The CYP2D6 gene locus in South African Coloureds: unique allele distributions, novel alleles and gene arrangements.

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Gaedigk A, Coetsee C

The CYP2D6 gene locus in South African Coloureds: unique allele distributions, novel alleles and gene arrangements.

Eur J Clin Pharmacol. 2008 May;64(5):465-75. doi: 10.1007/s00228-007-0445-7. Epub 2008 Jan 17.

PubMed ID

18202841 [ View in PubMed

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Abstract

OBJECTIVE: The highly polymorphic CYP2D6 gene locus has been extensively scrutinised in the major ethnic populations, but little is known about the locus for many indigenous and unique admixed populations, including the Coloureds of South Africa. This study aimed at characterising the CYP2D6 gene locus in Coloured subjects and predict their phenotype status. METHODS: CYP2D6 genotyping was performed on 99 Coloured subjects by long-range polymerase chain reaction (PCR) and PCR restriction fragment length polymorphism (RFLP). Testing included 25 allelic variants as well as gene duplications. Novel alleles were cloned and sequenced. A novel strategy for CYP2D7/2D6 hybrid gene detection is described. RESULTS: Thirteen alleles had a frequency of = 1%, three were infrequent (<1%) and 16 of the tested alleles were not detected. CYP2D6*5 had a frequency of 17.2%, one of the highest ever observed in any population. Two novel alleles, CYP2D6*64 and *65, were identified. In addition, four samples carried CYP2D7/2D6 hybrid genes, of which one matched the CYP2D6*66 allele of a resequenced Caucasian control subject. CYP2D6*66 is similar to CYP2D6*16, but its putative recombination point is further upstream. Genotyping identified three poor metabolisers (3%; predicted incidence 6.6%), and 12% of the population had an activity score of 0.5 indicative of intermediate metabolism. CONCLUSIONS: The Coloured population has a unique composition of alleles and a distinct frequency distribution. The preliminary data presented suggest decreased CYP2D6 activity compared with Caucasians. Follow-up studies including both genotyping and phenotyping will need to be conducted to further assess the relationship between genotype and phenotype in this population of complex ancestry.

DrugBank Data that Cites this Article

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*13	Not Available	CYP2D7/2D6 hybrid gene structure	ADR Inferred	Increased risk of slow heart rate (bradycardia)	Details
Venlafaxine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Amitriptyline	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	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*13	Not Available	CYP2D7/2D6 hybrid gene structure	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*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Nortriptyline	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	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*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor response to drug treatment, shorter time to relapse	Details
Desipramine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	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*13	Not Available	CYP2D7/2D6 hybrid gene structure	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*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer, increased side effects.	Details