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. 2010 Sep;24(5):365–373. doi: 10.1016/S1674-8301(10)60049-8

Arg462Gln and Asp541Glu polymorphisms in ribonuclease L and prostate cancer risk: a meta-analysis

Yuanyuan Mi a,Δ, Qianqian Yu b,Δ, Zhichao Min a,Δ, Bin Xu a, Lifeng Zhang a, Wei Zhang a, Ninghan Feng a,*, Lixin Hua a,*
PMCID: PMC3596682  PMID: 23554651

Abstract

Objective

The association between ribonuclease L (RNASEL) gene polymorphisms and prostate cancer risk has been widely reported, but the results of these studies remained controversial and underpowered. We performed a meta-analysis of 28 studies to evaluate the association between Arg462Gln and Asp541Glu polymorphisms in the RNASEL gene and prostate cancer risk.

Methods

Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between RNASEL polymorphisms and prostate cancer risk.

Results

A significantly increased prostate cancer risk was found for the Arg462Gln polymorphism in Africans (Gln/Gln vs Arg/Arg: OR = 2.50, 95%CI = 1.28-4.87; Gln/Gln vs Gln/Arg + Arg/Arg: OR = 2.54, 95%CI = 1.30-4.95), but not in Europeans and Asians. Additionally, the Asp541Glu polymorphism was associated with increased total prostate cancer risk (Glu-allele vs Asp-allele: OR = 1.04, 95%CI = 1.01-1.07; Glu/Glu vs Asp/Asp: OR = 1.22, 95%CI = 1.03-1.46; Glu/Glu vs Glu/Asp + Asp/Asp: OR = 1.09, 95%CI = 1.02-1.16). In the stratified analysis for the Asp541Glu polymorphism, there was a significantly increased prostate cancer risk in Africans and Europeans, and in hospital-based prostate cancer cases.

Conclusion

The meta-analysis results showed evidence that RNASEL Arg462Gln and Asp541Glu polymorphisms are associated with prostate cancer risk and could be low-penetrance prostate cancer susceptibility biomarkers.

Keywords: ribonuclease L, polymorphism, prostate cancer, risk, meta-analysis

INTRODUCTION

Prostate cancer is the most common non-skin cancer and the second leading cause of cancer-related-death of men in the USA, with an estimated 192,000 new cases and 27,000 deaths annually[1]. The underlying etiology of prostate cancer remains poorly understood, with both genetic predisposition and environmental factors likely to play a role. A recent study showed that prostate cancer patients with good and poor survival tend to aggregate in families, providing evidence of heritability in the prognosis of prostate cancer[2]. Despite this strong evidence for a genetic component in prostate cancer, little progress has been made in identifying a major gene or genes[3].

The ribonuclease L (RNASEL) gene locates on chromosome 1q24-25 and is comprised of 741 amino acids. One of the candidate genes within the hereditary prostate cancer gene region is the gene encoding 2′-5′-oligoadenylate-dependent RNASEL (MIM 601518 and 180435)[4]–[7], a constitutively expressed latent endonuclease that is involved in the antiviral and pro-apoptotic activities of the interferon-inducible 2-5A system, cellular viral defense, single-stranded RNA cleavage and tumor suppressor activities as stress could cause apoptosis, cell proliferation and regulation of protein synthesis[8]–[13].

There are different polymorphism sites in the RNASEL gene. Sequence analysis of RNASEL identified two common missense mutations: Arg462Gln (rs486907) and Asp541Glu (rs627928). The Arg462Gln polymorphism reduces the ability of the cell to cause apoptosis in response to activation by 2-5 (A) and the enzymatic activity is also three times less than normal[14], whereas the Asp541Glu variant has no known effects on RNASEL function[15]. Previously, Li et al.[16] performed a meta-analysis of the association of these two polymorphisms of RNASEL and prostate cancer risk, and found that the Asp541Glu polymorphism was associated with an increased risk of prostate cancer in Caucasians. However, they failed to find a significant association between the Arg462Gln polymorphism and prostate cancer risk in Africans. The main reason to explain this conclusion may be that they did not include any case-control studies with the African population.

Hitherto, there have been 15 studies that investigated the Arg462Gln polymorphism[17]–[27],[29], and 13 studies that investigated the Asp541Glu polymorphism and the risk of prostate cancer[17]–[20],[23]–[29]. Taking into consideration the extensive evidence for a role of RNASEL in prostate cancer, we performed a meta-analysis of all eligible case-control studies in order to derive a more precise estimation of the association of the Arg462Gln and Asp541Glu polymorphisms in RNASEL and prostate cancer risk.

MATERIALS AND METHODS

Publication search

We attempted to include all the case-control studies published to date on the association between RNASEL gene polymorphisms and prostate cancer risk. Eligible studies were identified by searching the electronic literature in PubMed for relevant reports (the last search update was 7 May 2010, using the search terms “RNASEL”, “polymorphism” and “prostate cancer”). A total of 64 articles were retrieved, of which 13 articles met the inclusion criteria for studies examining the association between the RNASEL Arg462Gln and/or Asp541Glu polymorphism and prostate cancer risk.

Inclusion and exclusion criteria

The following inclusion criteria were used for literature selection: 1) studies evaluating the RNASEL Arg462Gln and/or Asp541Glu polymorphism and prostate cancer risk; 2) case-control studies; 3) studies that contained information about available genotype frequency that could help evaluate the results in the papers; 4) studies that were published in English; 5) studies with full-text manuscripts. Major exclusion criteria were: 1) studies with no control population; 2) studies with no available data on genotype frequency; 3) studies with a clear bias of accrual.

Data extraction

Data was extracted from each study by two investigators independently according to the prespecified inclusion criteria. Data extracted from these articles included: first author, year of publication, origin, ethnicity, source of cases (population-based and hospital-based), sample size (case/control), frequency of genotype in cases and controls, and Hardy–Weinberg equilibrium of controls. Different ethnic descents were categorized as European, Asian and African.

Statistical analysis

Odds ratios (ORs) with 95% confidence intervals (CIs) were used to measure the strength of the association between the RNASEL Arg462Gln or Asp541Glu polymorphism and prostate cancer risk based on the genotype frequencies in cases and controls. We explored the association between allele Gln of RNASEL Arg462Gln or allele Glu of Asp541Glu and prostate cancer risk, as well as the heterozygote comparison Gln/Arg vs Arg/Arg or Glu/Asp vs Asp/Asp, the homozygote comparison Gln/Gln vs Arg/Arg or Glu/Glu vs Asp/Asp and the risk of (Gln/Gln+Gln/Arg) vs Arg/Arg or (Glu/Glu + Glu/Asp) vs Asp/Asp and Gln/Gln vs (Gln/Arg +Arg/Arg) or Glu/Glu vs (Glu/Asp + Asp/Asp) in dominant and recessive models, respectively. Subgroup analysis was performed by ethnicity and source of cases (population-based and hospital-based) for the Arg462Gln or Asp541Glu polymorphism.

The fixed effects model and the random effects model were used to calculate the pooled OR. Heterogeneity assumption was evaluated with a chi-square-based q test among the studies. A P value of more than 0.05 for the q-test indicated a lack of heterogeneity among the studies. A random effects model (DerSimonian and Laird method[30]) was used when the P value for the heterogeneity test was <0.05; otherwise, a fixed effects model (Mantel-Haenszel method[31]) was used. The departure of frequencies of RNASEL polymorphisms from expectation under Hardy-Weinberg equilibrium was assessed by χ2 test in controls, and P < 0.05 was considered statistically significant. Publication bias was assessed with the Egger test[32], and P < 0.05 was considered statistically significant. All statistical tests for this meta-analysis were performed with the Stata software (Version 10.0, StataCorp LP, USA).

RESULTS

Eligible studies

Overall, 13 articles (28 studies, 13 different first authors) were identified for evaluating the association of the RNASEL Arg462Gln or Asp541Glu polymorphism with risk for prostate cancer. The characteristics of the studies of the Arg462Gln or Asp541Glu polymorphism are summarized in Table 1 and 2 , respectively. According to the inclusion criteria, there were no genotypes of cases and controls in Wang et al.[26], but they were provided in the meta-analysis of Li et al.[16], so we included this case-control study in our meta-analysis. Breyer et al.[33] failed to provide the distribution of alleles. Therefore, there are 15 eligible studies with 7,461 cases and 6,963 controls concerning the Arg462Gln polymorphism and 13 studies with 5,353 cases and 4,321 controls concerning the Asp541Glu polymorphism. For the Arg462Gln polymorphism, there were 10 studies of European population[17],[19],[20],[22]–[24],[26],[27], 4 studies of African population[18],[19],[21],[29] and one study of Asian population[25]. Hospital-based cases were used in 7 studies. For the Asp541Glu polymorphism, there were nine studies of European population[17],[19],[20],[23],[24],[26]–[28], 3 studies of African population[18],[19],[29] and one study of Asian population[25]. Hospital-based cases were used in 8 studies. With the exception of one study[17], the distribution of genotypes in the controls was consistent with the Hardy-Weinberg equilibrium.

Table 1. Charateristics of studies of the RNASEL Arg462Gln polymorphism included in this meta-analysis.

First author Year Origin Ethnicity Source of cases Sample size (case/control) Cases
 Controls
 Pb
QQ QR RR QQ QR RR
Beuten[17] 2010 USA European HB 156/224 17 64 75 7 91 126 0.048
Robbins[18] 2008 USA African HB 243/296 5 55 183 5 66 225 0.950
Shook[19] 2007 USA European HB 430/503 60 183 187 57 225 221 0.981
Shook[19] 2007 USA European HB 150/239 16 62 72 7 96 136 0.093
Shook[19] 2007 USA African HB 68/145 10 13 45 3 31 111 0.633
Cybulski[20] 2006 Canada European PB 737/511 116 376 245 82 252 177 0.625
Daugherty[21] 2007 USA European PB 1,116/1,344 148 505 463 188 602 554 0.235
Daugherty[21] 2007 USA African PB 98/380 2 23 73 5 98 277 0.261
Nam[22] 2005 Canada European PB 996/1,092 110 409 477 112 459 521 0.464
Maiera[23] 2005 Germany European HB 363/207 59 171 133 37 97 73 0.629
Wiklunda[24] 2004 Sweden European PB 1,622/796 247 778 597 115 384 297 0.611
Nakazatoa[25] 2003 Japan Asian PB 101/105 0 32 69 8 26 71 0.085
Wanga[26] 2002 USA European HB 918/493 102 427 389 67 233 193 0.802
Rokmana[27] 2002 USA European PB 233/176 39 106 88 23 84 69 0.745
Shea[29] 2008 USA African PB 230/452 2 41 187 2 88 362 0.168
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a Studies were reported by Li et al; b Hardy-Weinberg equilibrium of controls.

RNASEL: Ribonuclease L; HB: Hospital-based; PB: Population-based; QQ: Gln/Gln; QR: Gln/Arg ; RR: Arg/Arg.

Table 2. Characteristics of studies of the RNASEL Asp541Glu polymorphism included in this meta-analysis.

First author Year Origin Ethnicity Source of cases Sample size (case/control) Cases
 Controls
 Pb
EE ED DD EE ED DD
Beuten[17] 2010 USA European HB 156/227 45 70 41 48 120 59 0.368
Robbins[18] 2008 USA African HB 243/296 38 102 103 24 129 143 0.495
Shook[19] 2007 USA European HB 430/484 140 190 100 139 254 91 0.187
Shook[19] 2007 USA European HB 150/242 43 66 41 48 125 69 0.525
Shook[19] 2007 USA African HB 68/146 9 28 31 15 60 71 0.661
Cybulski[20] 2006 Canada European PB 737/511 254 372 111 168 259 84 0.344
Rokmana[27] 2002 USA European PB 233/176 78 126 29 56 91 29 0.434
Wanga[26] 2002 USA European HB 929/508 181 476 272 107 228 173 0.050
Wiklunda[24] 2004 Sweden European PB 1,563/791 522 768 273 257 372 162 0.199
Maiera[23] 2005 Germany European HB 363/207 125 176 62 69 97 41 0.514
Nakazatoa[25] 2003 Japan Asian PB 101/105 51 32 18 59 43 3 0.138
Noonan-Wheeler a[28] 2006 USA European HB 150/170 55 73 22 44 93 33 0.198
Shea [29] 2008 USA African PB 230/458 26 97 107 40 201 217 0.496
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a Studies were reported by Li et al; b Hardy-Weinberg equilibrium of controls.

RNASEL: ribonuclease L; HB: Hospital-based; PB: Population-based; EE: Glu/Glu; ED: Glu/Asp; DD: Asp/Asp.

The RNASEL Arg462Gln polymorphism

In the overall analysis, no association could be observed between prostate cancer risk and the variant genotype of RNASEL Arg462Gln in different genetic models: in the comparison of the Gln allele vs the Arg allele (random-effects OR = 1.05, 95% CI = 0.97-1.13, Pheterogeneity = 0.028), the heterozygote comparison (Fixed-effects OR = 1.00, 95% CI = 0.96-1.04, Pheterogeneity = 0.997), the homozygote comparison (Random-effects OR = 1.20, 95% CI = 0.96-1.50, Pheterogeneity = 0.001), or the dominant models (fixed-effects OR = 1.01, 95% CI = 0.98-1.04, Pheterogeneity = 0.740), or the recessive models (Random-effects OR = 1.18, 95% CI = 0.96-1.46, Pheterogeneity = 0.001). However, a significant association between the Arg462Gln polymorphism and prostate cancer in African population was found in the stratified analysis by ethnicity, the homozygote comparison (Fixed-effects OR = 2.50, 95% CI = 1.28-4.87, P = 0.231 for heterogeneity; see Table 3 and Fig. 1) and the recessive models (Fixed-effects OR = 2.54, 95% CI = 1.30-4.95, Pheterogeneity = 0.224). In the subgroup analysis of the source of cases, association was found in hospital-based cases: the homozygote comparison (Random-effects OR = 1.74, 95% CI = 1.00-3.03, Pheterogeneity = 0.000) and the recessive models (Random-effects OR = 1.69, 95% CI = 1.01-2.83, Pheterogeneity = 0.000).

Table 3. Stratified analyses of the RNASEL Arg462Gln polymorphism and prostate cancer risk.

Variables na Cases/Controls Q- vs R-allele
 QQ vs RR
 QR vs RR
 QQ vs QR+RR
 QQ+QR vs RR
OR(95%CI) Pb OR(95%CI) Pb OR(95%CI) Pb OR(95%CI) Pb OR(95%CI) Pb
Total 15 7461/6963 1.05(0.97-1.13) 0.028 1.20(0.96-1.50) 0.001 1.00(0.96-1.04) 0.997c 1.18(0.96-1.46) 0.001 1.01(0.98-1.04) 0.740c
Ethnicity
 African 4 639/1273 1.10(0.92-1.32) 0.056c 2.50(1.28-4.87) 0.231 c 0.96(0.80-1.16) 0.959c 2.54(1.30-4.95) 0.224c 1.03(0.86-1.22) 0.433c
 Asian 1 101/105 0.75(0.45-1.25) - 0.06(0.00-1.07) - 1.27(0.69-2.34) - 0.06(0.00-0.99) - 0.97(0.54-1.74) -
 European 10 6721/5585 1.01(0.98-1.05) 0.061c 1.13(0.92-1.38) 0.006 1.00(0.96-1.04) 0.978c 1.11(0.93-1.34) 0.009 1.01(0.98-1.04) 0.594c
Source of cases
 Population-based 8 5133/4856 1.00(0.96-1.04) 0.948c 1.02(0.92-1.12) 0.597c 1.00(0.96-1.04) 0.985c 1.01(0.91-1.13) 0.511c 1.00(0.97-1.04) 0.999c
 Hospital-based 7 2328/2107 1.18(0.97-1.44) 0.001 1.74(1.00-3.03) 0.000 1.00(0.93-1.07) 0.902c 1.69(1.01-2.83) 0.000 1.02(0.96-1.08) 0.134c
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a Number of comparisons; b P value of q-test for heterogeneity test; c Random effects model was used when P for the heterogeneity test was <0.05; otherwise, fixed effects model was used.

RNASEL: ribonuclease L; 95% CI: 95% confidence interval; OR: odds ratio; QQ: Gln/Gln; QR: Gln/Arg; RR: Arg/Arg.

Fig 1. Forest plot of prostate cancer risk associated with the RNASEL Arg462Gln polymorphism (Gln/Gln vs Arg/Arg) stratified by ethnicity.

Fig 1

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The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the weight (inverse of the variance). The diamond represents the summary OR and 95% CI.

Test of heterogeneity of the RNASEL Arg462Gln polymorphism

There was significant heterogeneity for the Gln allele vs the Arg allele (Pheterogeneity = 0.028) in the homozygote comparison (Pheterogeneity =0.001) and the recessive models (Pheterogeneity = 0.001), but not in the heterozygote comparison (Pheterogeneity = 0.997) and the dominant models (Pheterogeneity = 0.740).

The RNASEL Asp541Glu polymorphism

In the overall analysis, the 541Glu allele was associated with increased prostate cancer risk, as compared with the Asp541 allele (Fixed-effects OR = 1.04, 95% CI = 1.01-1.07, Pheterogeneity = 0.164; Table 4 and Fig. 2), as well as in the homozygote comparison (random-effects OR = 1.22, 95% CI = 1.03-1.46, Pheterogeneity = 0.004) and the recessive models (Fixed-effects OR = 1.09, 95% CI = 1.02-1.16, Pheterogeneity = 0.104), but not in the heterozygote comparison (Random-effects OR = 1.03, 95% CI = 0.88-1.21, Pheterogeneity = 0.018) and the dominant models (Random-effects OR = 1.10, 95% CI = 0.96-1.26, Pheterogeneity = 0.016). Specifically, there was a significantly increased risk between prostate cancer and the RNASEL Asp541Glu polymorphism in ethnicity and source of cases, e.g. in the comparison of the Glu allele vs the Asp allele in African population (Fixed-effects OR = 1.13, 95% CI = 1.01-1.26, Pheterogeneity = 0.458), European population (Fixed-effects OR = 1.04, 95% CI = 1.01-1.07, Pheterogeneity = 0.828) and among studies with hospital-based prostate cancer cases (Fixed-effects OR = 1.06, 95% CI = 1.02-1.11, Pheterogeneity = 0.401). The same results were also observed in the homozygote comparison and the recessive models. Furthermore, there was significant association between the Asp541Glu polymorphism and hospital-based prostate cancer in the homozygote comparison and recessive models (data not shown).

Table 4. Stratified analyses of the RNASEL Asp541Glu polymorphism and prostate cancer risk.

Variables na Cases/Controls E- vs D-allele
 EE vs DD
 ED vs DD
 EE vs ED+DD
 EE+ED vs DD
OR(95%CI) Pb OR(95%CI) Pb OR(95%CI) Pb OR(95%CI) Pb OR(95%CI) Pb
Total 13 5353/4321 1.04(1.01-1.07) 0.164c 1.22(1.03-1.46) 0.004 1.03(0.88-1.21) 0.018 1.09(1.02-1.16) 0.104c 1.10(0.96-1.26) 0.016
Ethnicity
 African 3 541/900 1.13(1.01-1.26) 0.458c 1.49(1.11-2.00) 0.433c 1.02(0.90-1.15) 0.897c 1.53(1.13-2.08) 0.457 c 1.06(0.96-1.17) 0.699 c
 Asian 1 101/105 0.60(0.39-0.92) - 0.14(0.04-0.52) - 0.12(0.03-0.46) - 0.80(0.46-1.38) 0.14(0.04-0.48) -
 European 9 4711/3316 1.04(1.01-1.07) 0.828 c 1.07(1.01-1.13) 0.742c 1.03(0.99-1.07) 0.113c 1.07(1.00-1.15) 0.246c 1.03(1.00-1.05) 0.396 c
Source of cases
 Population-based 5 2864/2041 1.02(0.99-1.06) 0.106 c 1.09(0.76-1.54) 0.027c 1.02(0.74-1.41) 0.013 1.04(0.95-1.13) 0.718c 1.05(0.77-1.42) 0.015
 Hospital-based 8 2489/2280 1.06(1.02-1.11) 0.401c 1.11(1.02-1.21) 0.150c 1.02(0.96-1.07) 0.125c 1.16(1.05-1.28) 0.065c 1.03(0.99-1.07) 0.253c
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a Number of comparisons; b P value of q-test for heterogeneity test; c Random effects model was used when P for the heterogeneity test was <0.05; otherwise, fixed effects model was used.

RNASEL: ribonuclease L; 95% CI: 95% confidence interval; OR: odds ratio; E: Glu; D: Asp; EE: Glu/Glu; ED: Glu/Asp; DD: Asp/Asp.

Fig 2. Forest plot of prostate cancer risk associated with the RNASEL Asp541Glu polymorphism (the Glu-allele vs the Asp-allele) stratified by ethnicity.

Fig 2

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The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the weight (inverse of the variance). The diamond represents the summary OR and 95% CI.

Test of heterogeneity of the RNASEL Asp541Glu polymorphism

There was significant heterogeneity in the homozygote comparison (Pheterogeneity = 0.004), the heterozygote comparison (Pheterogeneity = 0.018) and the dominant models (Pheterogeneity = 0.016), but not in the Glu-allele vs the Asp-allele (Pheterogeneity = 0.164) and the recessive models (Pheterogeneity = 0.104).

Sensitivity analysis

Sensitivity analysis was used to determine whether modification of the inclusion criteria of the meta-analysis affected the final results. These were carried out by limiting the meta-analysis to the studies conforming to Hardy-Weinburg equilibrium and altering corresponding statistical variables and analysis models. Moreover, no other single study influenced the summary OR qualitatively as indicated by sensitivity analysis.

Bias diagnosis

The Begg's funnel plot and Egger's test were performed to assess the publication bias of the literature. The shape of the funnel plots did not reveal any evidence of obvious asymmetry in the homozygote comparison of the Arg462Gln and the Glu-allele vs the Asp-allele of Asp541Glu. Then, Egger's test was used to provide statistical evidence of funnel plot symmetry. The results still did not reveal any evidence of publication bias (Gln/Gln vs Arg/Arg, t = 1.91, P = 0.079; the Glu-allele vs the Asp-allele, t = 1.08, P = 0.305. Fig. 3).

Fig 3. Funnel plot analysis for publication bias.

Fig 3

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Each point represents a separate study for the indicated association. A: a funnel plot for allele contrast (Gln/Gln vs Arg/Arg) of the Arg462Gln polymorphism in overall analysis. B: a funnel plot for allele contrast (the Glu-allele vs the Asp-allele) of the Asp541Glu polymorphism in overall analysis.

DISCUSSION

RNASEL encodes the RNASEL protein, a constitutively expressed latent endoribonclease that mediates the IFN-inducible 2–5A system. The protein functions partly as a tumor suppressor, acting to induce apoptosis of cancer cells, is associated with the activity of interferons. Casey et al.[14] and Xiang et al.[15] found that deficiency in the Arg462Gln variant is correlated with a decrease in enzyme dimerization to the active form and a reduction in the ability to cause apoptosis. However, the Asp541Glu variant has no effect on RNASEL function. The rapid growth of RNASEL genetic studies provides numerous opportunities for studiny disease association. The present meta-analysis involved 7,461 cases and 6,963 controls concerning the Arg462Gln polymorphism in the protein kinase region of RNASEL, and 5,353 cases and 4,321 controls concerning the Asp541Glu polymorphism in the ribonuclease domain of RNASEL. We then explored the association between these two potentially functional polymorphisms of RNASEL and prostate cancer risk.

Previously, Li et al.[16] performed a meta-analysis of the association of these two variants in RNASEL and prostate cancer risk, which included 11 case-control studies (each study contains the frequency of genotypes), and suggested that the Asp541Glu polymorphism was associated with an increased risk of prostate cancer in Caucasians. In this article, the authors divided prostate cancer into familial/hereditary prostate cancer and familial/sporadic prostate cancer. In our meta-analysis, novel case-control studies in the last 4 y were included, and the familial/hereditary and familial/sporadic prostate cancer subjects were used together. The only Asian study[29] found decreased familial prostate cancer risk in Japanese with the genotype Gln/Gln. Larger studies involving a wider spectrum of Asian populations are needed for a more definitive evaluation of the relationship between the Arg462Gln polymorphism and prostate cancer risk in Asians.

The true role of the RNASEL Arg462Gln and Asp541Glu polymorphism and their influence on prostate cancer risk are similarly controversial. Genotype frequency of various polymorphic loci may exhibit racial differences. For our purposes, we divided the world's population into three broad racial groups, Asian, African and European[33].

The RNASEL Arg462Gln polymorphism was implicated in up to 13% of prostate cancer cases, with the resultant enzyme 3 times less active than the wildtype enzyme, and an association was found among Europeans and Africans between the RNASEL Arg462Gln polymorphism and sporadic prostate cancer risk[14]. Our results suggested that the RNASEL Arg462Gln polymorphism was associated with prostate cancer risk in the African population rather than in European and Asian population, which confirmed the hypothesis described above. Moreover, our analysis suggested that the Asp541Glu polymorphism was associated with increased prostate cancer risk among Europeans and Africans but not among Asians in all genetic models, although Asp541Glu produced similar levels of RNASEL activity to those of the wildtype enzyme[15]. It may be a reflection of the differences in genetic backgrounds and gene-environment interactions in the etiology. Other factors such as time-lag bias and publication bias may also have played a role. In time-lag bias, studies with ‘negative’ results take longer time to be published, whereas studies with ‘positive’ results are published much more quickly[34]. In publication bias, small studies with ‘negative’ results are never published, whereas equally small studies with similar quality but ‘positive’ results would appear in the literature[35]–[36]. We examined these possibilities and found that ‘positive’ studies were reported more in 462Gln and 541Glu allele carriers' studies (especially in the European and African studies).

In the source of cases, interestingly, we also found evidence for the association between the Arg462Gln polymorphism and prostate cancer risk using hospital-based cases, the same as the Asp541Glu polymorphism.

Some limitations of this meta-analysis should be mentioned. First of all, the number of published studies included in our meta-analysis was not sufficiently large for a comprehensive analysis, particularly for the Asian population. Further studies should be carried out to confirm such an effect in Asians. Second, pub-lication bias might have occurred, and our Egger's test results may have a substantial risk of being affected by such a bias. Third, the interactions between gene–gene, gene-environment and even different polymorphic loci of the same gene may modulate prostate cancer risk. Fourth, in some RNASEL polymorphism studies, a small number of cases and controls were included. Fifth, in some original studies, the authors divided the prostate cancer into two groups: familial/hereditary prostate and familial/sporadic prostate cancer, whereas, in our meta-analysis, we grouped them together, which may have influenced the results. Sixth, our meta-analysis was based on unadjusted estimates. A more precise analysis should be conducted if individual information, including other covariates, such as age, gender and prostate cancer stage, becomes available. In spite of these issues, our meta-analysis also had two advantages. First, substantial numbers of cases and controls were pooled from different studies, which significantly increased the statistical power of the analysis. Second, the quality of case–control studies included in the current meta-analysis was satisfactory based on our selection criteria.

In summary, the present meta-analysis found novel evidence that the RNASEL Arg462Gln polymorphism is associated with increased prostate cancer risk in Africans; moreover, the RNASEL Asp541Glu polymorphism is associated with prostate cancer risk in Europeans and Africans, confirming the results of previous meta-analyses. These two polymorphisms may be low-penetrance susceptibility biomarkers for prostate cancer. Further prospective studies with a larger population of participants worldwide are expected to examine associations between these two polymorphisms in RNASEL and prostate cancer.

Footnotes

☆

This study was supported by the program of key medical department of Jiangsu Province (No. XK17 200904).

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