Toxicities associated with MTHFR genotypes
MTX can cause a variety of adverse effects including, but limited to myelosuppression, elevated liver function tests (LFTs), mucositis, renal toxicity, and neurotoxicity. The mechanism by which MTHFR genotypes would influence MTX-induced toxicity is unclear. Therefore, we examined the EHR to best determine the causal reason for sending MTHFR genetic testing for each patient to better elucidate how MTHFR genotypes can influence intolerance to MTX. As detailed in Fig. 3, a significant proportion of patients with both the homozygous 677TT (8/9) and compound heterozygous 677CT/1298AC (6/9) genotypes were found to have myelosuppression as a primary reason for sending. This is in comparison to patients harboring the heterozygous 677CT (3/8), heterozygous 1298AC (3/6), and wildtype (5/13) genotypes which all had a lower frequency of myelosuppression as a cause for sending. Combining those with 677TT and 677CT/1298AC genotypes and comparing to those with wildtype, 677CT, and 1298AC genotypes, myelosuppression was significantly associated with identification of clinically meaning SNP (OR= 5.4, 95% CI 1.3-17.5, p< 0.02). In our data set, there were several causes attributed to the sending of MTHFR genetic testing, but were varied and only attributed to 1-2 patients at most with exception of elevated LFTs in the MTHFR wildtype group which was attributed to 3 patients.
We also examined two potential adverse effects experienced by ALL patients, thrombosis and MTX leukoencephalopathy (Table 2). Thrombosis risk is increased in patients with MTHFR SNPs and generally attributable to high homocysteine levels, however, this may only be modestly elevated for most individuals regardless of MTHFR genotype. In our population, we did not find any significant increase in the occurrence of thrombosis in any SNP group when compared to the control group. MTX leukoencephalopathy is also an important adverse effect commonly attributed to the intrathecal and high dose intravenous administrations of MTX. Likewise, when compared to the control group, there was no significant increase in the occurrence of MTX leukoencephalopathy.