no biggies, just parking..........
Arthritis Rheum 2001 Nov;44(11):2525-30
The C677T mutation in the methylenetetrahydrofolate reductase gene: a
genetic risk factor for methotrexate-related elevation of liver enzymes in
rheumatoid arthritis patients.
van Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA, de Boo
TM, van de Putte LB.
University Medical Center St. Radboud, Nijmegen, The Netherlands.
OBJECTIVE: To study the possible relationship between the C677T mutation in the
methylenetetrahydrofolate reductase (MTHFR) gene and the toxicity and efficacy of treatment
with methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: Genotype
analysis of the MTHFR gene was done in 236 patients who started MTX treatment with (n =
157) or without (n = 79) folic or folinic acid supplementation. Outcomes were parameters of
efficacy of MTX treatment, patient withdrawal due to adverse events, discontinuation of MTX
treatment because of elevated liver enzyme levels, and the total occurrence of elevated liver
enzyme levels during the study. Multivariate logistic regression analysis was used to study the
relationship between the presence of the MTHFR C677T mutation and toxicity outcomes of
MTX treatment. RESULTS: Forty-eight percent of the patients showed the homozygous (T/T) or
heterozygous (T/C) mutation. The presence of the C677CT or C677TT genotypes was
associated with an increased risk of discontinuing MTX treatment because of adverse events
(relative risk 2.01; 95% confidence interval 1.09, 3.70), mainly due to an increased risk of
elevated liver enzyme levels (relative risk 2.38; 95% confidence interval 1.06, 5.34). Efficacy
parameters were not significantly different between the patients with and those without the
mutation. CONCLUSION: The C677T mutation is the first identified genetic risk factor for
elevated alanine aminotransferase values during MTX treatment in patients with RA. We
postulate that the incidence of clinically important elevation of liver enzyme levels during MTX
treatment is mediated by homocysteine metabolism. Supplementation with folic or folinic acid
reduced the risk of toxicity-related discontinuation of MTX treatment both in patients with and in
patients without the mutation.
Acta Neurol Scand 2001 Nov;104(5):281-7
Evaluation of the roles of common genetic mutations in leukoaraiosis.
Szolnoki Z, Somogyvari F, Kondacs A, Szabo M, Fodor L.
Dept of Neurology and Neurophysiology, Central Laboratory, Pandy Kalman County Hospital,
Gyula, Hungary.
Objectives - Leukoaraiosis, a relatively frequent neuroimaging entity, is presumed to be primarily
a vascular problem. However, it can be explained only in part by vascular risk factors. With the
assumption of genetic susceptibility, the roles of common genetic polymorphisms and mutations in
leukoaraiosis were examined in this study. Material and methods - A detailed clinical scrutiny of
843 Hungarian neurological patients with mild cognitive-like complaints revealed 229 subjects
with leukoaraiosis that was probably vascular in origin: 143 with leukoaraiosis alone (group 1),
and 86 with leukoaraiosis plus cerebral infarction (group 2). In all 229 patients, the
methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutation and
angiotensin-converting enzyme (ACE I/D) polymorphism were examined by means of the PCR
technique. The prevalences of the different genotypes for the examined mutations in the 2 groups
were analysed in comparison with the data on 362 neuroimaging alteration-free subjects as
controls. Results - The ACE D/D genotype (38.37%, P<0.0005; OR 2.46, 95% CI, 1.49-4.08)
and ACE D allele (61%; P<0.001) were more frequent in group 2 than in the control group
(20.17%; 47%). Neither the homozygous nor the heterozygous MTHFR C677T mutation alone
was found to be a risk factor for leukoaraiosis. The homozygous MTHFR C677T mutation
combined with the ACE D/D genotype was significantly more frequent in group 1 (11.89%,
P<0.0005; OR 4.75, 95% CI, 2.12-10.65), in group 2 (12.79%, P<0.0005; OR 5.16, 95% CI,
2.12-12.6) and in combined group 1+2 (12.23%, P<0.0005; OR 4.9, 95% CI, 2.33-10.3) than
in the control group (2.76%). Conclusion - These data indicate that the contributions of the ACE
D/D genotype and the homozygous MTHFR C677T mutation to leukoaraiosis should be taken
into consideration not as major, but as additive factors. These findings draw attention to the fact
that genetic polymorphisms that alone are insignificant can be risk factors for leukoaraiosis if they
cluster in the same subjects. |
