Liu Chen-yu, Hsu Yi-Hsiang, Pan Pi-Chen, Wu Ming-Tsang, Ho Chi-Kung, Su Li, Xu Xin, Li Yi, Christiani David C
Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
Carcinogenesis. 2008 May;29(5):984-90. doi: 10.1093/carcin/bgn071. Epub 2008 Mar 13.
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.
醛酮还原酶1C3（AKR1C3）基因位于10号染色体p15 - p14，是髓样细胞增殖和分化的调节因子，是研究人类致癌作用的重要候选基因。在台湾南部高雄市进行的一项基于人群的前瞻性汉族病例对照研究中，1997年11月至2005年12月期间共招募了114例白血病病例和221名20岁以下的对照。本研究旨在评估儿童白血病与母亲及后代基因型之间的关联。为此，我们对AKR1C3基因5'侧翼10 kb至3'UTR区域的常见单核苷酸多态性（SNP）进行了系统评估。使用HapMap II数据集选择了Gln5His和三个标签SNP（rs2245191、rs10508293和rs3209896）以及一个多标记（rs2245191、rs10508293和rs3209896），平均覆盖未标记SNP的90%。比值比和95%置信区间根据年龄和性别进行了调整。在进行多重比较校正后，我们观察到儿童白血病发病风险与AKR1C3基因第4内含子上的rs10508293多态性在单独后代以及母亲和后代基因型组合中均显著相关（名义P < 0.0001，置换P < 0.005）。发现母亲亚甲基四氢叶酸还原酶A1298C多态性是AKR1C3基因母亲第4内含子多态性（rs10508293）与儿童白血病风险的效应修饰因子。总之，本研究表明AKR1C3多态性可能是儿童白血病易感性的重要预测标志物。
