Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution.

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Marez D, Legrand M, Sabbagh N, Lo Guidice JM, Spire C, Lafitte JJ, Meyer UA, Broly F

Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution.

Pharmacogenetics. 1997 Jun;7(3):193-202.

PubMed ID

9241659 [ View in PubMed

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Abstract

The polymorphic cytochrome P450 CYP2D6 is involved in the metabolism of various drugs of wide therapeutic use and is a presumed susceptibility factor for certain environmentally-induced diseases. Our aim was to define the mutations and alleles of the CYP2D6 gene and to evaluate their frequencies in the European population. Using polymerase chain reaction-single strand conformation polymorphism analysis, 672 unrelated subjects were screened for mutations in the 9 exons of the gene and their exon-intron boundaries. A total of 48 point mutations were identified, of which 29 were novel. Mutations 1749 G-->C, 2938 C-->T and 4268 G-->C represented 52.6%, 34.3% and 52.9% of the mutations in the total population, respectively. Of the eight detrimental mutations detected, the 1934 G-->A, the 1795 Tdel and the 2637 Adel accounted for 65.8%, 6.2% and 4.8% respectively, within the poor metabolizer subgroup. Fifty-three different alleles were characterized from the mutation pattern and by allele-specific sequencing. They are derived from three major alleles, namely the wild-type CYP2D6*1A, the functional CYP2D6*2 and the null CYP2D6*4A. Five allelic variants (CYP2D6*1A, *2, *2B, *4A and *5) account for about 87% of all alleles, while the remaining alleles occur with a frequency of 0.1%-2.7%. These data provide a solid basis for future epidemiological, clinical as well as interethnic studies of the CYP2D6 polymorphism and highlight that the described single strand conformation polymorphism method can be successfully used in designing such studies.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Cytochrome P450 2D6	P10635	Details

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Metoprolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*3	Not Available	C allele (rs35742686)	ADR Inferred	Increased risk of slow heart rate (bradycardia)	Details
Metoprolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*6	Not Available	1707delT (rs5030655)	ADR Inferred	Increased risk of slow heart rate (bradycardia)	Details
Metoprolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	ADR Inferred	Increased risk of slow heart rate (bradycardia)	Details
Metoprolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	ADR Inferred	Increased risk of slow heart rate (bradycardia)	Details
Venlafaxine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*3	Not Available	C allele (rs35742686)	Effect Inferred	Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea	Details
Venlafaxine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	Effect Inferred	Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea	Details
Venlafaxine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*3	Not Available	C allele (rs35742686)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Amitriptyline	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*3	Not Available	C allele (rs35742686)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Amitriptyline	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*6	Not Available	1707delT (rs5030655)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Amitriptyline	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Amitriptyline	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Imipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*3	Not Available	C allele (rs35742686)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Imipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*6	Not Available	1707delT (rs5030655)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Imipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Imipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Dextromethorphan	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*3	Not Available	C allele (rs35742686)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Dextromethorphan	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Dextromethorphan	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Nortriptyline	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*3	Not Available	C allele (rs35742686)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Nortriptyline	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*6	Not Available	1707delT (rs5030655)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Nortriptyline	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Nortriptyline	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Tamoxifen	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*3	Not Available	C allele (rs35742686)	Effect Inferred	Poor response to drug treatment, shorter time to relapse	Details
Tamoxifen	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*6	Not Available	1707delT (rs5030655)	Effect Inferred	Poor response to drug treatment, shorter time to relapse	Details
Tamoxifen	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	Effect Inferred	Poor response to drug treatment, shorter time to relapse	Details
Tamoxifen	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	Effect Inferred	Poor response to drug treatment, shorter time to relapse	Details
Desipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*3	Not Available	C allele (rs35742686)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Desipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*6	Not Available	1707delT (rs5030655)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Desipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Desipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Clomipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*3	Not Available	C allele (rs35742686)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Clomipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*6	Not Available	1707delT (rs5030655)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Clomipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Clomipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects	Details
Atomoxetine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	Effect Inferred	Poor drug metabolizer, increased side effects.	Details
Atomoxetine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer, increased side effects.	Details