2756GG genotype of methionine synthase reductase gene is more prevalent in rheumatoid arthritis patients treated with methotrexate and is associated with methotrexate-induced nodulosis.
OBJECTIVE
To investigate the distribution of the A2756G polymorphism of the methionine synthase reductase (MTR) gene in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) compared with a healthy control group; and to examine the relationships among the A2756G polymorphism, plasma total homocysteine (tHcy), serum folate and vitamin B12 levels, disease activity, and MTX toxicity in patients with RA.


METHODS
A cross-sectional study was performed on 86 MTX-treated RA patients, consisting of a clinical interview and physical examination to determine disease activity and MTX-related adverse reactions. Genotype analysis of the MTR gene was performed. Fasting plasma tHcy, serum folate, and vitamin B12 levels were measured. Allele and genotype distributions were compared to a healthy control group.


RESULTS
The frequency of the 2756GG genotype (16.3%) in the RA study group was higher than that expected in the general population (3.6%; p < 0.000001). This genotype was associated with MTX-induced accelerated rheumatoid nodulosis (MIARN). No association of disease activity variables or plasma homocysteine with MTR A2756G polymorphisms was observed. The MTR 2756GG genotype, low plasma vitamin B12 levels, and the presence of rheumatoid nodules predicted MIARN. No association of nodulosis with any other indicator of disease activity or medical treatment was found.


CONCLUSIONS
In our population of MTX-treated RA patients the 2756GG genotype of the MTR gene was more common than expected and was associated with MIARN.
Berkun
Yackov
Y
Department of Pediatrics, Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. berkun@md.huji.ac.il
Abou Atta
Iman
I
Rubinow
Alan
A
Orbach
Hedi
H
Levartovsky
David
D
Aamar
Suhail
S
Arbel
Ofer
O
Dresner-Pollak
Rivka
R
Friedman
Gideon
G
Ben-Yehuda
Arie
A
D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011624:Pteroylpolyglutamic Acids / Q000097:blood; D012215:Rheumatic Nodule / Q000139:chemically induced* / Q000235:genetics; D012720:Severity of Illness Index; D014805:Vitamin B 12 / Q000097:blood
D018501:Antirheumatic Agents; D011624:Pteroylpolyglutamic Acids; D006710:Homocysteine; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D014805:Vitamin B 12; D008727:Methotrexate