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Current Genomics


ISSN (Print): 1389-2029
ISSN (Online): 1875-5488

Dihydrofolate Reductase Gene Variations in Susceptibility to Disease and Treatment Outcomes

Author(s): Bahram S. Askari and Maja Krajinovic

Volume 11 , Issue 8 , 2010

Page: [578 - 583] Pages: 6

DOI: 10.2174/138920210793360925

Price: $65


Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate to tetrahydrofolate (THF). THF is needed for the action of folate-dependent enzymes and is thus essential for DNA synthesis and methylation. The importance of this reaction is demonstrated by the effectiveness of antifolate medications used to treat cancer by inhibiting DHFR, thereby depleting THF and slowing DNA synthesis and cell proliferation. Due to the pivotal role that DHFR plays in folate metabolism and cancer treatment, changes in the level of DHFR expression can affect susceptibility to a variety of diseases dependent on folate status such as spina bifida and cancer. Likewise, variability in DHFR expression can affect sensitivity to anti-cancer drugs such as the folate antagonist methotrexate. Alterations in DHFR expression can be due to polymorphisms in the DHFR gene. Several variations have recently been described in DHFR, including promoter polymorphisms, the 19-bp deletion allele and variations in 3UTR. These polymorphisms seem to be functional, affecting mRNA levels through various interesting mechanisms, including regulation through RNA interference. Several groups have assessed the association of these polymorphisms with folate levels, risk of cancer and spina bifida as well as the outcome of diseases treated with MTX. The latter may lead to different treatment schedules, improving treatment efficacy and/or allowing for a reduction in drug side effects. This review will summarize present knowledge regarding the predictive potential of DHFR polymorphisms in disease and treatment.

Keywords: Gene, dihydrofolate reductase (DHFR), polymorphisms, disease susceptibility, methotrexate (MTX), therapeutic response, dihydrofolate reductase, DHFR, methotrexate, MTX, dihydrofolate, tetrahydrofolate, S-adenosylmethionine, Neural tube defects, (NTD), folate cycle, methylene tetrahydrofolate reductase, MTHFR, spina bifida, homocysteine remethylation, DHFR polymorphisms, 5-methyl-THF, lymphoblastic leukemia, hMSH3

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