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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 12  |  Page : 1105-1109

Association of hypoxia-inducible factor-1 alpha gene polymorphism with renal cell carcinoma susceptibility


Department of Clinical Laboratory, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, P. R. China

Date of Web Publication11-Dec-2018

Correspondence Address:
Hao Huang
Department of Clinical Laboratory, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021
P. R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.199456

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 > Abstract 


Aim of Study: Association between hypoxia-inducible factor-1 alpha (HIF-1α) gene polymorphism and renal cell carcinoma (RCC) susceptibility is still being conflicting. This meta-analysis was performed to assess the relationship between HIF-1α C1772T (rs11549465)/G1790A (rs11549467) gene polymorphism and RCC risk.
Materials and Methods: Association studies were identified from the databases of PubMed and CBM-disc (China Biological Medicine Database) as of July 1, 2015, and eligible investigations were included and synthesized using meta-analysis method.
Results: Five investigations were identified, and the meta-analysis was conducted to assess the association between HIF-1α gene polymorphism and RCC risk. There was a marked association between HIF-1α C1772T TT genotype and RCC susceptibility, and the association between HIF-1α C1772T T allele/CC genotype and RCC risk was not found in overall populations (T: odds ratios [OR] =1.04, 95% confidence interval [CI]: 0.70–1.54, P = 0.84; TT: OR = 0.13, 95% CI: 1.60–2.34, P = 0.01; CC: OR = 1.18, 95% CI: 0.68–2.07, P = 0.55). Furthermore, a marked association between HIF-1α G1790A AA genotype and RCC susceptibility was found, and the association between HIF-1α G1790A A allele/GG genotype and RCC risk was not found in overall populations (A: OR = 1.53, 95% CI: 0.60–3.92, P = 0.38; AA: OR = 3.09, 95% CI: 1.38–6.92, P = 0.006; GG: OR = 0.63, 95% CI: 0.20–2.03, P = 0.44).
Conclusion: HIF-1α C1772T TT genotype and HIF-1α G1790A AA genotype were associated with RCC susceptibility. However, more investigations are required to further clarify the association.

Keywords: C1772T, G1790A, gene polymorphism, hypoxia-inducible factor-1 alpha, meta-analysis, renal cell carcinoma


How to cite this article:
Huang L, Li Mq, Ou C, Huang Wc, Liu Jf, Huang H. Association of hypoxia-inducible factor-1 alpha gene polymorphism with renal cell carcinoma susceptibility. J Can Res Ther 2018;14, Suppl S5:1105-9

How to cite this URL:
Huang L, Li Mq, Ou C, Huang Wc, Liu Jf, Huang H. Association of hypoxia-inducible factor-1 alpha gene polymorphism with renal cell carcinoma susceptibility. J Can Res Ther [serial online] 2018 [cited 2019 Sep 20];14:1105-9. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/1105/199456




 > Introduction Top


Renal cell carcinoma (RCC) is diagnosed in >200,000 individuals worldwide each year, accounting for ~2% of all cancers.[1] Classic manifestations of RCC include the triad of flank pain, hematuria, and a palpable renal mass. Patients with RCC can develop various extrarenal manifestations including involvements of the lungs, inferior vena cava, liver, and the bones.[2] Molecular markers might improve risk stratification of RCC. Some present reports have found that the gene polymorphism was associated with the RCC susceptibility. Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that triggers adaptive responses on low oxygen conditions and plays a crucial role in cancer metabolism and therapy resistance.[3] The HIF-1α C1772T/G1790A gene polymorphism might be implicated in the etiology of RCC. However, the available evidence is weak at present, due to the sparseness of data or disagreements among the reported investigations. We performed this meta-analysis to investigate whether the HIF-1α C1772T/G1790A gene polymorphism was associated with the onset of RCC.


 > Materials and Methods Top


Search strategy for the association of hypoxia-inducible factor-1 alpha gene polymorphism with renal cell carcinoma

The relevant studies were searched from the electronic databases of PubMed and CBM-disc (China Biological Medicine Database) as of July 1, 2015. The retrieval strategy of “(hypoxia-inducible factor) AND (renal cell carcinoma) AND polymorphism” was entered into these databases mentioned above for search.

Inclusion criteria

  1. The outcome had to be RCC
  2. There had to be at least two comparison groups (RCC group vs. control group)
  3. The investigation should provide the detailed data of HIF-1α genotype distribution.


Exclusion criteria

  1. Review articles and editorials
  2. Case reports
  3. Preliminary result not on HIF-1α gene polymorphism or RCC
  4. Investigating the role HIF-1α expression to RCC.


Data extraction and synthesis

Two investigators independently extracted the following information from each eligible study: first author's surname, year of publication and the number of cases and controls for HIF-1α genotypes. The frequency of T allele/A allele was calculated for RCC group and control group, from the corresponding genotype distribution. The results were compared, and disagreement was resolved by discussion.

Statistical analysis

Cochrane Review Manager Version 5 (Cochrane Library, UK) was used to calculate the available data from each investigation. The pooled statistic was counted using the fixed effects model, but a random effects model was conducted when the P value of heterogeneity test was <0.1. The results were expressed with odds ratios (OR) for dichotomous data, and 95% confidence intervals (CIs) were also calculated. P <0.05 was required for the pooled OR to be statistically significant. I2 was used to test the heterogeneity among the included studies. Sensitivity analysis was also performed by sample size of case or control (<100 vs. ≥100).


 > Results Top


Study characteristics for this meta-analysis

Five studies[4],[5],[6],[7],[8] were recruited into our investigation to study the relationship between HIF-1α gene polymorphism and RCC susceptibility. Five studies[4],[5],[6],[7],[8] reported the relationship between HIF-1α C1772T gene polymorphism and RCC susceptibility, and four studies[4],[5],[6],[7] reported the relationship between HIF-1α C1772T gene polymorphism and RCC susceptibility. The data of our interest were extracted: first author's surname, year of publication, and the number of cases and controls for ACE genotype [Table 1].
Table 1: Characteristics of the studies evaluating the effects of hypoxia-inducible factor-1 alpha genes on renal cell carcinoma risk

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Association of hypoxia-inducible factor-1α C1772T gene polymorphism with renal cell carcinoma risk

In this meta-analysis, a marked association between TT genotype and RCC susceptibility was found, and the association between T allele/CC genotype and RCC risk was not found in overall populations (T: OR = 1.04, 95% CI: 0.70–1.54, P = 0.84; TT: OR = 0.13, 95% CI: 1.60–2.34, P = 0.01; CC: OR = 1.18, 95% CI: 0.68–2.07, P = 0.55) [Figure 1] and [Table 2]. However, HIF-1α C1772T gene polymorphism was not associated with RCC susceptibility in Asians and in Caucasians [Table 2].
Figure 1: Association between hypoxia-inducible factor-1 alpha C1772T gene polymorphism and renal cell carcinoma risk

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Table 2: Meta-analysis of the association of hypoxia-inducible factor-1 alpha gene polymorphism with renal cell carcinoma risk

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Sensitivity analysis for the relationship between HIF-1α C1772T gene polymorphism and RCC risk was also performed according to sample size of the case (<100 vs. ≥100). In the meta-analysis of sample size of case ≥100, we found that TT genotype was associated with RCC susceptibility, and the association between T allele/CC genotype and RCC risk was not found. The results were similar to those from nonsensitivity analysis [Table 2]. Furthermore, in the meta-analysis of sample size of case <100, HIF-1α C1772T gene polymorphism was not associated with RCC susceptibility [Table 2].

Association of hypoxia-inducible factor-1α G1790A gene polymorphism with renal cell carcinoma risk

In this meta-analysis, a marked association between AA genotype and RCC susceptibility was found, and the association between A allele/GG genotype and RCC risk was not found in overall populations (A: OR = 1.53, 95% CI: 0.60–3.92, P = 0.38; AA: OR = 3.09, 95% CI: 1.38–6.92, P = 0.006; GG: OR = 0.63, 95% CI: 0.20–2.03, P = 0.44) [Figure 2] and [Table 2]. Furthermore, AA genotype was associated with RCC susceptibility, and the association between A allele/GG genotype and RCC risk was not found in Caucasians [Table 2]. However, HIF-1α G1790A gene polymorphism was not associated with RCC susceptibility in Asians [Table 2].
Figure 2: Association between hypoxia-inducible factor-1 alpha G1790A gene polymorphism and renal cell carcinoma risk

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Sensitivity analysis for the relationship between HIF-1α G1790A gene polymorphism and RCC risk was also performed according to sample size of the case (<100 vs. ≥100). In the meta-analysis of sample size of case ≥100, we found that AA genotype was associated with RCC susceptibility, and the association between A allele/GG genotype and RCC risk was not found. The results were similar to those from nonsensitivity analysis [Table 2]. Furthermore, in the meta-analysis of sample size of case <100, HIF-1α G1790A gene polymorphism was not associated with RCC susceptibility [Table 2].


 > Discussion Top


In this study, the association of HIF-1α C1772T/G1790A gene polymorphism with RCC susceptibility was studied, and five studies were included into this meta-analysis. The results from meta-analysis might be more convincing than those from separate studies. In our meta-analysis, there was a marked association between HIF-1α C1772T TT genotype and RCC susceptibility, and the association between HIF-1α C1772T T allele/CC genotype and RCC risk was not found in overall populations. The conclusion mentioned above indicated that HIF-1α C1772T TT genotype and HIF-1α G1790A AA genotype were associated with RCC susceptibility. In the subgroup, according to the population source, HIF-1α C1772T gene polymorphism was not associated with RCC susceptibility in Asians and in Caucasians. The results for this might be that the number in the Asians and Caucasians was small. In the sensitivity analysis, according to sample size of case ≥100, we found that HIF-1α C1772T TT was associated with RCC susceptibility. To sum up, those mentioned above, HIF-1α C1772T TT might be associated with RCC susceptibility. However, more studies should be performed to confirm it.

Furthermore, a marked association between HIF-1α G1790A AA genotype and RCC susceptibility was found, and the association between HIF-1α G1790A A allele/GG genotype and RCC risk was not found in overall populations. In the subgroup, according to the population source, the results for HIF-1α G1790A gene polymorphism with RCC susceptibility in Caucasians were similar to those in overall populations. However, the results for Asians indicated that HIF-1α G1790A gene polymorphism was not associated with RCC susceptibility. There was only one report in the Asian population, and the results were less robust. In the sensitivity analysis, according to sample size of case ≥100, we found that HIF-1α G1790A AA genotype was associated with RCC susceptibility. To sum up, those mentioned above, HIF-1α G1790A AA might be associated with RCC susceptibility. However, more studies should be performed to confirm it.

In the previous, Hu et al.[9] performed a meta-analysis and indicated that C1772T gene polymorphism was not associated with RCC risk. Zhou et al.[10] conducted a meta-analysis and reported that AA genotype of G1790A was associated with RCC risk. In our meta-analysis, we included more studies than the previous meta-analysis and our meta-analysis also performed the sensitivity analysis. Our study reported that HIF-1α C1772T TT genotype and HIF-1α G1790A AA genotype might be associated with RCC susceptibility. The results from our meta-analysis might be more robust than that from the previous meta-analysis.

In our meta-analysis, we drew the conclusion that HIF-1α C1772T TT genotype and HIF-1α G1790A AA genotype were associated with RCC risk, combination the results in nonsensitivity analysis. However, these findings should be regarded cautiously because many other ingredients, such as limited statistical power, heterogeneity of enrolled cases, variable study designs, and different interventions, were closely related to affect the results. To explore whether there exists the exact association between HIF-1α C1772T/HIF-1α G1790A gene polymorphism and RCC risk, further study is required.


 > Conclusion Top


We conducted the first meta-analysis to assess relationship between HIF-1α C1772T/HIF-1α G1790A gene polymorphism and RCC susceptibility. Our study indicated that HIF-1α C1772T TT genotype and HIF-1α G1790A AA genotype were associated with RCC risk. However, more case–control association investigations on larger, stratified populations are required to further clarify the role of HIF-1α C1772T and HIF-1α G1790A gene polymorphism in RCC susceptibility.

Financial support and sponsorship

This work was supported by grant from Guangxi science and technology development plan project funding (2015ED3202).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Ricketts CJ, Linehan WM. Gender Specific Mutation Incidence and Survival Associations in Clear Cell Renal Cell Carcinoma (CCRCC). PLoS One 2015;10:e0140257.  Back to cited text no. 1
    
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Kim KK, Abelman S, Yano N, Ribeiro JR, Singh RK, Tipping M, et al. Tetrathiomolybdate inhibits mitochondrial complex IV and mediates degradation of hypoxia-inducible factor-1 alpha in cancer cells. Sci Rep 2015;5:14296.  Back to cited text no. 3
    
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Clifford SC, Astuti D, Hooper L, Maxwell PH, Ratcliffe PJ, Maher ER. The pVHL-associated SCF ubiquitin ligase complex: Molecular genetic analysis of elongin B and C, Rb×1 and HIF-1 alpha in renal cell carcinoma. Oncogene 2001;20:5067-74.  Back to cited text no. 4
    
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Ollerenshaw M, Page T, Hammonds J, Demaine A. Polymorphisms in the hypoxia inducible factor-1 alpha gene (HIF1A) are associated with the renal cell carcinoma phenotype. Cancer Genet Cytogenet 2004;153:122-6.  Back to cited text no. 5
    
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Morris MR, Hughes DJ, Tian YM, Ricketts CJ, Lau KW, Gentle D, et al. Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma. Anticancer Res 2009;29:4337-43.  Back to cited text no. 6
    
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Qin C, Cao Q, Ju X, Wang M, Meng X, Zhu J, et al. The polymorphisms in the VHL and HIF1A genes are associated with the prognosis but not the development of renal cell carcinoma. Ann Oncol 2012;23:981-9.  Back to cited text no. 7
    
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Lessi F, Mazzanti CM, Tomei S, Di Cristofano C, Minervini A, Menicagli M, et al. VHL and HIF-1 alpha: Gene variations and prognosis in early-stage clear cell renal cell carcinoma. Med Oncol 2014;31:840.  Back to cited text no. 8
    
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Hu X, Fang Y, Zheng J, He Y, Zan X, Lin S, et al. The association between HIF-1 alpha polymorphism and cancer risk: A systematic review and meta-analysis. Tumour Biol 2014;35:903-16.  Back to cited text no. 9
    
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Zhou Y, Lin L, Wang Y, Jin X, Zhao X, Liu D, et al. The association between hypoxia-inducible factor-1 alpha gene G1790A polymorphism and cancer risk: A meta-analysis of 28 case-control studies. Cancer Cell Int 2014;14:37.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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