title: Catechol O-methyltransferase pharmacogenomics: human liver genotype-phenotype correlation and proximal promoter studies.
abstract: OBJECTIVE
  Catechol O-methyltransferase (COMT) is expressed as both soluble (S) and membrane-bound (MB) isoforms, with S-COMT predominantly expressed in the liver. A common nonsynonymous single nucleotide polymorphism (SNP), 472G > A (108/158Val > Met, S/MB), has been associated with variation in levels of COMT enzyme activity and thermal stability. We set out to test the hypothesis that additional COMT polymorphisms might also be associated with phenotypic variation.
  
  
  METHODS
  We phenotyped 268 liver biopsy samples for S-COMT activity and thermal stability, resequenced a portion of the gene that had not been resequenced earlier, and genotyped DNA from these same samples for 16 COMT polymorphisms.
  
  
  RESULTS
  There was a significant association between the two COMT phenotypes and genotype at the codon 108 SNP. A haplotype-based approach was then used to assess the possible association of other polymorphisms with phenotype. Specifically, the codon 108 SNP explained 20.4% of variance in enzyme activity (P < 10), and 59% of variance in thermal stability (P < 10). Haplotypes that included SNPs at cDNA nucleotides 408 and 472 explained additional variance in enzyme activity (up to 24.4%), and the addition to the haplotype of a SNP at intron 2 (51) explained a total of 27.5% of the variance. However, no SNPs beyond that at the nucleotide 472G > A polymorphism were associated with variation in thermal stability. We also observed a three-fold variation in the ability of reporter gene constructs for 'proximal promoter' haplotypes to drive transcription.
  
  
  CONCLUSIONS
  The common COMT 108Val > Met polymorphism is associated with human liver S-COMT activity and thermal stability, but additional COMT SNPs also contribute to variation in activity.
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ji
authors.forename: Irene
authors.initials: I
authors.lastname: Moon
authors.forename: Linda L
authors.initials: LL
authors.lastname: Pelleymounter
authors.forename: Oreste
authors.initials: O
authors.lastname: Ezequel Salavaggione
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Jenkins
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Batzler
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weinshilboum
mesh_terms: D001706:Biopsy; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D003062:Codon; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008957:Models, Genetic; D010597:Pharmacogenetics / Q000379:methods*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: D003062:Codon; D002394:Catechol O-Methyltransferase