Rheumatology International

, Volume 27, Issue 11, pp 1057–1061

Transcription regulatory polymorphism −43T>C in the 5′-flanking region of SLC19A1 gene could affect rheumatoid arthritis patient response to methotrexate therapy

  • Anthoula Chatzikyriakidou
  • Ioannis Georgiou
  • Paraskevi V. Voulgari
  • Christos G. Papadopoulos
  • Theodoros Tzavaras
  • Alexandros A. Drosos
Original Article


The reduced folate carrier (RFC) protein (SLC19A1-gene) has central role in the uptake and intracellular accumulation of folates. In this respect, we investigate whether SLC19A1 genetic variations could affect rheumatoid arthritis (RA) patient response to antifolate treatment. One hundred six unrelated RA patients were enrolled in this study. Polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) was used as the screening method for genetic variants. Unusual SSCP patterns were characterized by direct sequencing of the PCR products and subsequently restriction assays were established. Western blot analysis of RFC protein was performed in respect of the identified SLC19A1 genotypes. Patient response to methotrexate (MTX) was evaluated using disease activity for 28 joint indices score, American College of Rheumatology 20% and 50% scores. No mutation was found in the SLC19A1 gene, but three polymorphic variants: the −43T>C in the 5′-flanking sequence to the ATG-transcription start site; and the 80G>A (R27H) and 696C>T (P232P) in the coding gene sequence. The wild type alleles of the three polymorphisms were in strict linkage disequilibrium. Western blot analysis revealed that the non-wild type allele of polymorphism −43T>C is associated with low RFC protein expression levels. Furthermore, the genotypic analysis of the functional polymorphic variant −43T>C revealed to be insufficient to predict patient response to MTX therapy. According to recent literature, several transport systems account for folate membrane transport. Additionally, in previous studies discrepancies have been reported to exist between the same genetic variants and their use in prediction of patient response to MTX therapy. Therefore, the present genotypic–phenotypic association study of a functional polymorphism revealed the need of a complex genotypic analysis in order to predict patient response to folate antagonists’ therapy.


Folate transport Methotrexate Rheumatoid arthritis SLC19A1 gene Transcription regulation 


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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Anthoula Chatzikyriakidou
    • 1
  • Ioannis Georgiou
    • 1
  • Paraskevi V. Voulgari
    • 2
  • Christos G. Papadopoulos
    • 2
  • Theodoros Tzavaras
    • 3
  • Alexandros A. Drosos
    • 2
  1. 1.Genetics Unit, Department of Obstetrics and Gynaecology, Medical SchoolUniversity of IoanninaIoanninaGreece
  2. 2.Rheumatology Clinic, Department of Internal Medicine, Medical SchoolUniversity of IoanninaIoanninaGreece
  3. 3.Laboratory of General Biology, Medical SchoolUniversity of IoanninaIoanninaGreece

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