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Association of genetic polymorphisms in the interleukin-10 promoter with risk of prostate cancer in Chinese
- Jie Liu†1,
- Bao Song†2,
- Xueli Bai3,
- Wenjian Liu4,
- Zengjun Li1,
- Jialin Wang2,
- Yan Zheng1 and
- Zhehai Wang1Email author
© Liu et al; licensee BioMed Central Ltd. 2010
Received: 31 March 2010
Accepted: 24 August 2010
Published: 24 August 2010
Recent studies identified an increased risk of prostate cancer (PCa) in Caucasian men harboring polymorphisms of genes involved in innate immunity and inflammation. This study was designed to assess whether single nucleotide polymorphisms in the IL-10 promoter play a role in predisposing individuals to PCa in a Chinese population.
We genotyped three SNPs of the IL-10 promoter (-1082A/G, -819T/C and -592A/C) using polymerase chain reaction-restriction fragment length polymorphism analysis in 262 subjects with PCa and 270 age-matched healthy controls. Odds ratio and 95% confidence interval were determined by logistic regression for the associations between IL-10 genotypes and haplotypes with the risk of PCa and advanced PCa grade.
No significant differences in allele frequency or genotype distribution were observed for any of the IL-10 SNPs between PCa patients and control subjects. Significantly higher frequencies of -1082G, -819C and -592C allele and GCC haplotype were observed, however, in early stage patients in comparison to advanced PCa patients (for -1082 G, 13.9% vs 6.1%, OR = 2.48, P = 0.005; for -819 C 40.3% vs 30.8%, OR = 1.51, P = 0.043; for -512C, 40.3% vs 30.8%, OR = 1.51, P = 0.043; and for haplotype GCC 11.1%vs 5.1%, OR = 2.66, P = 0.008, respectively).
Our results identify that IL-10 promoter polymorphisms might not be a risk factor for PCa in Chinese cohorts, but rather incidence of polymorphisms associates with PCa grade, suggesting that IL-10 expression may impact PCa progression.
Prostate cancer (PCa) is among the most common malignant tumors in Western males, ranking second only to lung cancer in cancer mortality . PCa incidence in Asian men is significantly lower, however, the incidence of PCa in China has increased significantly in recent years . 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 . 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 .
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 .
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 . Similarly, the GCC haplotype exhibits significantly higher transcriptional activity than the ATA haplotype in a luciferase reporter system .
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  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.
The study included 262 newly diagnosed prostate cancer cases (aged 46-83 years) recruited from Shandong Cancer Hospital and Institute, Shandong Provincial Hospital and the Affiliated Hospital of Taishan Medical University between March 2006 and December 2008. The diagnosis of prostate cancer was based on digital rectal examination, serum Prostate specific antigen (PSA) concentration determination and transrectal ultrasound guided prostate biopsy. PSA concentration of 4.0 ng/mL was considered a cut-off value to carry out diagnostic work-up. Adenocarcinoma of the prostate was pathologically confirmed in all the cases, and the Gleason score (highly differentiated, score 2-5; moderately differentiated, score 6-7; poorly differentiated, score 8-10) was evaluated by pathologists working at each hospital using the Gleason scoring system . The clinical T stage of the patients with PCa was evaluated according to the 2002 TNM staging system for cancer . We defined more aggressive and less aggressive disease based on tumor stage and Gleason score. "Advanced prostate cancer" was defined as either a Gleason score >7 or clinical T stage >T2.
270 population controls (aged 46~81 years) were accrued from healthy volunteers who visited the three hospitals between July 2006 and July 2008 for general health exams. Controls were screened to ensure that they had never been diagnosed with cancer or other serious disease. The selected controls were matched to the cases by age (±5 years). Each subject was interviewed for family history of prostate cancer and smoking status. All subjects were unrelated ethnic Han Chinese. Written informed consent was obtained from each participant. The study was approved by the Review Boards of Shandong Cancer Hospital and Institute. Each study participant provided 2 ml peripheral blood sample.
Primers, restriction enzymes and length of digested fragments of IL-1 0 promoter polymorphism
The SPSS statistical software package ver.13.0 (SPSS Inc., Chicago, USA) was used for statistical analysis. Demographic data between the study groups were compared by chi-square test and by Student t-test. Each polymorphism was tested for deviation from Hardy-Weinberg equilibrium by comparing the observed and expected genotype frequencies using the chi-square test. For SNP analyses, genotype and allele frequencies of IL-10 were compared between groups using the chi-sqare test, and odds ratios (OR) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression with adjustment for age and smoking status. The linkage disequilibrium of the three loci and haplotypes of IL-10 (-1082,-819,-592) were conducted using the SHEsis software, from the website http://analysis.bio-x.cn/ (Bio-X Inc., Shanghai, China) , which uses a Full-Precise-Iteration (FPI) algorithm to reconstruct haplotypes. Additionally, the chi-sqare test was used to perform the association of IL-10 allelic and haplotype frequencies and the "advanced grade" among PCa patients. P values <0.05 were considered to be statistically significant.
Characteristics of PCa patients and controls
Characteristics of PCa patients and controls
Patients, n (%) (n = 262)
Controls, n (%) (n = 270)
70.7 ± 8.4
70.2 ± 8.5
History of prostate cancer
128.33 ± 634.21
2.146 ± 0.954
Clinical T Stage
IL-10gene polymorphisms and PCa
IL-10 polymorphisms and risk of PCa
Controls n (%)
PCa n (%)
Adjusted OR* (95%CI)
Association of IL-10polymorphisms with PCa aggressiveness
Association of IL-10 polymorphisms with PCa aggressiveness
Early stage (72)
Advanced stage (180)
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 . In contrast, Eder et al  or Michaud et al  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  and Japanese  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  and 1.6/105 PY in 2002. 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.
In conclusion, Our results suggest that IL-10 promoter polymorphisms might not be a risk factor of PCa development but may impact PCa progression in Chinese patients.
This paper was supported by Grant number 2004GCG2202152 provided by Department of Science Technology of Shandong Province.
- Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 2008, 58: 71-96. 10.3322/CA.2007.0010.View ArticlePubMedGoogle Scholar
- McCracken M, Olsen M, Chen MS, Jemal A, Thun M, Cokkinides V, Deapen D, Ward E: Cancer incidence, mortality, and associated risk factors among Asian Americans of Chinese, Filipino, Vietnamese, Korean, and Japanese ethnicities. CA Cancer J Clin. 2007, 57: 190-205. 10.3322/canjclin.57.4.190.View ArticlePubMedGoogle Scholar
- Hamasaki T, Inatomi H, Katoh T, Ikuyama T, Matsumoto T: Clinical and pathological significance of vitaminD receptor gene polymorphism for prostate cancer which is associated with a higher mortality in Japanese. Endocr J. 2001, 48: 543-9. 10.1507/endocrj.48.543.View ArticlePubMedGoogle Scholar
- Hayes VM, Severi G, Padilla EJ, Eggleton SA, Southey MC, Sutherl RL, Hopper JL, GilesGG : Genetic variants in the vitamin D receptor gene and prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2005, 14: 997-9. 10.1158/1055-9965.EPI-04-0660.View ArticlePubMedGoogle Scholar
- Habuchi T, Suzuki T, Sasaki R, Wang L, Sato K, Satoh S, Akao T, Tsuchiya N, Shimoda N, Wada Y, Koizumi A, Chihara J, et al: Association of vitaminD receptor gene polymorphism with prostate cancer and benign prostatic hyperplasia in a Japanese population. Cancer Res. 2000, 60: 305-8.PubMedGoogle Scholar
- Dennis LK, Lynch CF, Torner JC: Epidemiologic association between prostatitis and prostate cancer. Urology. 2002, 60: 78-83. 10.1016/S0090-4295(02)01637-0.View ArticlePubMedGoogle Scholar
- Huang S, Ullrich SE, Ber-Eli M: Regulation of tumor growth and metastasis by interleukin-10: the melanoma experience. J Interferon Cytokine Res. 1999, 19: 697-703. 10.1089/107999099313532.View ArticlePubMedGoogle Scholar
- Fortis C, Foppoli M, Gianotti L, Galli L, Citterio G, Consogno G, Gentilini O, Braga M: Increased interleukin-10 serum levels in patients with solid tumors. Cancer Lett. 1996, 104: 1-5. 10.1016/0304-3835(96)04213-9.View ArticlePubMedGoogle Scholar
- Stearns ME, Rhim J, Wang M: Interleukin 10 (IL-10) inhibition of primary human prostate cell-induced angiogenesis: IL-10 stimulation of tissue inhibitor of metalloproteinase-1 and inhibition of matrix metalloproteinase (MMP)-2/MMP-9 secretion. Clin Cancer Res. 1999, 5: 189-96.PubMedGoogle Scholar
- Kingo K, Ratsep R, Koks S, Karelson M, Silm H, Vasar E: Influence of genetic polymorphisms on interleukin-10 mRNA expression and psoriasis susceptibility. J Dermatol Sci. 2005, 37: 111-3. 10.1016/j.jdermsci.2004.10.002.View ArticlePubMedGoogle Scholar
- Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV: An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet. 1997, 24: 1-8.View ArticlePubMedGoogle Scholar
- Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP: Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol. 2001, 166: 3915-22.View ArticlePubMedGoogle Scholar
- Eskdale J, Gallagher G: A polymorphic dinucleotide repeat in the human IL-10 promoter. Immunogenetics. 1995, 42: 444-5. 10.1007/BF00179416.View ArticlePubMedGoogle Scholar
- Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P: Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis and Rheumatism. 1999, 42: 1101-8. 10.1002/1529-0131(199906)42:6<1101::AID-ANR6>3.0.CO;2-Y.View ArticlePubMedGoogle Scholar
- Wang MH, Helzlsouer KJ, Smith MW, Hoffman-Bolton JA, Clipp SL, Grinberg V, De Marzo AM, Isaacs WB, Drake CG, Shugart YY, Platz EA: Association of IL10 and other immune response- and obesity-related genes with prostate cancer in CLUE II. Prostate. 2009, 69: 874-85. 10.1002/pros.20933.View ArticlePubMedPubMed CentralGoogle Scholar
- Kesarwani P, Ahirwar DK, Mandhani A, Singh AN, Dalela D, Srivastava AN, Mittal RD: IL-10 -1082 G > A: a risk for prostate cancer but may be protective against progression of prostate cancer in North Indian cohort. World J Urol. 2009, 27: 389-96. 10.1007/s00345-008-0361-1.View ArticlePubMedGoogle Scholar
- McCarron SL, Edwards S, Evans PR, Gibbs R, Dearnaley DP, Dowe A, Southgate C, Easton DF, Eeles RA, Howell WM: Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res. 2002, 62: 3369-72.PubMedGoogle Scholar
- Faupel-Badger JM, Kidd LC, Albanes D, Virtamo J, Woodson K, Tangrea JA: Association of IL-10 polymorphisms with prostate cancer risk and grade of disease. Cancer Causes Control. 2008, 19: 119-24. 10.1007/s10552-007-9077-6.View ArticlePubMedGoogle Scholar
- Eder T, Mayer R, Langsenlehner U, Renner W, Krippl P, Wascher TC, Pummer K, Kapp KS: Interleukin-10 [ATA] promoter haplotype and prostate cancer risk: a population-based study. Eur J Cancer. 2007, 43: 472-5. 10.1016/j.ejca.2006.11.003.View ArticlePubMedGoogle Scholar
- Michaud DS, Daugherty SE, Berndt SI, Platz EA, Yeager M, Crawford ED, Hsing A, Huang WY, Hayes RB: Genetic polymorphisms of interleukin-1B (IL-1B), IL-6, IL-8, and IL-10 and risk of prostate cancer. Cancer Res. 2006, 66: 4525-30. 10.1158/0008-5472.CAN-05-3987.View ArticlePubMedGoogle Scholar
- Epstein JI, Allsbrook WC, Amin MB, Egevad LL, ISUP Grading Committee: The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005, 29: 1228-42. 10.1097/01.pas.0000173646.99337.b1.View ArticlePubMedGoogle Scholar
- Sabin LH, Wittekind C: TNM classification of malignant Tumors. 2002, New York: Wiley-Blackwell Press, 6Google Scholar
- Shi YY, He L: SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Research. 2005, 15: 97-8. 10.1038/sj.cr.7290286.View ArticlePubMedGoogle Scholar
- Jun TY, Pae CU, Kim KS, Han H, Serretti A: Interleukin-10 gene promoter polymorphism is not associated with schizophrenia in the Korean population. Psychiatry Clin Neurosci. 2003, 57: 153-9. 10.1046/j.1440-1819.2003.01095.x.View ArticlePubMedGoogle Scholar
- Ide A, Kawasaki E, Abiru N, Sun F, Takahashi R, Kuwahara H, Fujita N, Kita A, Oshima K, Sakamaki H, Uotani S, Yamasaki H, et al: Genetic association between interleukin-10 gene promoter region polymorphisms and type 1 diabetes age-at-onset. Hum Immunol. 2002, 63: 690-5. 10.1016/S0198-8859(02)00417-2.View ArticlePubMedGoogle Scholar
- Ferlay J, Bocani GLO: Cancer Incidence and Mortality Worldwide. 1998, Lyon: IARC PressGoogle Scholar
- Ferlay J, Bray F, Pisani P, Parkin DM: Globocan 2002: cancer incidence, mortality and prevalence worldwide. IARC Cancer-Base No 5, version 2.0. 2004, Lyon: IARC PressGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/10/456/prepub
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