School of Systems Biomedical Science, Soongsil University, Seoul, Korea.
J Hum Genet. 2013 Sep;58(9):600-3. doi: 10.1038/jhg.2013.62. Epub 2013 May 30.
The current study examined the promoter activity of an association signal in a 5'-upstream region of the gene encoding CCAAT/enhancer binding protein epsilon (CEBPE) identified from a recent genome-wide association study (GWAS) for complex acute lymphoblastic leukemia (ALL). This follow-up study first compared the activity of reporter constructs with three haplotypes estimated with the rs2239633 and its proximity nucleotide variants in strong linkage. The most frequent haplotype was CTTTTGT (H1), and the second most frequent haplotype consisted of entirely opposite alleles to H1 (TCGCACC, H2). Their luciferase activity revealed the strongest expression with H2 and the weakest with H1. Subsequent analysis revealed that different luciferase activity was found by the single-nucleotide substitution at rs2239632 and rs2239633 (P<0.05). Especially, the difference in luciferase activity between two alleles of rs2239632 corresponded to the difference between H1 and H2. We concluded that rs2239632 could regulate the expression of the CEBPE gene. We suggest a hypothesis that its risk allele (G) might increase the gene product and lead to leukemogenesis. As a result, a person with the allele or the corresponding haplotype might have increased susceptibility to ALL. Further research is warranted to investigate this hypothesis and the underlying mechanisms.
本研究检测了从最近全基因组关联研究（GWAS）鉴定出的编码 CCAAT/增强子结合蛋白ε（CEBPE）基因 5'-上游区域关联信号的启动子活性。这项后续研究首先比较了三种单倍型的报告构建体的活性，这些单倍型是根据 rs2239633 及其附近核苷酸变异进行估计的，它们之间存在强连锁关系。最常见的单倍型是 CTTTTGT（H1），其次常见的单倍型是与 H1 完全相反的等位基因（TCGCACC，H2）。它们的荧光素酶活性显示 H2 的表达最强，H1 的表达最弱。随后的分析表明，rs2239632 和 rs2239633 的单核苷酸取代导致了不同的荧光素酶活性（P<0.05）。特别是，rs2239632 两个等位基因的荧光素酶活性差异与 H1 和 H2 之间的差异相对应。我们得出结论，rs2239632 可以调节 CEBPE 基因的表达。我们提出了一个假设，即其风险等位基因（G）可能会增加基因产物并导致白血病发生。因此，携带该等位基因或相应单倍型的人可能对 ALL 的易感性增加。需要进一步研究来验证这一假设及其潜在机制。
