A Single Nucleotide Polymorphism and Its Haplotype of ZNF42 Transcriptional Modulator Gene Predisposes Individuals to High-Risk Acute Myelogenous Leukemia (AML).

ZNF42 (MZF-1 or Human Zinc finger protein 42) is a hematopoietic transcription factor regulating the differentiation and proliferation of myeloid cells. ZNF42 belongs to the Krupple-class zinc finger protein, which is expressed in myeloid progenitor cells. As a transcriptional regulator it has been found to be pivotal in hematopoietic development, especially in granulopoiesis. ZNF42 is a bi-functional transcriptional regulator, by repressing transcription in non-hematopoietic cells, but trans-activating hematopoiesis-related genes. Despite the important role of ZNF42 in differentiation and proliferation in the myeloid lineage cells, molecular epidemiologic studies of ZNF42 have not been conducted. In this case-control study, we conducted a comprehensive analysis of the genomic region of ZNF42, including SNP discovery by re-sequencing of the promoter and exon-encompassing regions, haplotype construction and construction of linkage disequilibrium (LD) map and comparison LD structure among four different populations data from the International HapMap project. In total, 275 de novo AML patients plus age- and sex-matched controls were recruited and four coding non-synonymous SNPs were genotyped by Pyrosequencing for this study. All genotypes frequencies were in Hardy-Weinberg equilibrium. A non-synonymous SNP (G/A altering amino acid R51H) revealed strong association with increased susceptibility to AML. Relative to individuals with the GG genotype, those with the A allele (AA + AG) had a 4.8-fold (95% CI, 3.3–7.0) (p=4.111e-17) risk of development of AML. Also four common (> 5% frequency, cumulative frequency of over 96%) haplotypes were identified and the frequencies of the common haplotypes predicted were similar between cases and controls. When we studied if there is haplotype-based association to examine the contribution of common genetic variation at the ZNF42 locus to AML risk among Korean, two haplotypes (G-G and A-G from R51H-R130Q) showed statistically significant association.. These results suggest that ZNF42 variants and its haplotypes are significantly associated with increased susceptibility to AML.