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.