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Human Molecular Genetics Advance Access originally published online on October 23, 2008
Human Molecular Genetics 2009 18(2):366-372; doi:10.1093/hmg/ddn345
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Population-specific GSTM1 copy number variation

R. Stephanie Huang1, Peixian Chen2, Steve Wisel1, Shiwei Duan1, Wei Zhang1, Edwin H. Cook4, Soma Das2, Nancy J. Cox3 and M. Eileen Dolan1,*

1 Section of Hematology-Oncology, Department of Medicine 2 Department of Human Genetics 3 Section of Genetic Medicine, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., PB Box MC2115, Chicago, IL 60637, USA 4 Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA

* To whom correspondence should be addressed. Tel: +1 7737024441; Fax: +1 7737020963; Email: edolan{at}medicine.bsd.uchicago.edu

Received August 10, 2008; Accepted October 15, 2008

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.


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