Huang R Stephanie, Chen Peixian, Wisel Steve, Duan Shiwei, Zhang Wei, Cook Edwin H, Das Soma, Cox Nancy J, Dolan M Eileen
Section of Hematology-Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., PB Box MC2115, Chicago, IL 60637, USA.
Hum Mol Genet. 2009 Jan 15;18(2):366-72. doi: 10.1093/hmg/ddn345. Epub 2008 Oct 23.
As one of the major glutathione conjugation enzymes, GSTM1 detoxifies a number of drugs and xenobiotics. Its expression and activity have been shown to correlate both with cancer risks and drug resistance. Through a genome-wide association study, we identified a significant association between HapMap SNP rs366631 and GSTM1 expression. In this study, utilizing lymphoblastoid cell lines derived from International HapMap Consortium CEU and YRI populations, we designed and performed site-specific genotyping assays for both rs366631 and a highly homologous GSTM1 upstream site. Copy number variation (CNV) assays were performed for three different regions of the GSTM1 gene. We demonstrated that HapMap SNP rs366631 is a non-polymorphic site. The false genotyping call arises from sequence homology, a common GSTM1 region deletion and a non-specific genotyping platform used to identify the SNP. However, the HapMap call for rs366631 genotype is an indicator of GSTM1 upstream region deletion. Furthermore, this upstream deletion can be used as a marker of GSTM1 gene deletion. Using a novel GSTM1 CNV assay, we showed a population-specific CNV in this region upstream of the gene. More than 75% of the Caucasian (CEU) samples exhibit GSTM1 deletion and none contain two copies of GSTM1. In contrast, up to 25% of African (YRI) samples were found to have two copies of GSTM1. In conclusion, HapMap rs366631 is a pseudo-SNP that can be used as a GSTM1 deletion marker. Both the pseudo-SNP allele frequency and GSTM1 upstream region CNV show population-specific patterns between CEU and YRI samples.
作为主要的谷胱甘肽结合酶之一，GSTM1可使多种药物和外源性物质解毒。其表达和活性已被证明与癌症风险和耐药性均相关。通过全基因组关联研究，我们确定了HapMap单核苷酸多态性（SNP）rs366631与GSTM1表达之间存在显著关联。在本研究中，我们利用源自国际HapMap联盟CEU和YRI群体的淋巴母细胞系，针对rs366631和一个高度同源的GSTM1上游位点设计并进行了位点特异性基因分型检测。对GSTM1基因的三个不同区域进行了拷贝数变异（CNV）检测。我们证明HapMap SNP rs366631是一个非多态性位点。错误的基因分型结果源于序列同源性、常见的GSTM1区域缺失以及用于鉴定该SNP的非特异性基因分型平台。然而，HapMap对rs366631基因型的判定是GSTM1上游区域缺失的一个指标。此外，这种上游缺失可作为GSTM1基因缺失的一个标记。使用一种新型的GSTM1 CNV检测方法，我们在该基因上游区域显示出群体特异性的CNV。超过75%的白种人（CEU）样本存在GSTM1缺失，且没有样本含有两个拷贝的GSTM1。相比之下，发现高达25%的非洲人（YRI）样本含有两个拷贝的GSTM1。总之，HapMap rs366631是一个假SNP，可作为GSTM1缺失标记。假SNP等位基因频率和GSTM1上游区域CNV在CEU和YRI样本之间均呈现群体特异性模式。
