Schirmer Markus, Rosenberger Albert, Klein Kathrin, Kulle Bettina, Toliat Mohammad R, Nürnberg Peter, Zanger Ulrich M, Wojnowski Leszek
Georg-August University, Department of Clinical Pharmacology, Göttingen, Germany.
Pharmacogenomics. 2007 May;8(5):443-53. doi: 10.2217/14622416.8.5.443.
To find genetic markers of the individual cytochrome P450 (CYP)3A expression.
A large collection of liver samples phenotyped for CYP3A expression and activity was genotyped for CYP3A variants. Data were analyzed for associations between CYP3A phenotypes and genotypes, and for evidence of recent selection.
We report associations between the hepatic CYP3A4 protein expression level, as well as its enzymatic activity, measured as verapamil N-dealkylation, and genetic polymorphisms from two regions within the CYP3A gene cluster. One region is defined by several variants, mostly located within CYP3A7, the other by a single nucleotide polymorphism in intron 7 of CYP3A4. The effects of these single nucleotide polymorphisms are sex-dependent. For example, female carriers of T alleles of the single nucleotide polymorphism rs4646437C>T in CYP3A4 intron 7 have, respectively, 5.1-fold and 2.7-fold higher expression and activity compared with male T-carriers, but only 2.2-fold and 1.4-fold higher expression and activity compared with males of genotype CC. A regression analysis indicates that the impact of these single nucleotide polymorphisms in men goes beyond the previously reported sex effect. The rs4646437C undergoes positive selection in Caucasians, as evidenced by its relative extended haplotype homozygosity value located within the uppermost percentile of a genome-wide test set of haplotypes in the same 5% frequency bin.
Our findings reconcile the apparent contradiction between the evidence for the influence of the individual genetic makeup on CYP3A4 expression and activity suggested by clinical studies, and the failure to identify the responsible gene variants.
寻找个体细胞色素P450（CYP）3A表达的遗传标记。
对大量已进行CYP3A表达和活性表型分析的肝脏样本进行CYP3A变体基因分型。分析数据以确定CYP3A表型与基因型之间的关联，以及近期选择的证据。
我们报告了肝脏CYP3A4蛋白表达水平及其以维拉帕米N - 去烷基化测量的酶活性与CYP3A基因簇内两个区域的基因多态性之间的关联。一个区域由几个变体定义，大多位于CYP3A7内，另一个区域由CYP3A4内含子7中的一个单核苷酸多态性定义。这些单核苷酸多态性的影响具有性别依赖性。例如，CYP3A4内含子7中rs4646437C>T单核苷酸多态性的T等位基因女性携带者，其表达和活性分别比男性T携带者高5.1倍和2.7倍，但与CC基因型男性相比，仅高2.2倍和1.4倍。回归分析表明，这些单核苷酸多态性对男性的影响超出了先前报道的性别效应。rs4646437C在高加索人中经历正选择，这通过其相对扩展单倍型纯合性值得到证明，该值位于相同5%频率区间内全基因组单倍型测试集的最高百分位数内。
我们的研究结果调和了临床研究表明的个体基因组成对CYP3A4表达和活性有影响的证据与未能鉴定出相关基因变体之间的明显矛盾。
