Potentially Functional Polymorphism in IL-23 Receptor and Risk of Acute Myeloid Leukemia in a Chinese Population

et al. (2013) Potentially Functional Polymorphism in IL-23 Receptor and Risk of Acute Myeloid Leukemia in a Chinese Population. PLoS ONE 8(2): e55473. doi:10.1371/journal.pone.0055473 Potentially Functional Polymorphism in IL-23 Receptor and Risk of Acute Myeloid Leukemia in a Chinese Population Xifeng Qian 0 Songyu Cao 0 Guohua Yang 0 Yun Pan 0 Chenyu Yin 0 Xiang Chen 0 Ying Zhu 0 Yun Zhuang 0 Yunfeng Shen 0 Zhibin Hu 0 0 1 Department of Hematology, Wuxi People's Hospital Affiliated to Nanjing Medical University , Wuxi , China , 2 Department of Epidemiology and Biostatistics and Ministry of Education Key Lab for Modern Toxicology, School of Public Health, Nanjing Medical University , Nanjing , China , 3 Wuxi People's Hospital Affiliated to Nanjing Medical University , Wuxi , China , 4 Jiangsu Key Lab of Cancer Biomarkers, Prevention and treatment, Cancer Center, Nanjing Medical University , Nanjing , China The interleukin-23 (IL-23) and its receptor (IL-23R) mediate the direct antitumor activities in human hematologic malignancies including pediatric acute leukemia. Two potentially functional genetic variants (IL-23R rs1884444 T.G and rs6682925 T.C) have been found to contribute to solid cancer susceptibility. In this study, we conducted a case-control study including 545 acute myeloid leukemia (AML) patients and 1,146 cancer-free controls in a Chinese population to assess the association between these two SNPs and the risk of AML. We found that IL-23R rs1884444 TG/GG and rs6682925 TC/CC variant genotypes were associated with significantly increased risk of AML [rs1884444: adjusted odds ratio (OR) = 1.28, 95% confidence interval (CI) = 1.01-1.62; rs6682925: adjusted OR = 1.30, 95%CI = 1.01-1.67], compared to their corresponding wild-type homozygotes, respectively. These findings indicated that genetic variants in IL-23R may contribute to AML risk in our Chinese population. - Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Introduction Acute myeloid leukemia (AML), a cancer of the myeloid line of blood cells, is the most common acute leukemia affecting adult [1]. The abnormal white blood cells accumulate in the bone marrow, thus interfering with the production of normal blood cells. Although most cases of AML have no obvious cause, it is considered that several factors may play a role in the increased occurrence of AML, including chemical exposure [2,3], ionizing radiation [4], and genetics [5]. Interleukin (IL)-23 is a heterodimeric proinflammatory cytokine composed of a p19 subunit and a p40 subunit, which is also part of IL-12 [6,7]. IL-23 is predominantly produced by antigenpresenting cells in response to microbial or host immune stimuli and is involved in the regulation of immune responses against infections and tumor development through the engagement of the IL-23 receptor (IL-23R) [8]. Recent studies also showed the direct antitumor activities of IL-23/IL-23R in human hematologic malignancies, i.e., pediatric acute leukemia, and IL-23 directly dampens tumor growth in vitro and in vivo through the inhibition of tumor cell proliferation and induction of apoptosis [9,10]. The IL-23R gene located on chromosome 1p31 encodes one subunit of the IL-23R [11].Two potentially functional common variants of IL-23R, rs6682925 (T.C) located at 907-bp upstream from the transcriptional start position, and rs1884444 (T.G) located at codon 3 with amino acid His substituted by Gln in exon 2, have been shown to have association with risk of several solid cancers [1214]. Here, we hypothesized these two single-nucleotide polymorphisms (SNPs) may also be associated with risk of AML. Of the 545 AML cases, 291 (53.4%) were males and the mean age at diagnosis was 44.1617.2 years old, while among the 1146 cancer-free controls, 820 (71.5%) were males and the mean age was 59.069.7 years old. The clinical and cytogenetic characteristics of the AML cases are summarized in Table 1. Genotyping was successfully performed in 537 cases and 1137 controls for rs1884444 (call rate = 99.0%) and 525 cases and 1117 controls for rs6682925 (call rate = 97.1%). The genotype distributions of these two variants between the cases and controls are shown in Table 2. The observed genotype frequencies for both variants were in Hardy-Weinberg equilibrium among the controls (P = 0.829 for rs1884444 and P = 0.686 for rs6682925). Multivariate logistic regression analysis showed that the rs1884444 TG and combined genotypes TG/GG were associated with a significantly increased risk of AML (adjusted OR = 1.34, 95%CI = 1.041.72 for TG; adjusted OR = 1.28, 95% CI = 1.011.62 for TG/GG), RARa and IL-23R variants in M2 and M3 AML, respectively, as shown in Table 4. AML (n = 545) Myeloid and Lymphoid Myeloid and Monocytic Classification of diagnosis Molecular subtype Common fusion gene transcripts MLL rearrangement No common fusion gene ranscripts compared with the rs1884444 wild-type TT, respectively. Similarly, compared to the wild TT genotype, rs6682925 CC and combined TC/CC genotypes contributed to AML risk by 1.48fold (95% CI = 1.032.13) and 1.30-fold (95% CI = 1.011.67), respectively. Stratified analyses of these two SNPs are summarized in Table 3. No significant heterogeneity between the subgroups was detected for rs6682925. For rs1884444, the increased risk of combined TG/GG genotypes was more significant in older patients (more than 45 years old at diagnosis), and P value for the heterogeneity was 0.030. However, there was no interaction between rs1884444 and age on AML risk (P = 0.097). As the fusion gene AML1/ETO and PML/RARarespectively accounted for the majority of molecular subtypes of M2 AML and M3 AML, we then investigated the association of these two genes and SNPs of IL-23R in M2 AML and M3 AML. However, there was no significant associations between AML1/ETO or PML/ IL-23 is a proinflammatory heterodimeric cytokine sharing common subunits with IL-12 [6,7], which could directly inhibit human acute myeloid leukemia cell growth [15]. With the similar structures and biological activities of IL-12, IL-23 may also have some effects on human malignancies, whereas its antitumor activity remains controversial. Some groups held the opinion that IL-23 can impair CD8+ T-lymphocyte-mediated immune surveillance and promote de novo carcinogenesis and tumor neovascularization [1618]. In contrast, other groups have shown that IL-23 exerts antitumor activity through stimulation of T cells and NK cells [1924]. IL-23 mediates these cancer-related effects through IL-23R. Cocco et al. demonstrated that IL-23/IL-23R acts as antitumor agent on hematologic malignancies including childhood acute leukemia [9,10]. Recently, several studies evaluated the association between two variants (rs1884444 and rs6682925) of IL23R polymorphisms and risk of solid cancers in Chinese population [1214]. Xu et al. [12] reported that the variant allele (...truncated)