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Table 1 Pharmacogene regulatory variants linked to drug response

From: Pharmacogene regulatory elements: from discovery to applications

Gene/miRNA

Drug

Comments

References

Promoters

   

MGMT

Temozolomide

Promoter methylation of the gene encoding O-6-methylguanine-DNA methyltransferase (MGMT) is associated with treatment outcome in patients with glioblastoma multiforme and anaplastic astrocytoma treated with temozolomide

[78, 79]

UGT1A1

Irinotecan

The UGT1A1*28 polymorphism (insertion of a seventh 'TA' repeat in the UGT1A1 promoter) leads to lower UGT1A1 expression levels, causing lower clearance of the active irinotecan metabolite, SN-38. This results in severe side effects, such as diarrhea and neutropenia

[23, 29–31]

VKORC1

Anticoagulant

A common promoter variant in VKORC1, -1639G>A (rs17878363), has significant implications for dosing algorithm of anticoagulant response. Patients with the variant G require higher dose of warfarin and have lower response to acenocoumarol

[22, 25–27]

Enhancers

   

SLCO1A2

Methotrexate

A screen of ECRs in the vicinity of nine pharmacologically relevant membrane transporters identified several enhancers, notably a region in the first intron of SLCO1A2. Common SNPs within this region were linked to reduced SLCO1A2 mRNA levels (rs4148981C>T) and methotrextate clearance (rs11045981 T>G)

[3]

miRNAs

   

miR-24

Methotrexate

A naturally occurring SNP near the miR-24 binding site in the 3' UTR of human DHFR (829C>T) interfered with miR-24 function and resulted in DHFR overexpression and methotrexate resistance

[73]

miR-27a and miR-451

Doxorubicin

P-glycoprotein, encoded by ABCB1, causes resistance in cancer cells to multiple chemotherapeutics, and can be activated by miR-27a and miR-451. Antagonizing these miRNAs results in increased uptake of doxorubicin

[71]

miR-27b

Cyclophosphamide

Overexpression of miR-27b in PANC1cells downregulated CYP3A4 and led to cyclophosphamide resistance

[69, 70]

miR-200b/200c/429 family

Cisplatin

A polymorphism (rs1045385) within the 3' UTR of TFAP2 prevents binding of this family of miRNAs, leading to higher levels of its product, transcription factor AP-2α. This variant allows drugs that induce AP-2α, such as cisplatin, to more effectively inhibit cancer cell growth

[4]

  1. ECR, evolutionarily conserved region; miRNA, microRNA; SNP, single nucleotide polymorphism; UTR, untranslated region.