Human SULT1A1 gene:: copy number differences and functional implications
Human SULT1A1 gene:: copy number differences and functional implications
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DOI：
10.1093/hmg/ddl468
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发表时间：
2007-03-01
影响因子：
3.5
通讯作者：
Thibodeau, Stephen N.
中科院分区：
文献类型：
--
作者：
Hebbring, Scott J.;Adjei, Araba A.;Thibodeau, Stephen N.
SULT 1A 1催化多种天然和合成化合物的硫酸盐结合，具有遗传多态性。生物化学和药物遗传学研究表明，酶活性水平的个体差异是遗传的。位于开放阅读框和5 '-侧翼区（5'-FR）的常见单核苷酸多态性（SNP）可能是这种个体变异的一部分。在这项研究中，我们证明了SULT 1A 1基因缺失和重复的存在，代表了这种酶的代谢活性的变异性的另一个来源。使用定量多重PCR测定来测量拷贝数差异的程度和这些事件在不同人群中的频率。对362名白人美国人和99名非洲裔美国人的DNA分析显示，个体样本中存在1至5个相似的SULT 1A 1拷贝：5%的白人受试者含有该基因的单个拷贝，26%含有三个或更多拷贝，而63%的非洲裔美国人受试者含有三个或更多拷贝。在三个单独的缺失病例中，对SULT 1A 1基因周围的基因组区域进行分析，结果表明整个SULT 1A 1基因受到影响。针对各种5 '-FR SNP单倍型中的每一种构建的报告基因测定表明，这些单倍型也可能在SULT 1A 1活性中发挥作用。然而，当考虑到所有遗传变异来源时，23份人血小板和267份人肝脏样本中酶活性水平的变异性最好用基因拷贝数差异来解释（P < 0.0001）。总体而言，这些观察结果对SULT 1A 1作为药物和激素代谢酶的有效性及其作为疾病风险因素的潜在作用具有明显的影响。
SULT1A1, which catalyzes the sulfate conjugation of a wide variety of natural and synthetic compounds, is genetically polymorphic. Biochemical and pharmacogenetic studies have demonstrated that individual variation in the level of enzyme activity is inherited. Common single-nucleotide polymorphisms (SNPs) located in the open reading frame and in the 5'-flanking region (5'-FR) may account for a portion of this individual variation. In this study, we demonstrate the presence of SULT1A1 gene deletions and duplications, representing an additional source of variability in the metabolic activity of this enzyme. A quantitative multiplex PCR assay was used to measure the extent of copy number differences and the frequency of these events in different populations. An analysis of DNA from 362 Caucasian-American and 99 African-American showed the presence of 1 to similar to 5 copies of SULT1A1 in individual samples: 5% of Caucasian subjects contained a single copy of the gene and 26% had three or more copies, while 63% of African-American subjects had three or more copies. Analysis of the genomic region surrounding the SULT1A1 gene in three separate cases with a deletion demonstrated that the entire SULT1A1 gene was affected. Reporter assays, constructed for each of the various 5'-FR SNP haplotypes, suggest that these may also play a role in SULT1A1 activity. However, the variability in the level of enzyme activity among 23 human platelet and 267 human liver samples was best explained by gene copy number differences when all sources of genetic variability were considered (P < 0.0001). Overall, these observations have obvious implications for the effectiveness of SULT1A1 as a drug and hormone metabolizing enzyme and its potential role as a risk factor for disease.