Polymorphisms in the human paraoxonase (PON1) promoter
Polymorphisms in the human paraoxonase (PON1) promoter
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DOI：
10.1097/00008571-200102000-00009
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发表时间：
2001-02-01
期刊：
影响因子：
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通讯作者：
Furlong, CE
中科院分区：
文献类型：
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作者：
Brophy, VH;Hastings, MD;Furlong, CE
对氧磷酶（PON 1）是高密度脂蛋白（HDL）颗粒的蛋白质组分，其保护低密度脂蛋白和HDL免受氧化损伤，并使有机磷农药和神经毒剂解毒。已观察到PON 1在个体中的广泛表达水平。我们研究了可能影响PON 1活性水平的遗传因素的PON 1的启动子区域。我们在瞬时转染试验中对PON 1启动子区域进行了缺失分析，发现肝脏和肾脏的细胞类型特异性启动子元件存在于编码序列上游的前200个碱基对中。对BAC克隆和YAC克隆的DNA进行序列分析，在编码区上游前1000个碱基的位置-108、-126、-162、-832和-909处鉴定出5种多态性。另外，对两个高表达PON 1和两个低表达PON 1的个体的启动子序列进行了分析，-126和-832位点的两个多态性对报告基因的表达水平没有明显影响。位置-909、-162（潜在的NF-1转录因子结合位点）和-108（潜在的SP1结合位点）的多态性各自对表达水平具有大约两倍的影响。这三种多态性的表达水平的影响似乎不是严格的加性，可能取决于上下文的影响。药理遗传学11：77-84（C）2001 Lippincott威廉姆斯&威尔金斯。
Paraoxonase (PON1) is a protein component of high-density lipoprotein (HDL) particles that protects against oxidative damage to both low-density lipoprotein and HDL and detoxifies organophosphorus pesticides and nerve agents. A wide range of expression levels of PON1 among individuals has been observed. We examined the promoter region of PON1 for genetic factors that might affect PON1 activity levels. We conducted a deletion analysis of the PON1 promoter region in transient transfection assays and found that cell-type specific promoter elements for liver and kidney are present in the first 200 bp upstream of the coding sequence. Sequence analysis of DNA from a BAC clone and a YAC clone identified five polymorphisms in the first 1000 bases upstream of the coding region at positions -108, -126, -162, -832 and -909. Additionally, the promoter sequences of two individuals expressing high levels of PON1 and two individuals expressing low levels of PON1 were analysed, The two polymorphisms at -126 and -832 had no apparent effect on expression level in the reporter gene assay. The polymorphisms at position -909, -162 (a potential NF-1 transcription factor binding site) and -108 (a potential SP1 binding site) each have approximately a two-fold effect on expression level. The expression level effects of the three polymorphisms appear not to be strictly additive and may depend on context effects. Pharmacogenetics 11:77-84 (C) 2001 Lippincott Williams & Wilkins.