Association of genetic polymorphisms in the interleukin-10 promoter with risk of prostate cancer in Chinese

Prostate cancer (PCa) is among the most common malignant tumors in Western males, ranking second only to lung cancer in cancer mortality [1]. PCa incidence in Asian men is significantly lower, however, the incidence of PCa in China has increased significantly in recent years [2]. While age, ethnicity, diet, and geographic factors are believed to contribute to the etiology of this disorder [3‐5], genetic variations may play a role in susceptibility to PCa [6]. Recent studies suggest that genetic polymorphisms of genes involved in innate immunity and chronic inflammation, including the anti-inflammatory cytokine Interleukin-10 (IL-10), may impact susceptibility to PCa [6].

IL-10 is produced primarily by macrophages and T lymphocytes. It has important anti-inflammatory and immunosuppressive activities, including the ability to downregulate T helper 1 (Th1) cytokine and macrophage costimulatory molecule expression. The impact of IL-10 on macrophage function appears to influence blood vessel growth, as reports indicate that IL-10 may contribute to the regulation of angiogenesis in various cancers [7, 8]. Due to its immunosuppressive and anti-inflammatory properties, it has been hypothesized that IL-10 contributes to tumor escape from immune surveillance, thereby enhancing tumor growth. Conversely, animal and in vitro studies demonstrate a correlation between high levels of IL-10 with smaller tumors and reduced metastasis [9].

Genetic polymorphisms and inherited factors modulate IL-10 expression. The gene encoding IL-10 is located on chromosome 1 (1q31-1q32), and many polymorphisms of the IL-10 gene promoter have been described. Examples of polymorphisms include -1082 A/G (rs 1800896), -819 T/C (rs1800871) and -592 A/C (rs1800872) in the proximal region, which influence the transcription of IL-10 mRNA and the expression of IL-10 in vitro [10‐12]. In vitro stimulation of peripheral blood lymphocytes using concanavalin A revealed that IL-10 -1082 GG is associated with a 1.3-fold increase in IL-10 protein production compared to the AA genotype [13]. Similarly, the GCC haplotype exhibits significantly higher transcriptional activity than the ATA haplotype in a luciferase reporter system [14].

Multiple studies have investigated the association between IL-10 expression and incidence of PCa [15‐17]. Polymorphisms of the IL-10 promoter at -1082 [13‐15], -819 or -592 [16] reduce protein expression, and associate with an increased incidence of PCa in some reports [15‐18]. In contrast, genetic variation at -592, -819, or -1082 or the promoter haplotype ATA resulted in no association in others [19, 20]. These discrepancies suggest that further investigation of the association of IL-10 SNPs with PCa is warranted. Additionally, no such studies have analyzed the impact of these polymorphisms on PCa risk in Chinese patients. Here, we report the association of IL-10 polymorphisms with prostate cancer risk in a Chinese population.

In the present study, we analyzed the association between 3 SNPs of the IL-10 promoter (-1082 A/G, -819 T/C, and -592 A/C) with incidence of prostate cancer in a Chinese cohort. No significant differences in allele frequency or genotype distribution for any of the IL-10 SNPs were observed between patients with PCa and control subjects. However, significantly higher frequencies of the -1082G, -819C and -592C allele and GCC haplotype were observed in early stage PCa patients in comparison to advanced PCa patients.

IL-10 is a multifunctional cytokine with both immunosuppressive and anti-angiogenic functions, consequently resulting in both tumor-promoting and tumor-inhibiting properties. Multiple epidemiological studies have investigated the association between the IL-10 polymorphisms and the risk of different cancer types. Increased serum and peritumoral IL-10 production have been reported in many malignancies. Results with respect to PCa, however, have been inconsistent. The A allele of IL-10-1082 was reported by several groups to be positively associated with incidence of PCa [15‐17]. Similarly, the T allele at -819 and A allele at -592 resulting in low IL-10 expression, have been associated with increased PCa risk, specifically in high grade tumors [18]. In contrast, Eder et al [19] or Michaud et al [20] report no correlation between IL-10 expression and PCa risk/status. The cause of these differences remains unclear, however several possibilities exist. Discrepancies may exist due to genetic trait differences, or the existence of distinct IL-10 genetic polymorphisms amongst specific populations, ethnicities and geographic regions. Furthermore, cancer is a multi-factorial disease. Individual exposures to various environmental factors in combination with genetic susceptibility may have contributed to these varied results.

We observe that the frequency of the IL-10-1082G allele in Chinese is similar to the frequencies observed in healthy Korean [24] and Japanese [25] populations, but significantly lower than those reported for Caucasian populations (where the frequency of IL-10-1082G is approximately 0.45) [18, 20]. Interestingly, the frequency of -1082A (93.9%) and ATA (68%) is higher in Chinese populations than in Caucasians, yet the incidence of PCa in Chinese populations is much lower than what is observed in Caucasians. As the IL-10 -1082 A allele and haplotype ATA are associated with increased PCa risk in Caucasian populations, the association of these polymorphisms with PCa appears to be ethnically or geographically regulated. The -819T allele and -592A allele are in complete linkage disequilibrium in the present study. The allele ratio for -819 T/-592 A is 0.69, significantly higher than those reported for Caucasians (where the frequency of -819T and -592A are approximately 0.22 to 0.32) [18, 20]. These data further confirm that IL-10 alleles vary significantly among ethnic groups, and warrant further investigation.

According to the International Agency for Research on Cancer (IARC), the incidence of prostate cancer in China was 1.1/10⁵ person years (PY) in 1990 [26] and 1.6/10⁵ PY in 2002[27]. China has the lowest incidence of prostate cancer in the world, yet the manjority of prostate cancers are not diagnosed until the advanced stages of disease progression. As serum prostate-specific antigen (PSA) screening is the only diagnostic for prostate cancer used in China diagnosis may be greatly enhanced by consideration of genetic background. Several studies have reported that the IL-10 -1082A allele and ATA haplotye, minor types in Caucasians but major types in China, were associated with increased PCa risk. These results, which suggest that the incidence of PCa patients in China would be greater, differ from the results of our study described here. Clearly, the association of IL-10 SNPs and PCa risk and progression warrant future large-scale investigation throughout multiple ethnic populations.

Here, we analyzed the association between IL-10 polymorphisms and PCa risks in a Chinese population. Our study revealed that there is no association between IL-10 SNPs and incidence of PCa, however a significantly higher frequency of -1082G, -819C and -592C alleles and GCC haplotype were observed in early stage patients compared to advanced PCa patients. To the best of our knowledge, this study is the first to assess the association of IL-10 gene polymorphisms with PCa for the Chinese population. Our results did not support a role for IL-10 SNPs in developing PCa, but as IL-10 expression alters according to cancer grade, our data suggest that IL-10 expression may impact prostate cancer progression. While the precise mechanisms by which IL-10 polymorphisms may modulate PCa progression remains known, evidence suggests that IL-10 modulates immune function, such as NK cell, T cells, and macrophages activity, which would alter disease progression. Additionally, increasing evidence suggests a role for IL-10 in inhibition of angiogenesis, therefore decreases IL-10 expression would de-repress angiogenic activity and promote cancer progression. Acknowledging the relatively limited sample size and for the low allelic frequencies, further studies are warranted.