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Human Molecular Genetics Advance Access originally published online on April 27, 2005
Human Molecular Genetics 2005 14(12):1621-1629; doi:10.1093/hmg/ddi170
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Global gene expression as a function of germline genetic variation

Deborah French1,{dagger}, Mark R. Wilkinson1,{dagger}, Wenjian Yang1, Luc de Chaisemartin1, Edwin H. Cook5,6, Soma Das6, Mark J. Ratain7, William E. Evans1,4, James R. Downing2, Ching-Hon Pui2,3 and Mary V. Relling1,4,*

1Department of Pharmaceutical Sciences, 2Department of Pathology and 3Department of Hematology–Oncology, St Jude Children's Research Hospital, Memphis, TN, USA, 4University of Tennessee, Memphis, TN, USA and 5Department of Psychiatry, 6Department of Human Genetics and 7Department of Medicine, University of Chicago, Chicago, IL, USA

* To whom correspondence should be addressed at: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794, USA. Tel: +1 9014952348; Fax: +1 9015256869; Email: mary.relling{at}stjude.org

Received January 5, 2005; Accepted April 19, 2005

Common, functional, germline genetic polymorphisms have been associated with clinical cancer outcomes. Little attention has been paid to the potential phenotypic consequences of germline genetic variation on downstream genes. We determined the germline status of 16 well-characterized functional polymorphisms in 126 children with newly diagnosed acute lymphoblastic leukemia (ALL). We assessed whether global gene expression profiles of diagnostic ALL blasts from the same patients differed by these germline polymorphic genotypes. Gene expression values were adjusted for ALL-subtype-specific patterns. Of the 16 loci, only the UGT1A1 promoter repeat polymorphism [A(TA)nTAA] (UGT1A1*28) and GSTM1 deletion were significant predictors of global gene expression in a supervised approach, which divided patients based on their germline genotypes [UGT1A1: 124 probe sets, false discovery rate (FDR)=13%, P≤0.0031; GSTM1: 112 probe sets, FDR=42.5%, P≤0.0084]. Genes whose expression distinguished the UGT1A1 (TA) 7/7 genotype from the other UGT1A1 genotypes included HDAC1, RELA and SLC2A1; those that distinguished the GSTM1 null genotype from non-null genotype included NBS1 and PRKR. In an unsupervised approach, the gene expression profiles using the entire array delineated two major clusters of patients. The only germline genotype frequency that differed between the two clusters was UGT1A1 (P=0.002; Fisher's exact test). Although their expression is limited to specific tissues, both GSTM1 and UGT1A1 are involved in the conjugation (and thus transport, excretion and lipophilicity) of a broad range of endobiotics and xenobiotics, which could plausibly have consequences for gene expression in different tissues.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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