Table 1

Select examples of SNPs with clinical significance.

Phase I metabolism enzymes,

Allele nomenclature for Cytochrome P450 enzymes [24]:


Gene

rs#

location

Function

SNPlex


CYP2C9

rs1799853

*2, R144C

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

No


rs1057910

*3, I359L

Yes


CYP2C19

rs4244285

*2, 681G>A, exon 5, splicing defect

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


rs4986893

*3, 17948G>A, exon 4 premature stop

Yes


rs28399504

*4, transcription ablation

Failed


90033C>T, R433W, *5A, *5B

No enzymatic activity

Yes


*7, 19294T>A

Splicing defect, no enzymatic activity

Yes


CYP2D6

rs16947

*2, 2851C>T, R296C

Normal, nucleotide position corrected according to [47]

Yes


rs3892097 or rs1800716

*4, 1847G>A, splicing defect

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

Yes


rs28371704

983A>G, H94R

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

Failed


rs5030867

*7, 2936A>C, H324P

No enzymatic activity

Yes


rs5030865

*8, 1759G>T

Stop codon, no enzymatic activity

Yes


rs1065852

*10, 100C>T, P34S

Decrease enzymatic activity

Yes


rs5030863

*11, 882G>C

Splicing defect, no enzymatic activity

Yes


rs28371706

*17, 1022C>T, T107I

Decrease enzymatic activity

Yes


rs28371717

*33, 2484G>T, A237S

Normal

Yes


*44, 2951G>C

Splicing defect, no enzymatic activity

Yes


CYP3A4

rs11773597

*1F, m747C>G

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]

Yes


rs2740574

*1B, m392A>G

Yes

Yes


*4, 13989A>G,

In AF209389

Yes


*8, 14026G>A

In AF209389, R130Q

Yes


CYP3A5

rs28365083

*2, 27289C>A, T398N

Failed


rs776746

*3, 6986A>G, splicing inclusion

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

Yes


rs28365085

*3d, 31551T>C, I488T

Yes


*5, 12952T>C

Splicing defect

Yes


*8, 3699C>T, R28C

Decreased enzymatic activity

Yes


rs28383479

*9, 19386G>A, A337T

Decreased enzymatic activity

Failed


rs15524

*10, 31611C>T

Decreasde enzymatic activity

Yes


DPYD

rs3918290

splice variant IVS14+1G>A

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

Yes


NQO1

rs1800566

*2, C609T, R187S

*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]

Yes


rs4986998

*3, C465T, R139W

Yes


Phase II metabolism enzymes

NAT allele nomenclature [26]:

UGT allele nomenclature [25]:


Gene

rs#

location

Function

SNPlex


NAT2

rs1801280

341T>C, I114T, *5A to*5J, *14C and *14F

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

Yes


rs1799929

481C>T, L161L, *5A, *5B, *5F, *5G, *5H, *5I, *6E, *11A, *11B, *12C and *14C

Yes


rs1208

803A>G, K268R,*5B, *5C, *5F, *5G, *5H, *5I, *6C, *12A, *12B, *12C, *12D, *14E and *14F

Yes


rs1041983

282C>T, Y94Y, *13, *5G, *5J, *6A, *6C, *6D, *7B, *12B, *14B, *14D, *14G

Yes


rs1799930

590G>A, R197Q *5E, *5J, *6A, *6B to *6E, *14D

Yes


rs1799931

, 857G>A, G286E *7A, *7B

Yes


499G>A in sequence X14672, E167K, *10

Yes


rs1801279

191G>A, R64Q *14A to *14G,

Yes


434A>C A in sequence X14672, Q145P, *17

Yes


845A>C A in sequence X14672, K282T, *18

Yes


rs1805158

190C>T, R64W, *19

Yes


TPMT

rs1800462

*2, 238G>C

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

No


rs1800460

*3A, 460G>A

No


rs1142345

*3C, 719A>G

No


UGT1A1

TA (5–8) TAA

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

No


rs4148323

211G>A, G71R, *6

Reduced enzymatic activity

Yes


rs34993780

1456T>G, Y486D, *7

Yes


rs35350960

686C>A, P229Q, *27

Yes


247T>C, F83L, *62

Causing Gilbert's syndrome

Yes


GSTT1

Deletion causing null genotype

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

No


GSTP1

rs947894

313A>G I105V

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

Yes


GSTM1

Deletion causing null genotype

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

No


SULT1A1

rs9282861

*2, R213H, HaeII

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

No


Transporter Genes


Gene

rs#

location

Function

SNPlex


ABCB1

rs1045642

3435C>T

C3435 associated with higher drug transport activity

Yes


rs1128503

1236T>C

Yes


rs2229109

1199G>A

Yes


ABCC2

rs2273697

1249G>A, Val417Ile

1249AA associated with decreased mRNA [56]

Yes


ABCG2

rs2231142

421C>A, Q141K

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

Yes


rs2231137

G34 G>A V12M

No


944–949 deletion

No


SLC19A1

rs1051266

80G>A Arg27His

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

Yes


SLCO1B1/SCL21A6

rs4149056

T521C, Val174Ala, *5

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

Yes


rs2306283

Asp130Asn, *15

Yes


DNA repair genes


Gene

rs#

location

Function

SNPlex


BRCA2

rs144848

N372H

Cancer risk [51]

Yes


OGG1

rs1052133

S326C

Cancer risk [51]

Yes


XRCC1

rs1799782

R194W

Cancer risk [51]

Yes


rs25487

R399Q

Gln399 associated with oxaliplatin/5-FU resistance

Yes


rs25489

R280H

Yes


ERCC2/XPD

rs13181

K751Q

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

Yes


TP53

rs1042522

R72P

Cancer risk

Failed


MGMT

rs12917

262C>T, L84F

Decreased repair of DNA damage [58]

Yes


CHEK2

1100delC

Protein truncation, cancer risk [59]

No


Drug target, pathway genes


Gene

rs#

location

Function

SNPlex


DHFR

rs5030762

829T>C

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

No


MTHFR

rs1801133

677C>T, A222V

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

Yes

rs1801131

1298A>C, E429A

Reduced MTHFR enzyme activity [13, 53]

Yes


TYMS

2–9 28 bp repeats in the 5' promoter enhancer

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

No


CDA

rs2072671

79A>C, K27Q

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

Yes


208G>A, A70T

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

Yes


Cell cycle genes


CCND1

rs603965

870A>G

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

Yes


Dai et al. BMC Medical Genomics 2008 1:24   doi:10.1186/1755-8794-1-24

Open Data