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OBJECTIVE: Excessively suppressed expression of the SLC22A4 gene by RUNX1 is associated with the pathogenesis of rheumatoid arthritis (RA). Two etiological polymorphisms in the RUNX1 and SLC22A4 genes have been defined in a Japanese population. We studied additional polymorphisms to ascertain whether any SLC22A4/SLC22A5 haplotype is relevant for RA predisposition in a Spanish population. METHOD: We performed a case-control study comprising 416 patients with RA and 501 healthy subjects. RESULTS: The etiologic SLC22A4 mutation was rarely found in homozygosis (0.72% patients vs 0.40% controls). None of the 4 haplotypes present in the SLC22A4/SLC22A5 region in 5q31 showed significant association with RA in our Spanish cohort. The causative RUNX1 variant found in a Japanese cohort displayed the same genotype distribution in our population. However, no difference was observed when allele or genotype frequencies were compared between Spanish patients with RA and controls. CONCLUSION: The SLC22A4 and RUNX1 polymorphisms described as etiological in the Japanese study did not show a significant role in RA susceptibility in our population. The mechanism proposed by these Japanese investigators could underlie RA susceptibility irrespective of ethnicity, but the lower mutation rate present in our population hampered detection of a significant effect. Most probably the lack of mutated SLC22A4 substrate explains the absence of RUNX1 association with RA observed in our population.