We have published a paper in the Journal of Personalized Medicine reporting a pharmacogenomic study of dried blood spot (DBS) samples to measure how methotrexate blood concentration varies with gene variations in patients with actively flaring arthritis.
Further study of the RADAR DBS samples provided data that genomic DNA and metabolites of drug treatments could be reliably extracted and used to study potential drug-gene interactions. Pharmacogenomics and stratified medicine are relative new branches of science which study how genetic variation between individuals influences the rate of drug metabolism and the efficacy of a particular treatment in people with the same diagnosis.
The variations in DNA sequence, known as single nucleotide polymorphisms (SNP), identified in DBS were known to have potential to affect the conversion of methotrexate into effective therapeutic metabolites. The study revealed that methotrexate metabolite concentrations across 100 RADAR study participants vary significantly with specific SNP genotypes. Identifying patients ahead of starting a course of methotrexate with tests for gene variants that adversely affect drug metabolism could therefore avoid reduced clinical benefit or increased toxicity.
Longitudinal views of drug metabolism and CRP were possible in participants who had been divided into genetic subgroups (see above illustration). This could also hold potential to help change treatments or dosage to reduce flare risk.
The abstract of the publication is below and full article can be accessed at the link.
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that causes loss of joint function and significantly reduces quality of life. Plasma metabolite concentrations of disease-modifying anti-rheumatic drugs (DMARDs) can influence treatment efficacy and toxicity. This study explored the relationship between DMARD-metabolising gene variants and plasma metabolite levels in RA patients.
DMARD metabolite concentrations were determined by tandem mass-spectrometry in plasma samples from 100 RA patients with actively flaring disease collected at two intervals. Taqman probes were used to discriminate single-nucleotide polymorphism (SNP) genotypes in cohort genomic DNA: rs246240 (ABCC1), rs1476413 (MTHFR), rs2231142 (ABCG2), rs3740065 (ABCC2), rs4149081 (SLCO1B1), rs4846051 (MTHFR), rs10280623 (ABCB1), rs16853826 (ATIC), rs17421511 (MTHFR) and rs717620 (ABCC2).
Mean plasma concentrations of methotrexate (MTX) and MTX-7-OH metabolites were higher (p < 0.05) at baseline in rs4149081 GA genotype patients. Patients with rs1476413 SNP TT or CT alleles have significantly higher (p < 0.001) plasma poly-glutamate metabolites at both study time points and correspondingly elevated disease activity scores.
Patients with the rs17421511 SNP AA allele reported significantly lower pain scores (p < 0.05) at both study intervals. Genotyping strategies could help prioritise treatments to RA patients most likely to gain clinical benefit whilst minimizing toxicity.
