Effects of 5′ regulatory-region polymorphisms on paraoxonase-gene (PON1) expression
Effects of 5′ regulatory-region polymorphisms on paraoxonase-gene (PON1) expression
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DOI：
10.1086/320600
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发表时间：
2001-06-01
影响因子：
9.8
通讯作者：
Furlong, CE
中科院分区：
文献类型：
--
作者：
Brophy, VH;Jampsa, RL;Furlong, CE
人HDL相关对氧磷酶（PON 1）水解许多有毒有机磷化合物并减少LDL和HDL的氧化。PON 1的这些特性解释了它对农药中毒和动脉粥样硬化的保护能力。PON 1还水解许多内酯和环状碳酸酯药物。在人群中的个体之间，PON 1水平变化很大。我们以前确定了PON 1调控区的三个多态性，影响培养的人肝细胞的表达水平。在这项研究中，我们确定了376个白色个体的三个调节区多态性的基因型，并研究了它们对血浆PON 1水平的影响，通过苯乙酸水解率来确定。-108多态性对PON 1活性水平有显著影响，而-162多态性的影响较小。-909多态性与其他位点连锁不平衡，对体内PON 1活性水平的影响很小或没有独立影响。其他研究发现，PON 1编码区的L55 M多态性与PON 1-mRNA和PON 1-活性水平的差异有关。这里呈现的结果表明，L55 M活性降低的效应不是由于氨基酸的变化，而是主要由于与-108调节区多态性的连锁不平衡。密码子55多态性似乎略微解释了PON 1活性变化的15.3%，但在对-108和Q192 R多态性的影响进行调整后，这一比例下降至5%。-108C/T多态性占PON 1表达水平变异的22.8%，远大于其他PON 1多态性。我们还鉴定了PON 1 mRNA的3' UTR中的四个序列差异。
Human HDL-associated paraoxonase (PON1) hydrolyzes a number of toxic organophosphorous compounds and reduces oxidation of LDLs and HDLs. These properties of PON1 account for its ability to protect against pesticide poisonings and atherosclerosis. PON1 also hydrolyzes a number of lactone and cyclic-carbonate drugs. Among individuals in a population, PON1 levels vary widely. We previously identified three polymorphisms in the PON1 regulatory region that affect expression levels in cultured human hepatocytes. In this study, we determined the genotypes of three regulatory-region polymorphisms for 376 white individuals and examined their effect on plasma-PON1 levels, determined by rates of phenylacetate hydrolysis. The -108 polymorphism had a significant effect on PON1-activity level, whereas the -162 polymorphism had a lesser effect. The -909 polymorphism, which is in linkage disequilibrium with the other sites, appears to have little or no independent effect on PON1-activity level in vivo. Other studies have found that the L55M polymorphism in the PON1-coding region is associated with differences in both PON1-mRNA and PON1-activity levels. The results presented here indicate that the L55M effect of lowered activity is not due to the amino acid change but is, rather, largely due to linkage disequilibrium with the -108 regulatory-region polymorphism. The codon 55 polymorphism marginally appeared to account for 15.3% of the variance in PON1 activity, but this dropped to 5% after adjustments for the effects of the -108 and Q192R polymorphisms were made. The -108C/T polymorphism accounted for 22.8% of the observed variability in PON1-expression levels, which was much greater than that attributable to the other PON1 polymorphisms. We also identified four sequence differences in the 3' UTR of the PON1 mRNA.