Rheumatology Advance Access originally published online on April 4, 2007
Rheumatology 2007 46(6):1034-1035; doi:10.1093/rheumatology/kem041
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LETTERS TO THE EDITOR |
Combined tumour necrosis factor-
and tumour necrosis factor receptor genotypes could predict rheumatoid arthritis patients’ response to anti-TNF- therapy and explain controversies of studies based on a single polymorphism
Genetics Unit, Department of Obstetrics and Gynaecology, and 1Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
Correspondence to: Prof. A. A. Drosos Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, 45110 Ioannina, Greece. E-mail: adrosos{at}cc.uoi.gr
SIR, Tumour necrosis factor-
(TNF-) blocker therapies are widely used in the treatment of chronic inflammatory diseases. However, patients show large heterogeneity in their response to anti-TNF- therapy. The genotypic background of TNF- and TNF receptor (TNFR) genes could account for patients’ resistance to TNF- blockers [1, 2]. HLA-DR haplotypes have been related with rheumatoid arthritis (RA) susceptibility, severity and course [3], but TNF and TNFR polymorphisms seem to have independent predictive value of patients’ response to anti-TNF- therapy [2, 4, 5].
In a previous study, we have investigated the efficacy, toxicity and drug discontinuation in RA patients treated with infliximab [6]. In the present retrospective study, 58 unrelated patients (46 females, mean age: 58.4 yrs, disease duration: 15.4 yrs, seropositivity: 67%) were studied in order to investigate genetic factors that could account for the lack of efficacy to anti-TNF- therapy. All patients gave informed written consent and approval had been granted by the local ethics committee.
Specifically, the polymorphism 36A > G (exon 1) of TNFR1 gene, the 676T > G (Met196Arg, exon 6) of TNFR2, and the polymorphisms –857C > T (promoter), –308G > A (promoter), –238G > A (promoter) and 489G > A (intron 1) of TNF- gene have been studied by polymerase chain reaction-single strand conformation polymorphism method. Their selection was based on the fact that the results of previous studies are controversial for their role in RA pathogenesis, severity and course, and in patients’ response to anti-TNF- treatment. Statistical analysis was performed by a population genetics data analysis software, the Arlequin, according to Raymond and Rousset [7].
Twenty-seven patients showed good response according to the disease activity score (DAS) for 28 joint indices ([DAS-28] > 2.2) to infliximab, 18 moderate response (1.2 
DAS-28 2.2), and 13 lack of efficacy (DAS-28 < 1.2). Table 1 shows the distribution of genotypes of the studied polymorphisms in accordance to their response to TNF- inhibitor. All patients were homozygous for the wild-type –238G allele. Very low heterogeneity was also revealed for polymorphism –308G > A (1 AA-homozygote and 14 GA-heterozygotes). Thus, these two polymorphisms were excluded from the statistical analysis, since they were not found in Hardy–Weinberg equilibrium.
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Statistical analysis revealed that polymorphisms –857C > T and 489G > A were in linkage disequilibrium (P = 0.000). Specifically, the C allele of –857C > T was linked with the G allele of 489G > A (only one RA patient carried the genotype 489G/489A together with the –857T/–857T). Therefore, polymorphisms –857C > T and 489G > A were studied as one.
No independent polymorphism could predict patients’ response to anti-TNF- therapy. However, the complex genotypic analysis of both TNFR2 and TNF- gene polymorphisms revealed statistical significant difference in the distribution of the genotypic association of 676T > G with –857C > T/489G > A between the good and poor responders to infliximab (P = 0.008). Good responders carried more frequently the TNFR2 allele 676T in homozygosity together with the homozygosity of TNF- allele –857C/489G compared with poor responders.
Previously, the genotypic analysis of polymorphism 676T > G revealed conflicting results concerning the association of 676G allele with the pathogenesis of RA and disease severity. However, in transfected HeLa cells, the functional analysis of the polymorphism revealed increased toxicity in cells with the 676G allele which may explain the report by Fabris et al. about poor response to anti-TNF- treatment in patients carrying the 676G allele [1, 8]. This may explain why the complex genotype in the majority of our patients who responded well to anti-TNF- treatment carried the 676T allele.
Moreover, controversial results exist in the association of polymorphism –857C > T with RA pathogenesis, disease severity and its effect on TNF- gene transcription. In our study, the complex genotype carried in homozygosity the –857C allele in good responders. However, according to Kang et al. the –857T allele is associated with good response to anti-TNF- therapy. In contrast, Soga et al. [9] reported a tendency for high TNF- productivity in the carriers of –857T allele and, therefore, increased toxicity. The later seems to be in accordance to our results for the association of –857C allele and the good response to anti-TNF- therapy.
Finally, according to the literature, polymorphism 489G > A could not predict alone the predisposition to RA and patients' response to anti-TNF- treatment. Kaijzel et al. [10] reported no correlation of the polymorphism 489G > A in TNF- gene transcription. In our study, the wild type allele of polymorphism 489G > A was in strict linkage disequilibrium with the wild type allele of –857C > T and therefore, does not contribute to the variability of genotypic combinations found in good and poor RA responders. Consequently, the reported functional polymorphism –857C > T seems to have higher predictive value compared with 489G > A.
In conclusion, no independent polymorphism can predict the optimal therapy and especially in complex diseases such as chronic inflammatory disorders. Thus, we suggest that the combined study of polymorphisms 676T > G (TNFR2) and –857C > T (TNF-) could be used in the prognosis of RA patients' response to anti-TNF- therapy. More studies in larger and of other ethnic groups could confirm the use of the suggested complex genotypic analysis.
The authors have declared no conflicts of interest.
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