| Summary: | Background: Methotrexate (MTX) is one of the most common medications used for rheumatoid arthritis (RA) treatment. Single-nucleotide polymorphisms (SNPs) could potentially predict variability in therapeutic outcomes. Aim: This study aims to assess the impact of SNPs in genes encoding for the MTX pathway for predicting clinical and therapeutic responses to MTX in a cohort of Egyptian patients with RA. Subjects and Methods: Data from 107 Egyptian RA patients (aged 44.4 ± 11.4 years) treated with MTX monotherapy, for a duration of 3.7 ± 3.3 years, were collected. Genotypes of 10 SNPs from four different genes were analyzed using the allelic discrimination PCR technique. Results: The <i>ATIC</i> rs3821353 G/T (<i>p</i> = 0.034) and the C/T and C/C of <i>SLC19A1</i> rs7279445 (<i>p</i> = 0.0018) were associated with a non-response to MTX, while <i>DHFR</i> rs10072026 C/T and C/C were associated with a good response (<i>p</i> < 0.001). Carriers of the <i>ATIC</i> rs382135 3 G (<i>p</i> = 0.001) and <i>ATIC</i> rs4673990 G (<i>p</i> < 0.001) alleles were more likely to develop RA, while the <i>SLC19A1</i> rs11702425 T (<i>p</i> < 0.001) and <i>GGH</i> rs12681874 T (<i>p</i> = 0.003) allele carriers were more likely to be protected against RA. Carriers of the <i>ATIC</i> rs4673990 A/G genotype (<i>p</i> < 0.001) were at risk of developing RA, while carriers of the following genotypes were mostly protected against RA: <i>ATIC</i> rs3821353 T/T (<i>p</i> < 0.001), <i>ATIC</i> rs3821353 G/G (<i>p</i> = 0.004), <i>SLC19A1</i> rs11702425 T/T (<i>p</i> = 0.001), <i>SLC19A1</i> rs11702425 C/T (<i>p</i> = 0.003), <i>GGH</i> rs12681874 C/T (<i>p</i> = 0.004) and <i>GGH</i> rs12681874 T/T (0.002). Conclusion: The genotyping of genes involved in the MTX pathway may be helpful to predict which RA patients will/will not benefit from MTX, and thus, may help to apply a personalized medicine approach in RA.
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