title: Linkage disequilibrium mapping identifies a 390 kb region associated with CYP2D6 poor drug metabolising activity.
abstract: The cytochrome p450 enzyme, CYP2D6, metabolises approximately 20% of marketed drugs. CYP2D6 multiple variants are associated with altered enzyme activities. Genotyping 1018 Caucasians for CYP2D6 polymorphisms (G1846A, delT1707, delA2549 and A2935C), known to result in the recessive CYP2D6 poor drug metaboliser (PM) phenotype, identified 41 individuals with predicted PM phenotype. These 41 individuals were classified as 'cases'. Single nucleotide polymorphisms (SNPs) mapping within an 880 kb region flanking CYP2D6, were identified to evaluate potential association between genetic variation and the CYP2D6 PM phenotype. The 41 PM cases and 977 controls were genotyped and analysed for 27 SNPs. Associations were observed across a 390 kb region between 14 SNPs and the PM phenotype (P values from 6.20 x 10(-4) to 4.54 x 10(-35)). Haplotype analysis revealed more significant levels of association (P = 3.54 x 10(-56)). Strong (D' > 0.7) linkage disequilibrium (LD) between SNPs was observed across the same 390 kb region associated with the CYP2D6 phenotype. The observed phenotype:genotype association reached genome-wide levels of significance, and supports the strategy for potential application of LD mapping and whole genome association scans to pharmacogenetic studies.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Stevenage, Herts, UK. lkh47482@gsk.com
authors.forename: L K
authors.initials: LK
authors.lastname: Hosking
authors.forename: P R
authors.initials: PR
authors.lastname: Boyd
authors.forename: C F
authors.initials: CF
authors.lastname: Xu
authors.forename: M
authors.initials: M
authors.lastname: Nissum
authors.forename: K
authors.initials: K
authors.lastname: Cantone
authors.forename: I J
authors.initials: IJ
authors.lastname: Purvis
authors.forename: R
authors.initials: R
authors.lastname: Khakhar
authors.forename: M R
authors.initials: MR
authors.lastname: Barnes
authors.forename: U
authors.initials: U
authors.lastname: Liberwirth
authors.forename: K
authors.initials: K
authors.lastname: Hagen-Mann
authors.forename: M G
authors.initials: MG
authors.lastname: Ehm
authors.forename: J H
authors.initials: JH
authors.lastname: Riley
mesh_terms: D002874:Chromosome Mapping / Q000379:methods*; D002875:Chromosomes / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005787:Gene Frequency; D005819:Genetic Markers; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics
chemical_list: D005819:Genetic Markers; D004364:Pharmaceutical Preparations; D019389:Cytochrome P-450 CYP2D6