Catechol O-methyltransferase pharmacogenomics: human liver genotype-phenotype correlation and proximal promoter studies.
Catechol O-methyltransferase pharmacogenomics: human liver genotype-phenotype correlation and proximal promoter studies.
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DOI：
10.1097/fpc.0b013e32832c15c6
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发表时间：
2009-08
影响因子：
2.6
通讯作者：
Weinshilboum RM
中科院分区：
文献类型：
--
作者：
Zhang J;Ji Y;Moon I;Pelleymounter LL;Ezequel Salavaggione O;Wu Y;Jenkins GD;Batzler AJ;Schaid DJ;Weinshilboum RM
儿茶酚o -甲基转移酶（COMT）以可溶性(S)和膜结合（MB）亚型表达，其中S-COMT主要在肝脏中表达。一个常见的非同义SNP， 472G>A (108/158Val>Met, S/MB)，与COMT酶活性和热稳定性水平的变化有关。我们开始测试额外的COMT多态性也可能与表型变异相关的假设。我们对268份肝活检样本进行了S-COMT活性和热稳定性表型分析，对之前未进行过基因测序的部分基因进行了重新测序，并对这些样本中的16个COMT多态性进行了基因分型。在密码子108 SNP处，两种COMT表型与基因型之间存在显著相关性。然后使用基于单倍型的方法来评估其他多态性与表型的可能关联。具体来说，密码子108 SNP解释了20.4%的活性变异（P<10−6）和59%的热稳定性变异（P<10−6）。包含cDNA核苷酸408和472 SNP的单倍型解释了酶活性的额外变异（高达24.4%），而包含内含子2 SNP的单倍型（51）解释了总共27.5%的变异。然而，在472G核苷酸之外的SNPs >a多态性与热稳定性的变化无关。我们还观察到报告基因构建的“近端启动子”单倍型驱动转录的能力有三倍的变化。常见的COMT 108Val>Met多态性与人类肝脏S-COMT活性和热稳定性有关，但其他COMT snp也有助于活性的变化。
Catechol O-methyltransferase (COMT) is expressed as both soluble (S) and membrane-bound (MB) isoforms, with S-COMT predominantly expressed in liver. A common nonsynonymous 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. We phenotyped 268 liver biopsy samples for S-COMT activity and thermal stability, resequenced a portion of the gene that had not previously been resequenced, and genotyped DNA from these same samples for 16 COMT polymorphisms. 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, codon 108 SNP explained 20.4% of variance in activity (P<10−6), and 59% of variance in thermal stability (P<10−6). 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 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. 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.