Hughes LB et al. (2006) Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis 65: 1213–1218

Methylenetetrahydrofolate reductase (MTHFR) has an important role in folate metabolism, and could affect a patient's response to the antifolate drug methotrexate. Previous studies of the MTHFR gene have indicated ethnic differences in allele frequency for certain MTHFR single-nucleotide polymorphisms (SNPs). A new study by Hughes and colleagues has now confirmed that MTHFR allele frequencies differ between white and African American patients with rheumatoid arthritis (RA) and that MTHFR genotype can affect response to methotrexate treatment.

The study included 393 white and 138 African American patients with RA, and 50 white and 53 African American healthy controls. Hughes and colleagues assessed five MTHFR SNPs: the allele frequencies of the rs4846051C, 677T, and 1298C alleles were 0.08, 0.30, and 0.34, respectively, among white RA patients, compared with 0.33, 0.11, and 0.13, respectively, among African American patients. There were no differences in the frequencies of the other two alleles assessed. There were also no differences in allele frequency between patient and control groups, regardless of ethnicity. Although the efficacy of methotrexate treatment was not affected by allele frequency, toxicity of the drug was: the 1298A allele was associated with an increased likelihood of adverse events in white patients, and the rs4846051C was associated with increased toxicity in African American patients.

The authors conclude that ethnic differences in allele frequency do exist, and call for larger trials, as their analysis might have been limited by the relatively small number of African Americans in their study.