Carcinogenesis Advance Access originally published online on March 13, 2008
Carcinogenesis 2008 29(5):984-990; doi:10.1093/carcin/bgn071
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Maternal and offspring genetic variants of AKR1C3 and the risk of childhood leukemia
1 Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA
2 Institute for Aging Research, Hebrew Rehabilitation Center, Harvard Medical School, Boston, MA 02131, USA
3 Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA
4 Department of Nursing, Yuh-Ing Junior College of Health Care and Management, Kaohsiung 807, Taiwan
5 Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
6 Clinical Training and Education Office, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
7 Graduate Institute of Occupational Safety and Health, Kaohsiung Medical University, Kaohsiung 807, Taiwan
8 Program for Population Genetics, Harvard School of Public Health, Boston, MA 02115, USA
9 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
10 Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA
11 Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
* To whom correspondence should be addressed. Tel: +1 617 432 3323; Fax: +1 617 432 3441;Email: dchris{at}hsph.harvard.edu
The aldo-keto reductase 1C3 (AKR1C3) gene located on chromosome 10p15-p14, a regulator of myeloid cell proliferation and differentiation, represents an important candidate gene for studying human carcinogenesis. In a prospectively enrolled population-based case–control study of Han Chinese conducted in Kaohsiung in southern Taiwan, a total of 114 leukemia cases and 221 controls <20 years old were recruited between November 1997 and December 2005. The present study set out to evaluate the association between childhood leukemia and both maternal and offspring's genotypes. To do so, we conducted a systematic assessment of common single-nucleotide polymorphisms (SNPs) at the 5' flanking 10 kb to 3' UTR of AKR1C3 gene. Gln5His and three tagSNPs (rs2245191, rs10508293 and rs3209896) and one multimarker (rs2245191, rs10508293 and rs3209896) were selected with average 90% coverage of untagged SNPs by using the HapMap II data set. Odds ratios and 95% confidence intervals were adjusted for age and gender. After correcting for multiple comparisons, we observed that risk of developing childhood leukemia is significantly associated with rs10508293 polymorphism on intron 4 of the AKR1C3 gene in both offspring alone and in the combined maternal and offspring genotypes (nominal P < 0.0001, permutation P < 0.005). The maternal methylenetetrahydrofolate reductase A1298C polymorphism was found to be an effect modifier of the maternal intron 4 polymorphism of the AKR1C3 gene (rs10508293) and the childhood leukemia risk. In conclusion, this study suggests that AKR1C3 polymorphisms may be important predictive markers for childhood leukemia susceptibility.
Abbreviations: AKR1C3, aldo-keto reductase 1C3; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CI, confidence interval; LD, linkage disequilibrium; LRT, likelihood ratio test; MTHFR, methylenetetrahydrofolate reductase; OR, odds ratio; PAH, polycyclic aromatic hydrocarbon; ROS, reactive oxygen species; SNP, single-nucleotide polymorphism
Received November 29, 2007; revised February 13, 2008; accepted March 6, 2008.