BACKGROUND: This study was designed to identify the relationship between the C677T mutants of MTHFR and methotrexate toxicities in Korean patients with RA and to determine whether MTHFR polymorphism will be useful predictor for adverse effects of low dose methotrexate treatment. METHODS: We enrolled 385 (355 females, 30 males) patients with RA, who had been received low dose methotrexate. Genotypes of MTHFR polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The correlations between MTHFR genotypes, age, RF positivity, RA progression stage, KHAQ and adverse effects were analyzed by Spearman's rank correlation test. The frequency analysis of C677T genotype and adverse effects was done by Chi-square test. RESULTS: The results of MTHFR genotypic analysis showed 133 patients (34.6%) with 677CC, 193 patients (50.1%) with 677CT and 59 patients (15.3%) with 677TT. One hundred fifty-four of the 385 patients (40.0%) had methotrexate-related side effects. The significant correlation between toxicities of methotrexate and MTHFR polymorphism was identified by Spearman's rank correlation test (p<0.05). The odd ratio, which of adverse effects could be occurred by low dose methotrexate in rheumatoid arthritis patients with MTHFR polymorphism, showed higher value than other studies (p<0.001, OR: 4.0, 95% CI 2.45-6.51). CONCLUSION: There was a positive association between methotrexate-related toxicities and MTHFR polymorphism. This study suggested that C677T mutant of MTHFR might be a powerful genetic indicator in predicting the adverse effects of low dose methotrexate therapy in patient with rheumatoid arthritis.
Arthritis, Rheumatoid* ; Female ; Genotype ; Humans ; Methotrexate* ; Methylenetetrahydrofolate Reductase (NADPH2)*

OBJECTIVE: Studies have suggested that the 5, 10-methylenetetrahydrofolate reductase (MTHFR) C677T mutation (alanine --< valine) is a risk factor for atherosclerotic disease. We assessed the association between MTHFR gene polymorphism and carotid atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: Forty postmenopausal RA women (mean age: 58+/-5 years, mean duration of RA 14+/-5 years) treated with low dose methotrexate, other concurrent disease modifying anti-rheumatic drugs, non-steroidal anti-inflammatory drugs, steroid (prednisolone < or =5 mg/day) and folic acid (> or =1 mg/day) were studied. The genetic polymorphism was detected by the polymerase chain reaction. We measured intima-media thickness (IMT) and plaques of the common carotid arteries by ultrasonography, and evaluated relations among the known risk factors for atherosclerosis, the genetic polymorphism, RA outcomes (Steinbrocker's radiological stage and functional class defined by the ACR criteria) and markers of inflammation (erythrocyte sedimentation rate and C-reactive protein). RESULTS: Among the 40 subjects, 12 had MTHFR genotype CC, 24 genotype CT, and 4 genotype TT. The frequencies of the MTHFR C and T allele were 0.6 and 0.4, respectively. Between the subjects with the CC genotype and those with the mutant T allele, there was no difference in age, body mass index, blood pressure (BP), lipid, duration of RA, RA outcome indices, rheumatoid factor, acute phase reactants and IMT. Carotid IMT was positively associated with age, systolic BP and antihypertensive drug use. There was no significant association between carotid IMT and the MTHFR C677T mutation. CONCLUSION: It is assumed that there was no significant relationship between the MTHFR C677T polymorphism and carotid atherosclerosis in Korean postmenopausal RA women.
Acute-Phase Proteins ; Alleles ; Antirheumatic Agents ; Arthritis, Rheumatoid* ; Atherosclerosis ; Blood Pressure ; Body Mass Index ; Carotid Artery Diseases* ; Carotid Artery, Common ; Female ; Folic Acid ; Genotype ; Humans ; Inflammation ; Methotrexate ; Methylenetetrahydrofolate Reductase (NADPH2)* ; Oxidoreductases ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Rheumatoid Factor ; Risk Factors ; Ultrasonography

OBJECTIVE: We examined the genetic polymorphisms of glutathione S-transferase M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1) in Korean patients with rheumatoid arthritis (RA) and studied to determine whether GSTs influence susceptibility or outcome in RA. METHODS: RA patients with disease duration above 2 years (n=267) and healthy control (n=400) were enrolled. Genetic polymorphism were determined using polymerase chain reaction-based assays. We assumed stage I (Steinbroker's radiologic stage by the ACR criteria) regarded as mild RA and stage II, III, IV as severe RA. Data were analysed using multiple regression analysis with correction for age, sex, disease duration, and rheumatoid factor positivity. RESULTS: The frequency of GSTM1 null genotype in Korean RA patients was significantly higher than that of control (61.7% vs 53.5%, p=0.04). No significant differences in the frequency of the GSTT1 null genotype and GSTP1 genotypes between RA patients and normal controls were identified. The GSTM1 null genotype significantly influence the disease progression and bony erosive change in severe RA groups (p=0.03) compared with in mild RA groups. CONCLUSION: The GSTM1 null genotype increases the risk of rheumatoid arthritis in Korean patients. More severe erosive damage was associated with GSTM1 null genotype. Our study suggests that GSTM1 null genotype may be an independent marker for development of more erosive disease in RA.
Arthritis, Rheumatoid* ; Disease Progression ; Genotype ; Glutathione Transferase* ; Glutathione* ; Humans ; Polymorphism, Genetic ; Rheumatoid Factor

OBJECTIVE: To determine whether GSTM1, GSTT1 and GSTP1 polymorphisms are associated with susceptibility or disease manifestations in patients with SLE. METHODS: Two hundred eighty-six SLE patients who fulfilled the American College of Rheumatology (ACR) criteria were compared with 271 cases of age and sex matched controls to examine association between GST genotypes and susceptibility to SLE. The effect of genotype on SLE manifestations was assessed using the comparison of ACR diagnostic criteria. GST gene polymorphisms were determined by a multiplex polymerase chain reaction and antibodies to SS-A and SS-B were determined by double immunodiffusion. RESULTS: No association was found in the comparison of GSTM1 null, GSTT1 null, GSTP1 Ile105-- Antibodies ; Exanthema ; Genotype ; Glutathione Transferase* ; Glutathione* ; Heterozygote ; Humans ; Immunodiffusion ; Lupus Erythematosus, Systemic* ; Multiplex Polymerase Chain Reaction ; Nephritis ; Psychotic Disorders ; Rheumatology

OBJECTIVE: To investigate the association between a single nucleotide polymorphism in the catalase and peroxisome proliferator activated receptor- gamma (PPAR-gamma) genes with risk and severity of rheumatoid arthritis (RA) in Korea. METHODS: DNA was isolated from blood samples collected from 473 Korean patients with RA and 400 Korean controls. Genotyping for the C-262T polymorphism of catalase and the Pro12Ala polymorphism of PPAR-gamma was performed by PCR-RFLP (restriction fragment length polymorphism) analysis. Subjects were classified according to ACR criteria for RA, KHAQ, and radiological severity classification by Steinbroker. RESULTS: In patient group, catalase C/T and T/T polymorphism was seen in 23 (4.9%) and 0 patients while Pro/Ala and Ala/Ala PPAR-gamma polymorphism was seen in 42 (8.9%) and 1 (0.2%) patients. In control group, catalase C/T and T/T polymorphism was seen in 25 (6.3%) and 1 (0.2%) controls while Pro/Ala and Ala/Ala PPAR-gamma polymorphism was seen in 34 (8.5%) and 4 (1%) controls. Catalase and PPAR-gamma polymorphism showed no association with the susceptibility to RA individually but, when combined association was found although it had no statistical significance, which was possibly due to its low frequency. Catalase and HLA-DRB1 polymorphism showed significant interaction on development of RA but, no interaction was found between PPAR-gamma and HLA-DRB1. Catalase and PPAR-gamma polymorphism showed no association with the severity or functional status of RA. CONCLUSION: Our results show that genetic polymorphisms of catalase and PPAR-gamma has no association with the susceptibility to RA. Catalase and HLA-DRB1 polymorphism showed significant interaction on development of RA.
Arthritis, Rheumatoid* ; Catalase* ; Classification ; DNA ; HLA-DRB1 Chains ; Humans ; Korea ; Peroxisomes ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide

OBJECTIVE: We assessed the contribution of genetic polymorphisms of glutathione S-transferase M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1, Ile105Val) to carotid atherosclerosis in 40 postmenopausal rheumatoid arthritis (RA) women without histories of smoking. METHODS: We measured mean intima-media thickness (IMT) and plaque of the common carotid arteries by ultrasonography, and evaluated relations among the known risk factors for atherosclerosis, genetic polymorphisms, RA outcomes and markers of inflammation. RESULTS: Subjects with the GSTT1-null genotype had greater IMT (p<0.05). On univariate analysis, carotid IMT was positively associated with age, systolic BP, antihypertensive drug use and the GSTT1-null genotype (p<0.05). When compared to subjects with a double- positive GSTM1/T1 genotype, IMT in subjects with concurrent lack of the GSTM1 and GSTT1 gene was significantly increased (p=0.008). CONCLUSION: This study suggests that the GSTT1-null genotype might have an interaction with carotid atherosclerosis related to RA in Korean postmenopausal RA women free of smoking history.
Arthritis, Rheumatoid* ; Atherosclerosis ; Carotid Artery Diseases* ; Carotid Artery, Common ; Female ; Genotype ; Glutathione Transferase* ; Glutathione* ; Humans ; Inflammation ; Polymorphism, Genetic ; Risk Factors ; Smoke ; Smoking ; Ultrasonography