The effect of exon (19C>A) dihydroorotate dehydrogenase gene polymorphism on rheumatoid arthritis treatment with leflunomide.
OBJECTIVE
Leflunomide is an isoxazole derivative structurally and functionally unrelated to other known immunomodulatory drugs. The main molecular target of leflunomide is dihydroorotate dehydrogenase (DHODH), a key enzyme of de novo pyrimidine synthesis. The human DHODH gene sequence is highly conserved and contains only one common missense polymorphism in the coding regions. This SNP (refSNP ID: rs3213422) is localized in the first exon of the DHODH gene (19C>A) and leads to Gln7Lys amino acid substitution in the cationic N-terminal region of the DHODH polypeptide, and it has not yet been investigated in relation to enzyme activity or DHODH inhibitor efficacy. The aim of the study was to examine the effect of this polymorphism on leflunomide treatment outcome in rheumatoid arthritis (RA) patients.


METHODS
The study was carried out on 147 patients (123 women, 24 men, mean age: 52.8 +/- 11.03 years) diagnosed with RA and treated with leflunomide 20 mg daily. Clinical improvement was evaluated according to the American College of Rheumatology 20% and 50% response criteria.


RESULTS
The frequency of remission was increased in C allele carriers compared with patients with the A allele.


CONCLUSIONS
The results of this study suggest that DHODH polymorphism may be associated with leflunomide treatment outcome in RA patients.
Pawlik
Andrzej
A
Department of Pharmacology, Pomeranian Medical University, ul. Powst. Wlkp. 72, 70111 Szczecin, Poland. pawand@poczta.onet.pl
Herczynska
Magdalena
M
Kurzawski
Mateusz
M
Safranow
Krzysztof
K
Dziedziejko
Violetta
V
Drozdzik
Marek
M
D000328:Adult; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D002353:Carrier State; D017124:Conserved Sequence; D017931:DNA Primers; D000090722:Dihydroorotate Dehydrogenase; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use*; D000077339:Leflunomide; D008297:Male; D008875:Middle Aged; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide
D018501:Antirheumatic Agents; D017931:DNA Primers; D000090722:Dihydroorotate Dehydrogenase; D007555:Isoxazoles; D044925:Oxidoreductases Acting on CH-CH Group Donors; D000077339:Leflunomide