Table 1 Select examples of SNPs with clinical significance.

PM 0.25% in Caucasians, life-threatening bleeding after given warfarin

PM phenotype 2–5% in Caucasians, 18–23% in Asians, > 87% PM in Caucasians is *2 and *3; > 99% PM in Asians has *2 and *3. CYP2C19*2 homozygotes did not respond to antiangiogenic drug thalidomide treatment

No enzymatic activity

Splicing defect, no enzymatic activity

Normal, nucleotide position corrected according to [47]

The CYP2D6 PM is about 5–10% of Caucasians. 99% PM has *3, *4, *5, *6, *7, *8 and *11. *3, *5 and *6 are deletions

In *4A, *4B, *4F, *4G, *4H and *4J

No enzymatic activity

Stop codon, no enzymatic activity

Decrease enzymatic activity

Splicing defect, no enzymatic activity

Decrease enzymatic activity

Normal

Splicing defect, no enzymatic activity

Trans-regulation of gene expression is important. Overall, no major pharmacokinetic consequences for the identified CYP3A4 SNPs have been observed for the metabolism of anti-cancer drugs [12]

In AF209389

In AF209389, R130Q

*3 is the most frequent polymorphism (about 90% in Caucasians). Splicing defect, severely decrease of enzymatic activity [12]

Splicing defect

Decreased enzymatic activity

Decreased enzymatic activity

Decreasde enzymatic activity

*2A, Skipping exon 14, ↑ 5FU neurotoxicity [12]

*2 and *3 have reduced protein level and enzymatic activity. NQO1 is needed for the activation of mitomycin C, 17AAG (HSP90 inhibitor) and inactivation of benzene-like leukemogenic agents [13]

Phase II metabolism enzymes

NAT allele nomenclature [26]:

UGT allele nomenclature [25]:

Function

Alleles with decreased activity include NAT2*5B, NAT2*6A, NAT*7A or B, NAT2*10, NAT2*14A or B, NAT2*17, NAT2*18 and NAT2*19 [12, 14]

Low NAT2 activity is related to the increased risk of isoniazid hepatotoxicity

Null genotype associated with hematopoietic thiopurine toxicity, homozygous frequency 1/300 [4]

UGT1A1 *28 (7 TAs) associated with increased irinotecan toxicity. Caucasians ~32%

Reduced enzymatic activity

Causing Gilbert's syndrome

Null allele has been associated with better or poorer survival in leukemia patients following chemotherapy [12]

Val associated with decreased enzyme activity and increased survival after 5FU/oxaliplatin treatment of colorectal cancer patients [54]

Null allele is associated with increased survival after chemotherapy for multiple cancers [13, 14]

His/His has lower enzymatic activity and is associated with poor survival following tamoxifen therapy [55]

Transporter Genes

Function

C3435 associated with higher drug transport activity

1249AA associated with decreased mRNA [56]

Minor alleles with lower BRCP expression, enhanced drug sensitivity [12]

Patients with the 80AA genotype had higher plasma MTX levels, suggesting decreased cellular uptake of MTX

*5 and *15 are associated with decreased transport activity [57]

DNA repair genes

Function

Cancer risk [51]

Cancer risk [51]

Cancer risk [51]

Gln399 associated with oxaliplatin/5-FU resistance

Lys751 associated with improved oxaliplatin/5-FU treatment outcome [52]

Cancer risk

Decreased repair of DNA damage [58]

Protein truncation, cancer risk [59]

Drug target, pathway genes

Function

SNP 829T>C located in the untranslated region of the DHFR, associated with ↑ of DHFR mRNA, ↓ responsiveness to methotrexate

minor allele frequency 24–46%% in Caucasians, T allele is associated with reduced enzyme activity, increased toxicity to methotrexate [13, 53]

Reduced MTHFR enzyme activity [13, 53]

3 repeats ↑ RNA, TSER*3 associated with drug resistance of 5FU and methotrexate

Minor allele has lower activity to inactivate gemcitabine than the wild-type [60]

70TT has lower activity to inactive cytidine and ara-C than the wild-type [61]

Cell cycle genes

Alternative transcript encodes a protein with enhanced cell transformation activity, and modifies caner risk [62]