Important Haplotype Information for CYP2D6
Submitted by: Ryan Owen (PharmGKB)
Reviewed by: Under Review
Submitted date: October 5th, 2007
There are Twelve Important Haplotypes for CYP2D6.
- CYP2D6*1
- CYP2D6*2
- CYP2D6*3
- CYP2D6*4
- CYP2D6*5
- CYP2D6*6
- CYP2D6*9
- CYP2D6*10
- CYP2D6*17
- CYP2D6*29
- CYP2D6*41
- CYP2D6UM
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Haplotype Significance: | CYP2D6*1 is the reference haplotype for CYP2D6 [2574001]. Together with CYP2D6*2, this haplotype forms the group of individuals known as extensive metabolizers or EMs [11972444]. CYP2D6*1 is usually the majority allele for populations of European and African descent [11972444 17301689]. Allele frequencies of CYP2D6*1 in many different populations are shown in the table below the haplotype descriptions. EMs are considered the norm, and all the other haplotypes are defined as deviations from CYP2D6*1. |
| Does this haplotype span more than one gene? | Unknown |
| Definitive Publication or Website: | http://www.cypalleles.ki.se/cyp2d6.htm |
| Drugs: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| Phenotype Data Sets: | Metabolism of yohimbine by human CYP450 isoforms , Lipid measurements in tamoxifen study , Meperidine N-demethylation by human CYP450 isoforms , Patient responses to tamoxifen , Thyroid binding globulin in tamoxifen patients , Hot flashes in tamoxifen patients , Lipid measurements in tamoxifen study - set 2 , Pharmacokinetics of Tamoxifen at 4 months |
| Key PubMed IDs: | 2574001 11972444 17301689 |
| How many SNPs, indels, repeats define this haplotype? | CYP2D6 haplotypes are typically determined by a genotyping algorithm. For the purposes of this VIP, we will define the SNPs that make up a haplotype from those SNPs which have variant pages. For fully defined CYP2D6 haplotypes, please see http://www.cypalleles.ki.se/cyp2d6.htm CYP2D6*1 - Reference haplotype, no SNPs. |
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Haplotype Significance: | CYP2D6*2 [7903454] has slightly reduced function when compared with CYP2D6*1 [11972444]. However, this is not considered a significant difference, and the two haplotypes are typically combined and listed under the EM designation [11972444]. The genotyping algorithm proposed by Gaedigk et al defaults to either CYP2D6*1 or CYP2D6*2, with the differentiating SNP being the presence of CYP2D6 2850C>T [10634130]. In the early days of CYP2D6 genotyping, several reduced function haplotypes were misdiagnosed as CYP2D6*2, leading to some confusion about the apparent reduction of activity in those alleles [8971426]. The subsequent discovery of additional SNPs that define CYP2D6*17 and CYP2D6*29 have helped resolve this apparent contradiction. Allele frequencies of CYP2D6*2 in many populations are shown below the haplotype descriptions. |
| Does this haplotype span more than one gene? | Unknown |
| Definitive Publication or Website: | http://www.cypalleles.ki.se/cyp2d6.htm |
| Drugs: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| Key PubMed IDs: | 7903454 11972444 10634130 8971426 |
| How many SNPs, indels, repeats define this haplotype? | CYP2D6 haplotypes are typically determined by a genotyping algorithm. For the purposes of this VIP, we will define the SNPs that make up a haplotype from those SNPs which have variant pages. For fully defined CYP2D6 haplotypes, please see http://www.cypalleles.ki.se/cyp2d6.htm CYP2D6*2 - CYP2D6 2850C>T |
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Haplotype Significance: | CYP2D6*3 [2211621] is a completely non-functional allele that is caused by a frameshift mutation which causes a premature truncation of the CYP2D6 protein [2211621]. CYP2D6*3 is one of several CYP2D6 haplotypes that can contribute to the phenotypic observation of a poor metabolizer (PM) [11972444]. CYP2D6*3 makes a minor contribution to the poor metabolizer phenotype in Caucasian populations, and is virtually non-existant in non-Caucasian populations (see allele frequency table following haplotype descriptions) [17301689]. |
| Does this haplotype span more than one gene? | Unknown |
| Definitive Publication or Website: | http://www.cypalleles.ki.se/cyp2d6.htm |
| Drugs: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| Key PubMed IDs: | 2211621 11972444 17301689 |
| How many SNPs, indels, repeats define this haplotype? | CYP2D6 haplotypes are typically determined by a genotyping algorithm. For the purposes of this VIP, we will define the SNPs that make up a haplotype from those SNPs which have variant pages. For fully defined CYP2D6 haplotypes, please see http://www.cypalleles.ki.se/cyp2d6.htm CYP2D6*3 - CYP2D6 2549 del A |
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Haplotype Significance: | CYP2D6*4 [2211621 1978251 1978565] is a non-functional haplotype that contributes to the majority of PMs observed in Caucasian populations [17301689]. This allele has achieved a very high frequency (see allele frequency table), and homozygous individuals are common [17301689]. These individuals are at increased risk when compared to their EM counterparts for toxicities or lack of efficacy due to CYP2D6 inactivity [16968950]. For example, in situations in which the drug that is given needs to be converted to an active metabolite before some phenotypic effect is observed (such as the conversion of codeine to morphine by CYP2D6 [9352573]), individuals possesing a PM phenotype (most commonly caused by CYP2D6*4, although also caused by CYP2D6*3, CYP2D6*5, and CYP2D6*6) will face a lack of efficacy. Another potential adverse effect can result from high concentrations of parent drug that may build up in individuals who are PMs that is not seen in their EM counterparts, who are quickly able to reduce concentrations of parent drug by CYP2D6 metabolism [16958828 16968950]. |
| Does this haplotype span more than one gene? | Unknown |
| Definitive Publication or Website: | http://www.cypalleles.ki.se/cyp2d6.htm |
| Drugs: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| Phenotype Data Sets: | Lipid measurements in tamoxifen study , Patient responses to tamoxifen |
| Key PubMed IDs: | 2211621 1978251 1978565 17301689 16968950 9352573 16958828 |
| How many SNPs, indels, repeats define this haplotype? | CYP2D6 haplotypes are typically determined by a genotyping algorithm. For the purposes of this VIP, we will define the SNPs that make up a haplotype from those SNPs which have variant pages. For fully defined CYP2D6 haplotypes, please see http://www.cypalleles.ki.se/cyp2d6.htm CYP2D6*4 - CYP2D6 100C>T and CYP2D6 1846G>A |
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Haplotype Significance: | CYP2D6*5 results in a non-functional haplotype [1673290 8634695]. CYP2D6*5 is effectively a whole gene deletion. This allele also contributes to the PM phenotype and is found in the 1-7% allele frequency range in most populations [17301689] (see allele frequency table following the haplotype descriptions). |
| Does this haplotype span more than one gene? | Unknown |
| Definitive Publication or Website: | http://www.cypalleles.ki.se/cyp2d6.htm |
| Drugs: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| Key PubMed IDs: | 1673290 8634695 17301689 |
| How many SNPs, indels, repeats define this haplotype? | CYP2D6 haplotypes are typically determined by a genotyping algorithm. For the purposes of this VIP, we will define the SNPs that make up a haplotype from those SNPs which have variant pages. For fully defined CYP2D6 haplotypes, please see http://www.cypalleles.ki.se/cyp2d6.htm CYP2D6*5 - Whole gene deletion |
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Haplotype Significance: | CYP2D6*6 [7951238] is yet another non-functional haplotype of CYP2D6. Similar to CYP2D6*3, CYP2D6*6 is caused by a frameshift mutation that results in a truncated and non-functional CYP2D6 protein [7951238]. CYP2D6*6 is found primarily in Caucasian populations, although with a low allele frequency when compared with the more common CYP2D6*4 and CYP2D6*5 [11972444 17301689] (see allele frequency table following haplotype descriptions). |
| Does this haplotype span more than one gene? | Unknown |
| Definitive Publication or Website: | http://www.cypalleles.ki.se/cyp2d6.htm |
| Drugs: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| Key PubMed IDs: | 7951238 11972444 17301689 |
| How many SNPs, indels, repeats define this haplotype? | CYP2D6 haplotypes are typically determined by a genotyping algorithm. For the purposes of this VIP, we will define the SNPs that make up a haplotype from those SNPs which have variant pages. For fully defined CYP2D6 haplotypes, please see http://www.cypalleles.ki.se/cyp2d6.htm CYP2D6*6 - CYP2D6 1707 del T |
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Haplotype Significance: | CYP2D6*9 is a reduced function haplotype that is caused by the deletion of a single amino acid [1844820 8101460]. In vitro studies have suggested that the reduction in function may be due to decreased expression level, as the kinetics (Km) of various CYP2D6 substrates do not appear to be affected by the mutant protein [1844820]. One in vivo study showed that CYP2D6*9 tended to cluster with the extensive metabolizers (EMs), but that study did not consider the presence of the intermediate metabolizers (IMs), which are individuals that possess residual CYP2D6 activity, and are phenotypically between PMs and EMs [8101460]. The general consensus is that CYP2D6*9 is a reduced function allele [11972444 17301689] (allele frequencies can be seen in the table following the haplotype descriptions). |
| Does this haplotype span more than one gene? | Unknown |
| Definitive Publication or Website: | http://www.cypalleles.ki.se/cyp2d6.htm |
| Drugs: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| Key PubMed IDs: | 1844820 8101460 11972444 17301689 |
| How many SNPs, indels, repeats define this haplotype? | CYP2D6 haplotypes are typically determined by a genotyping algorithm. For the purposes of this VIP, we will define the SNPs that make up a haplotype from those SNPs which have variant pages. For fully defined CYP2D6 haplotypes, please see http://www.cypalleles.ki.se/cyp2d6.htm CYP2D6*9 - CYP2D6 2613-2615 del AGA |
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Haplotype Significance: | CYP2D6*10 [8287064] is a reduced function haplotype of CYP2D6. This haplotype is extremely common in populations of Asian ancestry [11972444 17301689], and is often the majority allele in those populations (see table following haplotype descriptions). Homozygotes of this allele are common, and result in the IM phenotype [17570739]. IMs are also at risk for adverse events and lack of efficacy similar to those seen in PMs, although not as severe due to the residual activity of CYP2D6*10 [14618296]. |
| Does this haplotype span more than one gene? | Unknown |
| Definitive Publication or Website: | http://www.cypalleles.ki.se/cyp2d6.htm |
| Drugs: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| Phenotype Data Sets: | Patient responses to tamoxifen |
| Key PubMed IDs: | 8287064 11972444 17301689 17570739 14618296 |
| How many SNPs, indels, repeats define this haplotype? | CYP2D6 haplotypes are typically determined by a genotyping algorithm. For the purposes of this VIP, we will define the SNPs that make up a haplotype from those SNPs which have variant pages. For fully defined CYP2D6 haplotypes, please see http://www.cypalleles.ki.se/cyp2d6.htm CYP2D6*10 - CYP2D6 100C>T |
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Haplotype Significance: | CYP2D6*17 is a reduced function allele of CYP2D6 [8971426]. CYP2D6*17 was frequently misdiagnosed as CYP2D6*2 in the early studies of CYP2D6 genotyping, particularly in populations of African origin [8971426]. Eventually, the discovery of additional SNPs allowed for the differentiation between CYP2D6*2, CYP2D6*17, and CYP2D6*29, another reduced function CYP2D6 haplotype. Copies of CYP2D6*17 would contribute towards an IM phenotype [9415713] (see allele frequency table following the haplotype descriptions). |
| Does this haplotype span more than one gene? | Unknown |
| Definitive Publication or Website: | http://www.cypalleles.ki.se/cyp2d6.htm |
| Drugs: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| Key PubMed IDs: | 8971426 9415713 |
| How many SNPs, indels, repeats define this haplotype? | CYP2D6 haplotypes are typically determined by a genotyping algorithm. For the purposes of this VIP, we will define the SNPs that make up a haplotype from those SNPs which have variant pages. For fully defined CYP2D6 haplotypes, please see http://www.cypalleles.ki.se/cyp2d6.htm CYP2D6*17 - CYP2D6 2850C>T and CYP2D6 1023C>T |
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Haplotype Significance: | CYP2D6*29 [9241659] is a reduced functioning haplotype of CYP2D6 [11470994]. Much like CYP2D6*17, this haplotype was often misdiagnosed for CYP2D6*2 in the early days of CYP2D6 genotyping [11470994]. This haplotype was originally discovered in African populations, and contributes towards the IM phenotype of CYP2D6 [11470994 17301689] (see table following haplotype descriptions for allele frequencies). |
| Does this haplotype span more than one gene? | Unknown |
| Definitive Publication or Website: | http://www.cypalleles.ki.se/cyp2d6.htm |
| Drugs: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], |