\n\nMethods. Genomic DNA samples were collected

from a prospective cohort of 400 RA patients. TRAF1/C5 rs3761847 was identified using real-time KU 57788 polymerase chain reaction and melting curve analyses. The association of TRAF1/C5 rs3761847 alleles with the risk of death was assessed using Cox proportional hazards regression analyses.\n\nResults. TRAF1/C5 rs3761847 GG homozygote status was associated with an increased risk of death (hazard ratio 3.96 [95% confidence interval 1.24-12.6], P = 0.020) as compared with AA homozygote status. The excess mortality was attributed to deaths due to malignancies and sepsis but not cardiovascular disease (CVD). This polymorphism was one of the strongest predictors of death in RA (for TRAF1/C5 GG versus AA, hazard ratio 3.85 [95% confidence interval 1.18-12.59], P = 0.026) alongside the erythrocyte sedimentation rate, triglyceride level, prednisolone use, and age.\n\nConclusion. The risk of death in RA is increased in TRAF1/C5 rs3761847 GG homozygotes and appears to be independent of RA activity and severity as well as comorbidities relevant to CVD. If this finding is replicated in future studies, TRAF1/C5 genotyping could identify patients at increased risk of death, particularly death due to malignancy or sepsis.”
“Pharmacogenetics represents SB203580 an exciting, new promising tool for the individualisation of therapy. Several genetic polymorphisms and haplotypes

have been considered in an attempt to optimise therapy with specific drugs but, up to now, their clinical applications remain limited.\n\n5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme of one-carbon metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Two common non-synonymous variants, the C677T (Ala222Val) and A1298C (Glu429Ala), were described for the MTHFR gene and associated with a decreased enzymatic activity and an alteration of intracellular folate distribution. Other MTHFR polymorphisms with marginal impact on enzymatic activity were also reported.\n\nSeveral published clinical studies have investigated the potential predictive role of C677T and A1298C

genetic variants on toxicity and efficacy of antifolate and fluoropyrimidine P505-15 agents, such as methotrexate (MTX), 5-fluorouracil (5-FU) and raltitrexed. Many of these studies show significant associations with MTHFR variants, but others report neither association nor opposite results. A significant interaction between MTHFR polymorphisms and nutrient/environmental factors (i.e. folate status) as well as the ethnicity was reported. Finally, a haplotype approach and the combined analysis of multiple folate pathway gene variants seem to provide a more comprehensive strategy compared to single-locus investigations.\n\nThe aim of this review is to critically analyse the available data on the importance of MTHFR polymorphisms in modulating the clinical outcome of antifolate and fluoropyrimidine therapies. (C) 2008 Elsevier Ltd.