TY - JOUR
T1 - Catechol O-methyltransferase pharmacogenomics
T2 - Human liver genotype-phenotype correlation and proximal promoter studies
AU - Zhang, Jianping
AU - Ji, Yuan
AU - Moon, Irene
AU - Pelleymounter, Linda L.
AU - Ezequel Salavaggione, Oreste
AU - Wu, Yanhong
AU - Jenkins, Gregory D.
AU - Batzler, Anthony J.
AU - Schaid, Daniel J.
AU - Weinshilboum, Richard M.
PY - 2009/8
Y1 - 2009/8
N2 - OBJECTIVES: 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. CONCLUSION: 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.
AB - OBJECTIVES: 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. CONCLUSION: 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.
KW - Catechol O-methyltransferase
KW - Genetic polymorphism
KW - Haplotype
KW - Single nucleotide polymorphism
KW - Thermal stability
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U2 - 10.1097/FPC.0b013e32832c15c6
DO - 10.1097/FPC.0b013e32832c15c6
M3 - Article
C2 - 19641441
AN - SCOPUS:68849113359
SN - 1744-6872
VL - 19
SP - 577
EP - 587
JO - Pharmacogenetics and genomics
JF - Pharmacogenetics and genomics
IS - 8
ER -