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Tumor Biology

, Volume 35, Issue 5, pp 4735–4739 | Cite as

The Glu298Asp polymorphism in the NOS3 gene and the risk of prostate cancer

  • Yonggang Zhang
  • Qingyi Jia
  • Qing He
  • Jiani Shen
  • Jiqiao Yang
  • Pei Xue
  • Mengmeng Ma
  • Rui Xu
  • Liang Du
Research Article

Abstract

The Glu298Asp polymorphism in the NOS3 gene has been implicated as a risk factor for prostate cancer. To date, several studies have evaluated the associations between the Glu298Asp polymorphism and prostate cancer risk; however, the results were inconclusive. The aim of the current study was to perform a meta-analysis to investigate the association between the polymorphism and the risk of prostate cancer. A total of 3,206 cases and 3,880 controls from eight case-control studies were included for data synthesis. The overall results suggested no significant association between the polymorphism and the risk of prostate cancer (OR=1.01, 95 % CI=0.92–1.11, p = 0.83 for Asp/Asp+Glu/Asp vs. Glu/Glu). In the stratified analysis according to ethnicity, no significant associations were observed in Asians and Europeans. The current meta-analysis suggested that the Glu298Asp polymorphism of the NOS3 gene might not contribute to the risk of prostate cancer.

Keywords

Prostate cancer Polymorphism NOS3 Meta-analysis 

Introduction

Prostate cancer is one of the most frequently diagnosed cancers and a common cause of mortality in men in the Western populations [1, 2]. It has become a major public health challenge around the world. The mechanism for PCA is still not fully understood. Several risk factors for prostate cancer have been identified, such as age, hormones, and dietary factors [3]. In addition, there is considerable evidence for a genetic basis underlying risks for prostate cancer. Numerous studies have shown that nitric oxide synthases might contribute to the pathogenesis of prostate cancer [4, 5, 6].

The nitric oxide synthases are a family of enzymes responsible for the generation of nitric oxide from l-arginine [4, 5, 6]. NO is a multifaceted compound that may contribute to multistage carcinogenic process. The NO is synthesized by at least three isoenzymes of NO synthase, of which one is called endothelial NOS, also named NOS3. The NOS3 have important roles in mechanisms such as vascular development, maintenance of vascular tone, and tumor growth in human prostate cancer. The gene encode NOS3 is located on 7q35-36. It contains 26 exons, and one important polymorphism in the exon 7 has been widely studied. That polymorphism (Glu298Asp) is based on a G to T at codon 298 leading a glutamic acid to aspartic acid change [7]. An increasing number of case-control studies were performed to identify the association of the polymorphism with the risk of prostate cancer. However, the results were inconclusive. A single study might not be powered sufficiently to detect a small effect of one single polymorphism, especially in relatively small sample sizes [8, 9]. Thus, we performed the current meta-analysis to assess the association between the polymorphism with the risk of prostate cancer. This is, to our knowledge, the first meta-analysis regarding the association between the variant in the NOS3 gene and the risk of prostate cancer risk.

Materials and methods

Literature and search strategy

Published reports assessing the association between polymorphism of NOS3 gene and the risk of prostate cancer were collected from four databases, including PubMed database, EMbase (Ovid) database, CNKI database, and Wanfang database. The search terms were as follows: prostate cancer or prostate carcinoma in combination with polymorphism or variant or mutation and in combination with NOS3 or eNOS or endothelial nitric oxide synthase or nitric oxide synthase 3. All related studies published in English and Chinese languages were included. The search was updated on Sep 23, 2013.

Inclusion criteria, exclusion criteria, and data extraction

The studies included in the meta-analysis must meet all the following inclusion criteria: (a) studies evaluating the association between the Glu298Asp polymorphism in the NOS3 gene and prostate cancer risk, (b) the design should be a case-control design, (c) sufficient data (genotype distributions of cases and controls) available to calculate an odds ratio (OR) with its 95 % CI (confidence interval), and (d) genotype distributions in control group should be consistent with the Hardy-Weinberg equilibrium (HWE). Studies were excluded if one of the following existed: (a) the studied populations were based on family or sibling pairs, (b) genotype frequencies or numbers were not presented in the original studies, and (c) reviews and abstracts. If more than one study was published by the same authors using the same case series or overlapping case series, studies with the largest size of samples were included. The following information was extracted from each study: first author’s name, publication year, country, ethnicity, age of cases, genotype number in cases, and controls.

Statistical analysis

The strength of associations between the Glu298Asp polymorphism and prostate cancer risk was assessed by OR with the corresponding 95 % CI under a dominant model (Asp/Asp+Glu/Asp vs. Glu/Glu). The significance of pooled OR was analyzed by Z test (p < 0.05 was considered statistically significant). Heterogeneity was assessed by a χ2-based Q statistic and was considered statistically significant at p value <0.10. When the p value was more than 0.10, the pooled OR was calculated by the fixed-effects model; otherwise, a random-effects model was used. Subgroup analysis by ethnicity types was performed to assess the ethnic effects. Publication bias was assessed by Begg’s test and Egger’s test (p < 0.05 was considered statistically significant) [10]. Other genetic models were also used to assess the association with the risk of prostate cancer (Asp/Asp vs. Glu/Glu+Glu/Asp, Asp/Asp vs. Glu/Glu, Glu/Asp vs. Glu/Glu, Asp vs. Glu). HWE was tested by Pearson’s χ2 test. Statistical analysis was performed using Revman4.2 software and Stata10.0 software.

Results

Study characteristics

The process of selection of studies for inclusion in the meta-analysis is summarized as follows. The database search identified 48 potentially relevant results. Of them, 39 results were excluded because of obvious irrelevance by reading the titles and abstracts, or duplicated searched results. The nine studies were left to read full-text. In addition, one study was not concerned on the Glu298Asp polymorphism; thus, eight studies were used for data extraction. Among them, one study that did not report usable data was excluded; one study reported two populations, and each population could be treated as one separate case-control study [11]. Thus, eight case-control studies were extracted. After assessing the HWE for the control population and duplicated, no study was excluded. Thus, a total of eight case-control studies from seven articles were included for data analysis [4, 5, 6, 7, 11, 12, 13]. A summary of the properties of the studies are listed in Table 1. The genotype distributions for the polymorphism are listed in Table 2.
Table 1

Summary of the properties of the studies

Author

Year

Country

Ethnicity

Case

Control

Brankovic et al. [4]

2013

Serbia

European

150

100

Chen et al. [12]

2011

China

Asian

78

88

Jacobs et al. [5]

2008

USA

Mixed

1,420

1,446

Lee et al. [11]

2009

USA

European and mixed

1,185

1,666

Medeiros et al. [6]

2002

Portugal

European

125

153

Safarinejad et al. [7]

2012

Iran

Asian

170

340

Ziaei et al. [13]

2013

Iran

Asian

78

87

Table 2

Genotype distributions for the polymorphism

Author

Case

Control

Case

Control

Glu/Glu

Glu/Asp

Asp/Asp

Glu/Glu

Glu/Asp

Asp/Asp

Glu

Asp

Glu

Asp

Brankovic et al. [4]

76

65

9

54

40

6

217

83

148

52

Chen et al. [12]

64

12

2

66

21

1

140

16

153

23

Jacobs et al. [5]

659

632

129

682

600

164

1,950

890

1,964

928

Lee et al. (A) [11]

77

20

0

280

88

5

174

20

648

98

Lee et al. (E) [11]

517

468

103

607

557

129

1,502

674

1,771

815

Medeiros et al. [6]

49

61

15

70

65

18

159

91

205

101

Safarinejad et al. [7]

120

48

2

248

89

3

288

52

585

95

Ziaei et al. [13]

44

23

11

48

33

6

111

45

129

45

A African American, E European

Quantitative synthesis

A total of 3,206 cases and 3,880 controls from eight case-control studies were included for data synthesis. As is shown in Fig. 1, we analyzed the heterogeneity of Asp/Asp+Glu/Asp vs. Glu/Glu for all eight studies, and the value of χ2 was 3.98 with 7 degrees of freedom and p value = 0.78 in a fixed-effects model. Additionally, an I-square value is another index of the test of heterogeneity. In Fig. 1, the I-square was 0 %, suggesting a lack of heterogeneity. Then the fixed-effects model was chosen to synthesize the data (Fig. 2). Overall, there was no statistical evidence of an association between the Glu298Asp polymorphism and prostate cancer risk (OR = 1.01, 95 % CI = 0.92–1.11, p = 0.83 for Asp/Asp+Glu/Asp vs. Glu/Glu). Statistically similar results were obtained after sequentially excluding each case-control study for the Asp/Asp+Glu/Asp vs. Glu/Glu comparative, suggesting a satisfactory stability of our meta-analysis. No publication bias was detected in the funnel plot (Fig. 3) or the Egger’s test (t = −1.38, p = 0.218), which also indicated no publication bias. In the subgroup analysis by ethnicity (Fig. 2), no significantly increased/decreased cancer risks were found among Asians (OR=0.98, 95 % CI=0.72–1.34, p = 0.90) or among Europeans (OR=1.02, 95 % CI=0.88–1.18, p = 0.82). Other comparatives were also performed to assess the associations, and no significant association was found (Table 3).
Fig. 1

Meta-analysis with a fixed-effects model for the association between prostate cancer risk and the NOS3 Glu298Asp polymorphism (Asp/Asp+Glu/Asp vs. Glu/Glu)

Fig. 2

Meta-analysis with a fixed-effects model for the association between prostate cancer risk and the NOS3 Glu298Asp polymorphism (Asp/Asp+/Asp vs. Glu/Glu); subgroup analysis by ethnicity

Fig. 3

Funnel plot of the meta-analysis

Table 3

Summary results of all comparatives

 

Numbera

Asp/Asp+Glu/Asp vs. Glu/Glu

Asp/Asp vs. Glu/Glu+Glu/Asp

Asp/Asp vs. Glu/Glu

Glu/Asp vs. Glu/Glu

Asp vs. Glu

OR (95 % CI)

p

OR (95 % CI)

p

OR (95 % CI)

p

OR (95 % CI)

p

OR (95 % CI)

p

Total analysis

8

1.01 (0.92, 1.11)

0.83

0.89 (0.75, 1.05)

0.17

0.91 (0.76, 1.09)

0.30

1.03 (0.93, 1.14)

0.51

0.98 (0.91, 1.06)

0.66

Subgroup analysis by ethnicity

  European

3

1.02 (0.88, 1.18)

0.82

0.96 (0.75, 1.22)

0.72

0.97 (0.75, 1.26)

0.82

1.03 (0.88, 1.20)

0.72

1.00 (0.90, 1.12)

0.99

  Asian

3

0.98 (0.72, 1.34)

0.90

2.00 (0.87, 4.63)

0.10

1.85 (0.97, 4.37)

0.16

0.92 (0.66, 1.26)

0.59

1.06 (0.81, 1.39)

0.67

  Mixed

2

1.01 (0.88, 1.16)

0.88

0.77 (0.61, 0.99)

0.04

0.81 (0.63, 1.04)

0.09

1.07 (0.92, 1.24)

0.39

0.95 (0.86, 1.06)

0.40

aNumber of case-control studies

Discussion

The data from the meta-analysis showed no significant association between the Asp/Asp+Glu/Asp genotype of the Glu298Asp polymorphism in patients with prostate cancer and controls, which suggested that the genotype Asp/Asp+Glu/Asp might not increase or decrease the risk of prostate cancer. These results were consistent with most of the studies that were included into our meta-analysis. When stratifying the data by ethnicity, the results also showed that no significant association was found either among Asians or among Europeans, suggesting that the environment they lived did not play an obvious role in the association between the polymorphism and the risk of prostate cancer.

Between-study heterogeneity may be attributed to many factors including the sample sizes, source of controls, and so on. For the polymorphism, we did not find heterogeneity in the total analysis, suggesting that the results might be more reliable. Publication bias is another important factor affecting the quality of our study. In order to assess publication bias, the funnel plot and Egger’s test were performed. No publication bias was observed when all studies were included.

There are several limitations in the meta-analysis. First, although no publication bias was obtained from the data analysis, it is likely that relevant unpublished studies that might have met our inclusion criteria were not included. Selection bias for the meta-analysis might have occurred. Second, although all eligible studies were summarized, the total sample sizes might still not large. When stratified analysis of ethnicity was performed, the number of each subgroup was smaller. Thus, the results may be interpreted with care. Third, some factors such as age, smoking status, drinking status, and environmental factors were assessed.

In summary, the current meta-analysis suggests that the Glu298Asp polymorphism in the NOS3 gene was not associated with susceptibility of prostate cancer. Larger and well-designed studies based on different ethnic populations should be performed to confirm our results, especially in other populations.

Notes

Conflict of Interest

None.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Yonggang Zhang
    • 1
  • Qingyi Jia
    • 2
  • Qing He
    • 2
  • Jiani Shen
    • 2
  • Jiqiao Yang
    • 2
  • Pei Xue
    • 2
  • Mengmeng Ma
    • 1
  • Rui Xu
    • 2
  • Liang Du
    • 1
  1. 1.The Periodical Press of West China HospitalSichuan UniversityChengduChina
  2. 2.West China Hospital/West China Medical SchoolSichuan UniversityChengduChina

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