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We read with interest the editorial “Methotrexate pharmacogenomics” by Kremer, recently published in the Annals of Rheumatic Diseases.1 Several reports have proposed a fundamental role of the folate pathway in the clinical effects of methotrexate (MTX) treatment in rheumatoid arthritis, mainly due to genetic variations in the methylene tetrahydrofolate reductase (MTHFR) gene. The observations by Hughes et al of ethnic differences in the frequencies of single‐nucleotide polymorphisms (SNPs) in the MTHFR coding region suggest possible links between other specific genotypes and MTX response.2
We recently identified an association between the 14 bp deletion/insertion polymorphism in exon 8 at the 3′ untranslated region (UTR) of the HLA‐G gene and the clinical response to MTX treatment in rheumatoid arthritis.3 The HLA‐G antigens are non‐classic MHC class Ib molecules with limited allelic polymorphisms,4 restricted tissue distribution,5,6,7 and alternative splicing mechanisms for mRNA that allow the production of both membrane‐bound and soluble isoforms.8 HLA‐G molecules are associated with the development or persistence of several autoimmune diseases because of their tolerogenic capacity against innate and adaptive responses.7,9 The 14 bp insertion/deletion polymorphism in the HLA‐G gene influences mRNA stability and quantitative protein production. Furthermore, the 14 bp insertion allele (+14 bp) destabilises mRNA and decreases soluble HLA‐G (sHLA‐G) protein production.10
In this study, we showed that MTX can induce the in vitro production of circulating HLA‐G molecules by peripheral blood monocyte cells from healthy subjects and patients with rheumatoid arthritis, with interindividual differences. Moreover, the highest quantitative in vitro production of sHLA‐G molecules was associated with the presence of the deletion (−14/−14 bp) genotype.
To have in vivo confirmation of the pharmacogenetic role of the 14 bp polymorphism in MTX response, we also performed a retrospective study of the genotype distribution in 156 patients with rheumatoid arthritis, who were subdivided into two cohorts on the basis of their clinical response to MTX. The data obtained indicated a significantly higher frequency of the −14/−14 bp genotype in “responder” patients compared with “non‐responders” (χ2=6.12; df=1; p=0.02 (χ2 test); odds ratio 2.46, 95% CI 1.26 to 4.84; p<0.009).
These results suggest a pharmacogenetic role for the HLA‐G 14 bp polymorphism, and that there is clinical advantage of the −14/−14 bp genotype in response to MTX. The HLA‐G 14 bp polymorphism should be investigated in association with other MTHFR SNPs that predominantly show a role in MTX toxicity.1 The combined analysis of such MTHFR SNPs and the HLA‐G 14 bp polymorphism could help in assessing the likelihood that patients will experience MTX‐related toxicity or benefits.
In conclusion, in rheumatoid arthritis it seems to be important to consider the concurrence of different genetic polymorphisms to help predict the clinical response to MTX treatment.
MTHFR - methylene tetrahydrofolate reductase
MTX - methotrexate
sHLA‐G - soluble HLA‐G
SNP - single‐nucleotide polymorphism
UTR - untranslated region