HLA-G 14-bp polymorphism regulates the methotrexate response in rheumatoid arthritis.
OBJECTIVE
Methotrexate (MTX) represents the antirheumatic drug mainly used in rheumatoid arthritis (RA). HLA-G antigens are inducible nonclassical major histocompatibility complex class Ib molecules important for maintaining anti-inflammatory conditions. The HLA-G gene is characterized by a deletion/insertion polymorphism of 14 bp that controls specific mRNA stability and protein levels. It has been reported that MTX therapy mediates an increase of interleukin-10-producing cells. This cytokine up-regulates HLA-G expression. For this, we tested the hypothesis of an MTX-mediated HLA-G production and the possible relationship with the HLA-G 14-bp polymorphism.


METHODS
Peripheral blood mononuclear cells from healthy individuals and non-MTX-treated RA patients were activated with different MTX concentrations, and soluble HLA-G (sHLA-G) and interleukin-10 production was investigated by specific immunoenzymatic assay. HLA-G 14-bp polymorphism genotyping was performed in healthy individuals and RA patients, defined as 'responders' and 'nonresponders' to the MTX therapy.


RESULTS
MTX activation induces the production of sHLA-G molecules. A significant association was observed between the highest sHLA-G1 concentrations and the -14/-14 bp genotype. The analysis of the HLA-G 14-bp polymorphism in MTX-treated RA patients has confirmed an increase of the -14/-14 bp genotype in the responder group (chi=6.12, P=0.02; chi test) (odds ratio=2.46 (95% confidence interval, 1.26-4.84) P=0.009; logistic regression model).


CONCLUSIONS
Our results propose that the MTX induces the production of the anti-inflammatory sHLA-G molecules that concur with the therapy response. Furthermore, the association between -14/-14 bp genotype and MTX clinical outcome proposes this polymorphism as a therapy marker in the early phases of the disease.
Rizzo
Roberta
R
Section of Medical Genetics, Department of Experimental and Diagnostic Medicine University of Ferrara, Ferrara, Italy.
Rubini
Michele
M
Govoni
Marcello
M
Padovan
Melissa
M
Melchiorri
Loredana
L
Stignani
Marina
M
Carturan
Sabrina
S
Ferretti
Stefano
S
Trotta
Francesco
F
Baricordi
Olavio R
OR
D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005838:Genotype; D006680:HLA Antigens / Q000097:blood / Q000235:genetics*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000235:genetics*; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D007962:Leukocytes / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000502:physiology*; D012189:Retrospective Studies; D013223:Statistics as Topic; D016896:Treatment Outcome
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C508609:IL10 protein, human; D018950:Lipopolysaccharide Receptors; D016753:Interleukin-10; D008727:Methotrexate