Important Haplotype Information for CYP2A6
Submitted by: Manki Ho, Jill Mwenifumbo, Ryan Owen (PharmGKB), and Rachel Tyndale PNAT
Reviewed by: Under Review
Submitted date: Feb 28, 2007
- Jump To:
- Overview
- Important Variants
- All Annotated Genes
There are Ten Important Haplotypes for CYP2A6
CYP2A6*1B
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Does this haplotype span more than one gene? |
Yes |
| What is the definitive publication or website defining this haplotype? |
Relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans. Nakajima M, Kwon JT, Tanaka N, Zenta T, Yamamoto Y, Yamamoto H, Yamazaki H, Yamamoto T, Kuroiwa Y and Yokoi T. Clin Pharmacol Ther. 2001 Jan;69(1):72-8. [PMID: 11180041] |
| What is the significance of this haplotype? |
CYP2A6*1B does not cause any changes in enzyme structure or function, as it is located in a noncoding region. However, this variant has been associated with increased nicotine metabolism, increased cigarette consumption and increased odds of being a current smoker [PMID: 11434509, 1180041, 15618666, 15534625, 15940289, 14981342 and 16272956]. In vitro data indicates that the CYP2A6*1B variant may be involved with mRNA stabilization [PMID:16378601]. |
| How many SNPs, indels, repeats define this haplotype? | 58 bp gene conversion |
| Indicate if this haplotype should be linked to specific variant worksheets |
CYP2A6*1B, *7 and *10 |
| Key PubMed IDs: |
11180041 11434509 15618666 15534625 15940289 14981342 16272956 16378601 |
| Phenotype Information: |
In vivo the CYP2A6*1B variant is associated with higher cotinine/nicotine ratios, higher odds of being a current smoker and higher cigarette consumption [PMID: 11434509, 1180041, 15618666, 14981342, 15534625, 15940289and 16272956]. |
CYP2A6*1X2
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Does this haplotype span more than one gene? | Yes |
| What is the definitive publication or website defining this haplotype? |
http://www.imm.ki.se/CYPalleles |
| What is the significance of this haplotype? |
The CYP2A6*1X2 (duplication) allele is thought to be the result of an unequal crossover event between CYP2A6 and CYP2A7. It's allele frequency is 0.8% to 1.3% in Caucasians [PMID: 10999944and 16041240]; 0% to 1.1% in Chinese, Koreans and Japanese [PMID: 16041240, 15475735and 12844137]; and 1.1% in African North Americans [PMID: 16041240]. No in vitro or in vivo data is available to describe the impact of this variant. |
| How many SNPs, indels, repeats define this haplotype? | CYP2A6 gene duplication |
| Indicate if this haplotype should be linked to specific variant worksheets |
No |
| Key PubMed IDs: |
10999944 16041240 15475735 12844137 |
| Phenotype Information: |
Smokers with the CYP2A6*1X2 allele seem to compensate for more CYP2A6 gene copies by increasing the intensity of smoking [PMID: 10999944]. |
CYP2A6*2
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Does this haplotype span more than one gene? | Unknown |
| What is the definitive publication or website defining this haplotype? |
Yamano S, Tatsuno J, Gonzalez FJ. The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes. Biochemistry. 1990 Feb 6;29(5):1322-9. PMID: 2322567 |
| What is the significance of this haplotype? |
CYP2A6*2 contains two SNPs. One is synonymous (V17V) and is located in exon 1. The other (A50707T) is nonsynonymous (L160H) and is located in exon 3. This haplotype results in an inactive enzyme due to failure to incorporate a heme molecule. The CYP2A6*2 frequency is 1.2% to 3.0% in Caucasians [PMID: 9827545, 10544257, 15225612, 11684323, 15475735, 16272956 and 16041240]; 0% in Chinese, Koreans and Japanese [PMID: 16041240, 15475735 and 10544257, 11434509and 11180041and 15660270]; 0% to 1.1% in African North Americans [PMID: 16041240, 15225612, 11684323and 15475735]; 0% in Canadian Native Americans [PMID: 15475735]; and 0.5% in South Asians [PMID: 16272956]. |
| How many SNPs, indels, repeats define this haplotype? | 2 |
| Indicate if this haplotype should be linked to specific variant worksheets |
CYP2A6-A50707T |
| Key PubMed IDs: |
2322567 9827545 10544257 15225612 11684323 15475735 16272956 16041240 |
CYP2A6*4
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Does this haplotype span more than one gene? | Unknown |
| What is the definitive publication or website defining this haplotype? |
The CYP2A6*4 alleles are thought to have occurred by homologous unequal cross-over within the human CYP2A gene cluster that resulted in the deletion of the CYP2A6 gene [PMID: 9755457and 10423536]. |
| What is the significance of this haplotype? |
The CYP2A6*4 alleles are thought to have occurred by homologous unequal cross-over within the human CYP2A gene cluster that resulted in the deletion of the CYP2A6 gene [PMID: 9755457and 10423536]. When referred to as the CYP2A6*4 allele, this genotype group contains both CYP2A6*4A and CYP2A6*4D. The CYP2A6*4 allele frequency is 0.3% to 4.0% in Caucasians [PMID: 16272956, 16041240, 15475735, 15225612, 11186131, 10544257and 1497084]; 6.7% to 24.2 % in Chinese, Koreans and Japanese [PMID: 16041240, 11186131, 12445030, 15475735and 10544257]; 1.0% to 1.9% in African North Americans [PMID: 15225612, 16041240and 15475735]; 1.0% in Canadian Native Americans [PMID: 15475735] and 0.5% in South Asians [PMID: 16272956]. Human liver microsomes with CYP2A6*4 have been shown to have significantly reduced coumarin 7-hydroxylation [PMID: 9682269] and SM-12502 S-oxidation [PMID: 9682269]. |
| How many SNPs, indels, repeats define this haplotype? | CYP2A6*4A - gene deletion. Exons 1 to 9 are CYP2A7 but the sequence is CYP2A6 in the 3' UTR. CYP2A6*4D - gene deletion. Exons 1 to 8 and part of 9 are CYP2A7 but the sequence is CYP2A6 in exon 9. |
| Indicate if this haplotype should be linked to specific variant worksheets |
No |
| Key PubMed IDs: |
9755457 10423536 16272956 16041240 15475735 15225612 11186131 10544257 1497084 12445030 9682269 10448083 15265511 15618666 12042667 10087035 15564629 10999944 11207029 15940289 15564629 14981342 15308589 12832682 12223434 11241319 11725533 12749606 16176798 11960911 14633739 10093988 12115524 16048566 |
| Phenotype Information: |
In vivo, CYP2A6*4 has been associated with decreased nicotine C-oxidation [PMID: 12445030, 10448083and 15265511], coumarin 7-hydroxylation [PMID: 15618666], Tegafur metabolism [PMID: 12042667] and plus-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502) S-oxidation [PMID: 10087035] in Asian populations. In non-Asian smoking and CYP2A6 genotype association studies, the CYP2A6*4 allele is commonly grouped with other loss of function alleles (e.g. CYP2A6*2) to form the slow metabolizer group. Slow metabolizers have decreased cigarette consumption [PMID: 15475735, 15564629and 10999944] 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: 15534625and 15940289] or cigarette consumption [PMID: 11207029and 15940289]. In Caucasian adolescents, the slow metabolizer genotype is associated with a substantially increased risk of becoming tobacco dependent but decreased cigarette consumption [PMID: 15564629]. In Caucasian young adults, the slow metabolizer genotype was associated with a greater risk of being a smoker [PMID: 16272956]. Asian populations have substantially higher frequencies of CYP2A6*4. In CYP2A6 genotype association studies, CYP2A6*4 has been found to be associated with a decreased likelihood of being a smoker [PMID: 12749606and 14981342] and a decrease in cigarette consumption [PMID: 15308589, 12832682and 12223434]. In contrast some studies have shown no association with smoking status [PMID: 11241319and 11725533] or cigarette consumption [PMID: 12749606and 11725533]. Cancer and CYP2A6 genotype association studies have shown decreased risk [PMID: 12223434, 15308589, 15940289, 16176798and 11960911], no association [PMID: 14633739and 10093988] and increased risk [PMID: 11241319, 12115524and 16048566] of cancer with the CYP2A6*4 allele. CYP2A6*4 has also been associated with decreased risk of having pulmonary emphysema [PMID: 12832682]. |
CYP2A6*7
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Does this haplotype span more than one gene? | Unknown |
| What is the definitive publication or website defining this haplotype? |
A novel single nucleotide polymorphism altering stability and activity of CYP2A6. Ariyoshi N, Sawamura Y, Kamataki T. Biochem Biophys Res Commun. 2001 Mar 2;281(3):810-4. [PMID:11237731]. |
| What is the significance of this haplotype? |
When expressed in E.coli and subjected to heat treatment (37 degrees C), the enzyme encoded by CYP2A6*7 was less stable than its wild type counterpart. Also, this variant lacked nicotine C-oxidase activity while maintaining ~60% of coumarin 7-hydroxylase activity [PMID: 11237731]. |
| How many SNPs, indels, repeats define this haplotype? | 1 SNP and the 58 bp gene conversion |
| Indicate if this haplotype should be linked to specific variant worksheets |
CYP2A6-58 bp gene conversion, CYP2A6-A45948G |
| Key PubMed IDs: |
11237731 11779172 |
| Phenotype Information: |
In vivo, subjects with the CYP2A6*7 allele have decreased nicotine metabolism and normal coumarin metabolism [PMID: 11779172]. |
CYP2A6*9
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Does this haplotype span more than one gene? | Unknown |
| What is the definitive publication or website defining this haplotype? | Identification of a single nucleotide polymorphism in the TATA box of the CYP2A6 gene: impairment of its promoter activity. Pitarque M, von Richter O, Oke B, Berkkan H, Oscarson M and Ingelman-Sundberg M. Biochem Biophys Res Commun. 2001 Jun 8;284(2):455-60. [PMID: 11394901 |
| What is the significance of this haplotype? |
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]. |
| How many SNPs, indels, repeats define this haplotype? | 2 SNPs |
| Indicate if this haplotype should be linked to specific variant worksheets |
CYP2A6-A52553G |
| Key PubMed IDs: |
11394901 14583682 16041240 15469410 15475735 12844137 11394901 15469410 16452582 15327835 |
| Phenotype Information: |
CYP2A6*9 is associated with lower cotinine/nicotine ratios, which infers slower nicotine metabolism, and lower cigarette consumption [PMID: 12844137and 16452582]. 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]. |
CYP2A6*10
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Does this haplotype span more than one gene? |
Unknown |
| What is the definitive publication or website defining this haplotype? |
An in vivo pilot study characterizing the new CYP2A6*7, *8 and *10 alleles. Xu C, Rao YS, Xu B, Hoffman E, Jones J, Sellers EM, Tyndale RF. Biochem Biophys Res Commun. 2002 Jan 11; 290(1): 318-24. [PMID: 11779172] |
| What is the significance of this haplotype? |
CYP2A6*10 is a haplotype containing both the nonsynonymous SNPs found CYP2A6*7 and CYP2A6*8. These resulting amino acid changes lie within or close to substrate recognition site 6, a highly conserved region. In vitro studies have not been done on CYP2A6*10. CYP2A6*10 contains variations in amino acid residues lying within or close to substrate recognition site 6, a highly conserved region. In vitro studies have not been done with CYP2A6*10. The allele frequency is reported as: 0% in Caucasians [PMID: 15861044]; 4.0 to 4.3% in Chinese, Koreans and Japanese [PMID: 15861044] and 0% in African North Americans [PMID: 15861044]. Old genotyping methods underestimated the CYP2A6*10 allele frequency [PMID: 15861044], therefore only selected frequencies are reported here. |
| How many SNPs, indels, repeats define this haplotype? | 2 SNPs and 58 bp gene conversion |
| Indicate if this haplotype should be linked to specific variant worksheets |
CYP2A6-58 bp gene conversion, CYP2A6-A45948G, CYP2A6-C45906A |
| Key PubMed IDs: |
11779172 15861044 12445030 |
| Phenotype Information: |
Subjects with CYP2A6*10 have impaired nicotine and coumarin metabolism in vivo [PMID: 12445030and 11779172]. |
CYP2A6*12
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Does this haplotype span more than one gene? | Yes |
| What is the definitive publication or website defining this haplotype? |
This variant is thought to result from an unequal crossover event between CYP2A6 and CYP2A7 in intron 2. The 5' flanking region and exons 1-2 has the CYP2A7 sequence and exons 3-9 have the CYP2A6 sequence; thus the resulting protein has a 10 amino acid substitution [PMID: 12325023]. |
| What is the significance of this haplotype? |
Expression of CYP2A6*12 is controlled by the CYP2A7 promoter. When CYP2A6*12 is expressed in COS-cells, both protein level and coumarin 7-hydroxylation activity was decreased to ~50-60% of the wild type enzyme. The allele frequency is reported as: 2% to 2.2% in Caucasians [PMID: 12325023and 15475735]; 0% to 0.8% in Chinese and Japanese [PMID: 12325023and 15475735]; 0.4% in African North Americans [PMID: 15475735]; and 0.5% in Canadian Native Americans [PMID: 15475735]. |
| How many SNPs, indels, repeats define this haplotype? | 5' flanking region and exons 1-2 have the CYP2A7 sequence, Exons 3-9 have the CYP2A6 sequence. |
| Indicate if this haplotype should be linked to specific variant worksheets | No |
| Key PubMed IDs: |
12325023 15475735 |
| Phenotype Information: |
Individuals with the CYP2A6*12 allele have decreased coumarin 7-hydroxylation activity [PMID: 15475735]. |
CYP2A6*17
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Does this haplotype span more than one gene? | Unknown |
| What is the definitive publication or website defining this haplotype? |
CYP2A6*17 has an amino acid substitution (V365M) that decreases enzymatic activity in vitro and in vivo. Fukami T, Nakajima M, Yoshida R, Tsuchiya Y, Fujiki Y, Katoh M, McLeod HL, Yokoi T. Clin Pharmacol Ther. 2004 Dec;76(6):519-27. PMID: 15592323 |
| What is the significance of this haplotype? |
This haplotype contains 7 SNPs: 4 are in introns, 3 occur in exons, but two of these are synonymous. The non-synonymous change (C47441T, V365M) is believed to be the causative SNP. When CYP2A6-C47441T variant enzyme is expressed in E. coli, the intrinsic clearance was decreased by 40% for coumarin 7-hydroxylation and 60% and nicotine C-oxidation. |
| How many SNPs, indels, repeats define this haplotype? | 7 SNPs |
| Indicate if this haplotype should be linked to specific variant worksheets |
CYP2A6-C47441T |
| Key PubMed IDs: |
15592323 |
| Phenotype Information: |
In vivo, subjects with CYP2A6*1A/*17 genotype had decreased cotinine/nicotine ratio and one subject with CYP2A6*17/*17 genotype had the lowest cotinine/nicotine ratio compared to CYP2A6*1A/*1A subjects following nicotine gum administration [PMID: 15592323]. |
CYP2A6*20
| Gene HGNC Name: | CYP2A6 |
|---|---|
| Does this haplotype span more than one gene? | Unknown |
| What is the definitive publication or website defining this haplotype? |
Fukami T, Nakajima M, Higashi E, Yamanaka H, McLeod HL, Yokoi T. A novel CYP2A6*20 allele found in African-American population produces a truncated protein lacking enzymatic activity. Biochem Pharmacol. 2005 Sep 1;70(5):801-8. PMID: 15993850 |
| What is the significance of this haplotype? |
This variant encodes a truncated protein, which results from 2 deleted nucleotides in exon 4 that creates a new stop codon in exon 5. When CYP2A6.20 is expressed in E.coli, no coumarin 7-hydroxylation or nicotine C-oxidation activity was detected [PMID: 15993850]. |
| How many SNPs, indels, repeats define this haplotype? | 5 |
| Indicate if this haplotype should be linked to specific variant worksheets |
CYP2A6-50364-50365delTT |
| Key PubMed IDs: |
15993850 |
| Phenotype Information: |
Two subjects with CYP2A6*1/*20 and CYP2A6*17/*20 genotypes had lower cotinine/nicotine ratio following dosage by nicotine gum compared to CYP2A6*1/*1 subjects [PMID: 15993850]. |