Important Variant Information for CYP2A6
Submitted by: Manki Ho, Jill Mwenifumbo, Ryan Owen (PharmGKB), Rachel Tyndale (PNAT)
Reviewed by: Under Review
Submitted date: Feb 28, 2007
There are Seven Important Variants for CYP2A6
- CYP2A6:58 bp gene conversion
- CYP2A6:A52553G (rs28399433)
- CYP2A6:A50707T (rs1801272)
- CYP2A6:50364-50365delTT (rs28399444)
- CYP2A6:C47441T (rs28399454)
- CYP2A6:A45948G (rs5031016)
- CYP2A6:C45906A (rs28399468)
1. CYP2A6:58bp gene conversion
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Key Haplotypes: |
*1B, *7 and *10 |
| Genomic Variant & GenBank ID: | 58 bp gene conversion in the 3'UTR NG_000008.6 |
| mRNA Variant & GenBank ID: |
N/A |
| Protein Variant & GenBank ID: |
N/A |
| Variant Summary: | CYP2A6 58 bp gene conversion allele frequency is 27.6% - 33.5% in Caucasians [PMID:11186131, 11159795, 14974084, 15940289, 15225612, 16272956, 16041240and 15475735]; 40.6% to 51.3% in Chinese, Koreans and Japanese [PMID: 11159795, 12445030and 15475735]; 11.2% to 13.0% [PMID: 15475735 and 15225612] in African North Americans; 55% in Canadian Native Americans [PMID: 15475735] and 34.9% [PMID: 16272956] in South Asians. |
| Key PubMed IDs: | 15225612, 16041240, 16272956, 15475735, 11159795, 12445030, 15618666, 15534625, 15660270, 14974084, 15940289, 11186131, 11434509, 11180041 |
| Phenotype Informaton: |
In vivo, CYP2A6 58 bp gene conversion, the defining allele in CYP2A6*1B, is associated with increased nicotine C-oxidation and/or coumarin 7-hydroxylation in Asian populations [PMID:11434509, 1180041and 15618666]. CYP2A6*1B is associated with an increased risk of being a smoker and increased cigarette consumption in Caucasian and Japanese populations [PMID: 15534625, 16272956, 15940289and 14981342]. |
2. CYP2A6:A52553G (rs28399433)
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Key Haplotypes: | CYP2A6*9 |
| Genomic Variant & GenBank ID: |
A52553G on NG_000008.5 |
| mRNA Variant & GenBank ID | N/A |
| Protein Variant & GenBank ID | N/A |
| dbSNP rs# | rs28399433 |
| GoldenPath Position: | Chr19:46048219;(hg18) |
| Variant Summary: |
This SNP (CYP2A6-A52553G) disrupts the TATA box; it has only been found on the CYP2A6*1A allele and not on CYP2A6*1B [PMID: 12844137]. In vitro, CYP2A6-A52553G substitution resulted in a 50% decrease in transcription activity [PMID: 11394901]. Human liver samples with the CYP2A6*9 SNP have decreased CYP2A6 mRNA expression and coumarin 7-hydroxylase activity [PMID: 14583682]. The allele frequency is reported as: 5.1% to 7.2% in Caucasians [PMID: 16041240, 15469410, 15475735and 11394901]; 15% to 38% in Chinese, Koreans and Japanese [PMID: 12844137, 16041240, 15469410and 11394901]; 7.1% to 8.8% (n = 80) in African North Americans [PMID: 15475735, 15469410, 16041240]; 15.5% in Canadian Native Americans [PMID: 15475735]; and 15% in Southeast Asians [PMID: 15469410] |
| Key PubMed IDs: | 11394901, 12844137, 14583682, 15475735, 16041240, 15469410 |
| Phenotype Information: |
In vivo, subjects homozygous for CYP2A6*9/*9 generally have lower cotinine/nicotine ratios compared to CYP2A6*1A/*1A individuals [PMID: 12844137]. A study found that the CYP2A6*9 allele was less frequent in Turkomans, an Iranian population with a high incidence of esophageal cancer, compared to two Japanese populations that had a lower incidence of esophageal cancer [PMID: 15327835]. |
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Key Haplotypes: |
CYP2A6*2 |
| Genomic Variant & GenBank ID | A50707T on NG_000008.6 |
| mRNA Variant & GenBank ID | T488A on NM_000762.4 |
| Protein Variant & GenBank ID | L160H on NP_000753.2 |
| dbSNP rs#: | rs1801272 |
| GoldenPath Position: | Chr19:46046373 (hg18) |
| Variant Summary: |
The CYP2A6-A50707T allele contains a SNP in exon 3 that results in an amino acid change (L160H). This variant fails to incorporate heme and is enzymatically inactive [PMID: 2322567]. |
| Key PubMed IDs: | 2322567, 11684323, 15475735, 16041240, 15225612, 16272956, 15660270, 10544257, 16041240, 11180041, 11434509, 9827545, 15534625 and 16272956 |
| Phenotype Information: |
An individual homozygous for the CYP2A6-A50707T allele was found to be completely deficient in coumarin 7-hydroxylase activity [PMID: 9409631]. In smoking and CYP2A6 genotype association studies, those with the CYP2A6- A50707T allele are commonly grouped with others who have loss of function alleles (e.g. CYP2A6*4) to form the slow metabolizer group. Slow metabolizers have been shown to start smoking later in life [PMID:11281276], to smoke fewer cigarettes/day [PMID: 10999944, 15475735, 15564629and 965539], to have a greater likelihood of quitting smoking [PMID: 11281276] and are less likely to be a smoker [PMID: 15475735]. In contrast, the slow metabolizer genotype has also shown no association with smoking status [PMID: 15534625] or cigarette consumption [PMID: 16272956, 11281276, 11207029]. In one study, slow metabolizer adolescents were at increased risk of becoming tobacco dependent [PMID: 15564629]. In Caucasian young adults, the slow metabolizer genotype was associated with a greater risk of being a smoker [PMID: 16272956]. No association between risk for cancer and CYP2A6*2 allele has been shown [PMID: 11207029and 14644339]. |
4. CYP2A6:50364-50365delTT (rs28399444)
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Key Haplotypes: | CYP2A6*20 |
| Genomic Variant & GenBank ID: | T50364del, T50365del on NG_000008.6 |
| mRNA Variant & GenBank ID | 596-597delAA on NM_000762 |
| Protein Variant & GenBank ID | Frameshift resulting in early stop codon at residue 220 in exon 5 |
| dbSNP rs#: | rs28399444 |
| GoldenPath Position: | chr19:46046030-46046031;(hg18) |
| Variant Summary: | This variant (CYP2A6-50364-50365delTT) encodes a truncated protein as a result of 2 deleted nucleotides in exon 4, leading to a frameshift that creates a new stop codon in exon 5. When CYP2A6-50364-50365delTT is expressed in E.coli, no coumarin 7-hydroxylation or nicotine C-oxidation activity was detected. The allele frequency is reported as: 0% in Caucasians, Japanese and Koreans and 1.6% in African North Americans [PMID: 15993850]. |
| Key PubMed IDs: | 15993850 |
5. CYP2A6:C47441T (rs28399454)
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Key Haplotypes: | CYP2A6*17 |
| Genomic Variant & GenBank ID | C47441T on NG_000008.6 |
| mRNA Variant & GenBank ID | G1102A on NM_000762.4 |
| Protein Variant & GenBank ID | V365M on NP_000753.2 |
| dbSNP rs#: | rs28399454 |
| GoldenPath Position: | chr19:46043107;(hg18) |
| Variant Summary: | This variant is found in exon 7, and amino acid 365 is located in substrate recognition site 5. When the variant enzyme is expressed in E. coli, the intrinsic clearance was decreased by 40% for coumarin 7-hydroxylation and 60% for nicotine C-oxidation. The allele frequency is reported as: 0% in Caucasians [PMID: 16041240, 15592323and 15469410]; 0% in Chinese, Koreans and Japanese [PMID: 15469410, 15592323and 16041240]; and 4% to 9.4% in African North Americans [PMID: 15469410, 16041240, 15592323]. |
| Key PubMed IDs: | 15592323, 15469410, 16041240 |
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Key Haplotypes: | CYP2A6*7. CYP2A6*10 |
| Genomic Variant & GenBank ID | A45948G on NG_000008.6 |
| mRNA Variant & GenBank ID | T1421C on NM_000762.4 |
| Protein Variant & GenBank ID | I471T on NP_000753.2 |
| dbSNP rs#: | rs5031016 |
| GoldenPath Position: | Chr19:46041614;(hg18) |
| Variant Summary: | This variant is found in exon 9 and is linked to CYP2A6*1B. When the CYP2A6-A45948G variant was expressed in E.coli and subjected to heat treatment (37 degrees C), the enzyme encoded by this variant was less stable than its wild type counterpart. Also, the variant lacked nicotine C-oxidase activity while maintaining ~60% of coumarin 7-hydroxylase activity [PMID: 11237731]. The allele frequency was reported as 0% in Caucasians: 9.4% - 12.5% in Chinese, Koreans and Japanese; and 0% in African North American [PMID: 15861044]. Note: The frequency of CYP2A6*7 has been underestimated in earlier studies because of inaccurate genotyping assays [PMID: 15861044], therefore only selected frequencies are reported here. |
| Key PubMed IDs: | 11237731, 15861044 |
7. CYP2A6:C45906A (rs28399468)
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Key Haplotypes: | CYP2A6*10 |
| Genomic Variant & GenBank ID | C45906A on NG_000008.6 |
| mRNA Variant & GenBank ID |
G1463T on NM_000762.4 |
| Protein Variant & GenBank ID | R485L on NP_000753.2 |
| dbSNP rs#: | rs28399468 |
| GoldenPath Position: | chr19:46041572;(hg18) |
| Key PubMed IDs: | 12445030, 15861044 |