Do snapshot statistics fool us in MTX pharmacogenetic studies in arthritis research?

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Sir, Recently, an interesting discussion was published in Rheumatology on discrepant literature results concerning MTX pharmacogenetics in RA [1–3]. This discussion was triggered by the paper of Lee et al. [2] introducing the concept of false-positive report probability (FPRP) in the field of arthritis research. The discussion focused on the discrepant results observed for single nucleotide polymorphisms (SNPs) in the ATIC gene (rs4673993 and rs2372536, both in linkage disequilibrium): the 347 C-allele [4, 5] and the G-allele [2, 6] were both associated with increased efficacy of MTX. Similar discrepancies for SNPs in the methylenetetrahydrofolate reductase (MTHFR) gene were reported in a meta-analysis earlier this year [7]. In trying to explain the discrepancy, Dervieux [1] pointed out the challenges and difficulties that researchers face when validating associations between low-penetrance genetic polymorphisms and complex phenotypes such as drug response. The discussion focused on differences between studies in the FPRP, differences in sample size or power, demographic dissimilarities among cohorts, environmental factors such as folate status, duration of disease and treatment duration.