM3 or GSTT1 genotypes and disease markers were identified althoug
h the association between GSTP1*B/*B and Larsen score approached significan
ce (p=0.096).
Conclusion-It is proposed that certain GSTs may influence susceptibility an
d 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 t
o be because of differences in the ability of various GST enzymes to utilis
e the cytotoxic products of oxidant stress. Although significance was lost
after correction for multiple testing, the data indicate that further studi
es may be of value in RA to determine the influence of the GST and other ge
nes involved in cellular protection against oxidative stress.