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ORIGINAL ARTICLE
Year : 2013  |  Volume : 9  |  Issue : 4  |  Page : 660-663

Association between TGM5, PPAP2B and PSMA4 polymorphisms and NSCLC in never-smoking Chinese population


Department of Integration of Traditional Chinese and Western Medicine, Zhejiang cancer hospital, Hangzhou, 310022, China

Date of Web Publication11-Feb-2014

Correspondence Address:
M M Yongjun Zhang
Department of Integration of Traditional Chinese and Western Medicine, Zhejiang Cancer Hospital, 38 Banshan Road, Hangzhou 310022.
China
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Source of Support: University Grants Commission, New Delhi, India, Conflict of Interest: None


DOI: 10.4103/0973-1482.126473

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 > Abstract 

Aim: To explore the potential association between SNPs in transglutaminase 5 (TGM5), phosphatidic acid phosphatase type 2B (PPAP2B) and proteasome subunit, alpha type 4 (PSMA4) and non-small cell lung cancer (NSCLC) susceptibility in Chinese patients who were non-smokers.
Setting and Design: A case-controlled study was conducted among Chinese population.
Materials and Methods: Two hundred NSCLC patients and 200 healthy controls who were age and sex matched were genotyped for rs504417 of TGM5, rs1261411 of PPAP2B and rs7164594 of PSMA4. Genotyping was performed using the Sequenom MassARRAY system based on the chip-based matrix-assisted laser desorption ionization time-of-flight mass spectrometry platform.
Statistical Analysis Used: The association between genotype and lung cancer risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) from multivariate unconditional logistic regression analyses.
Results: There was no significant difference for the TGM5 rs504417, PPAP2B rs1261411 and PSMA4 rs716459 in allele or genotype frequencies, whether between controls and NSCLC or between controls and subgroups.
Conclusions: polymorphisms of TGM5, PPAP2B and PSMA4 are not major contributors to NSCLC susceptibility, this primarily be attributed to the significantly distinct genetic background of Asian populations from western populations.

Keywords: Chinese, genetic polymorphism, non-small cell lung cancer


How to cite this article:
Yongjun Zhang M M, Zhang A, Hua Shi M M, Xiangming Kong M M. Association between TGM5, PPAP2B and PSMA4 polymorphisms and NSCLC in never-smoking Chinese population. J Can Res Ther 2013;9:660-3

How to cite this URL:
Yongjun Zhang M M, Zhang A, Hua Shi M M, Xiangming Kong M M. Association between TGM5, PPAP2B and PSMA4 polymorphisms and NSCLC in never-smoking Chinese population. J Can Res Ther [serial online] 2013 [cited 2019 Nov 14];9:660-3. Available from: http://www.cancerjournal.net/text.asp?2013/9/4/660/126473


 > Introduction Top


The lung and bronchus cancer was the most common fatal cancer in man and woman in US. [1] The single most important factor influencing the risk of lung cancer is smoking. Although, smoking is the primary cause of lung cancer, only about 15% of lifelong smokers develop the disease. [2],[3] Furthermore, studies on lung cancer risk in family members of lung cancer probands have shown that genetic factors contribute to the risk of developing the disease. [4],[5],[6] Recently, three Genome-wide association studies reported that variants on TGM5 rs504417 (OR=0.88; P=0.0043), [7] PPAP2B rs1261411 (OR=1.65; P=0.0114) and PSMA4 rs7164594 (OR=0.73; P=0.004) were significant association with lung cancer risk among Icelanders, Italian and African-Americans, respectively. [8],[9] But, Amos CI et al found that the polymorphisms of rs7164594 at PSMA4 were not associated with lung cancer developing in African-American (OR=0.76; P=0.02387>0.00147 (the Bonferroni-adjusted level)). [10] Based on these findings, genetic susceptibility is one possible factor influencing this disparity. [11] So, the question was raised whether the impact of these polymorphisms on susceptibility to lung cancer was existed in a Chinese population. Up to date, it remains unknown. In order to investigate this further, we conducted this case-control study to examine polymorphisms of TGM5 rs504417, PPAP2B rs1261411 and PSMA4 rs7164594 with risks for NSCLC and further stratified based on two major histological subtypes of NSCLC (ADC and SQC) in a never-smoking Chinese.


 > Materials and Methods Top


Patients and Controls

Two hundred patients with NSCLC were matched with 200 unrelated healthy controls who had never smoked. The patients was consecutively selected and enrolled from 2011-05-01 to 2011-11-28. The study protocol was approved by the Ethical Review Committee. Informed consent was provided by all cases and controls.

DNA preparation and genotyping

Four hundred subjects (145 ADC and 55 SQC, 200 healthy controls) were genotyped for polymorphisms of rs504417, rs7164594 and rs1261411 at TGM5, PSMA4 and PPAP2B, respectively. DNA was isolated from 1ml whole blood using the AxyPrep Blood Genomic DNA Miniprep kit (Axygen Biosciences, Union City, CA, USA). Genotyping of each participant was finished by MassARRAY compact analyzer based on the chip-based matrix-assisted laser desorption ionization time-of-flight mass spectrometry platform (Sequenom, San Diego, CA, USA). Multiplex reaction was designed using Assay Designer software version 3.0 (Sequenom) and was processed following standard protocols for iPLEX chemistry. Primers were synthesized by Sangon Biotech (Shanghai, China) [Table 1].
Table 1: Oligonucleotide sequence used for genotyping

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Statistical analysis

Calculations of allele frequency and genotype frequency, tests of Hardy- Weinberg equilibrium (HWE) were performed using Microsoft Excel macro PHARE version 2.1. Comparing of the allele and 3 genotypes in cases versus controls was carried out using Pearson's chi-squared tests. OR and 95% CI were obtained with Plink software. P value of less than 0.05 was considered statistically significant. Statistical powers were calculated using software of Power for Association with Error (PAWE version 1.2, Chad Haynes Laboratory of Statistical Genetics, The Rockefeller University)


 > Results Top


A total of 400 subjects (200 patients with 145 ADCs and 55 SQCs and 200 controls) were successfully genotyped for polymorphisms of rs504417, rs7164594 and rs1261411. The sizes of samples included in the present study had 20% power (at the 5% level). We examined Hardy-Weinberg equilibrium in the controls and cases, and no evidence of deviation from Hardy-Weinberg equilibrium in each gene was found [Table 2]. There was no significant difference for the 3 markers in allele or genotype frequencies whether between controls and cases or between controls and subgroups (ADC and SQC) [Table 3].
Table 2: HWE Pearson's P in cases and controls

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Table 3: Allele and Genotypes distribution and controls and their association with risk of lung cancer in never-smoking Chinese

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 > Discussion Top


We undertook the present study to investigate the association between NSCLC and the polymorphisms of TGM5, PSMA4 and PPAP2B in never-smoking Chinese. Our findings show that none of TGM5, PSMA4 and PPAP2B variant contributed to the susceptibility of NSCLC in Chinese population.

Transglutaminases is Ca 2+ -dependent enzymes, which catalyze intermolecular isopeptide bonds by transamidation of specific glutamine residues. [12],[13] Transglutaminases 5 (TGM5) was identified member of the TGM family in 1998, and was expressed in keratinocyte differentiation, and cross-links specific substrates. [14],[15],[16] In addition, TGM5 is associated with cytoskeletal elements, colocalizing with the vimentin network [17] and required for structural integrity of the outermost epidermal layers. [18] TGM5 can induce cell death in over- expression, and seems to retain the residues involved in GTP regulation. [19] While the polymorphism of rs504417 in TGM5 was shown to be strongly associated with NSCLC patients in Icelanders with a P value of 0.0043, this association was not observed in our study. Much work should, therefore be launched in the future, in particular, further investigation in large samples is expected on the contribution of TGM5 to susceptibility risk of NSCLC.

Recently genome-wide association studies of lung cancer have shown common variation at 15q24-25.1 as a determinant of risk. [20],[21],[22] PSMA4 was located at the 15q24-25.1 locus and encodes a structural protein of the 20S proteasome core [23],[24] and was required for proteasomal activities. [25] The proteasome is the central proteolytic system that also plays an important role in the major histocompatibility complex-class I antigen processing. [26] PSMA4 is a component of the Adenosine Triphosphate- and ubiquitin-dependent nonlysosomal pathway, and it is involved in the processing of class I major histocompatibility complex peptides. [20] PSMA4 has a role in modulating human lung cancer cell proliferation. Expression of PSMA4 was increased in lung tumors compared with matched normal lung tissues. [25] But, there was not association between polymorphism of PSMA4 and NSCLC in our study. We believe this primarily be attributed to the significantly distinct genetic background of Asian populations from western populations.

Phosphatidic acid phosphatases type-2 (PPAP2) are a group of integral membrane enzymes that participate in intracellular lipid metabolism and which also regulate the biological activity and signaling of several bioactive phospholipids such as phosphatidic acid, diacylglycerol, lysophosphatidic acid, sphingosine-1-phosphate, ceramide-1-phosphate, and ceramide. [27],[28] PPAP2B was one of three members of PAP2 family, human PPAP2B contains an exposed arginine- glycine-aspartate (RGD) cell adhesion sequence, and which expression increases cell/cell interactions through αvβ3 and anti-α5β1 integrins. [29] PPAP2B plays a fundamental role during early spinal neuroepithelium development and that it could also be instrumental in regulating neurite and axon outgrowth in vivo dephosphorylated. [30] PPAP2B-inducedβ-catenin/ LEF-1 signaling plays a critical role in EC migration, cell-cell adhesion, and formation of branching point structures. [31] Furthermore, PPAP2B can potentiate tumor growth by amplifying β-catenin and Cyclin-D1 activities. [32] However, we did not find an association between PPAP2B polymorphisms and NSCLC in never-smoking Chinese population. Further biological analysis of PPAP2B in cancer cells should be done to identify the functional association with lung cancer.

To conclude, the study showed no relationship between polymorphisms of the three SNPs (TGM5 rs504417, PPAP2B rs1261411 and PSMA4 rs7164594) and NSCLC in Chinese populations. However, the number of cases was small in this study, and more research is required to test our results.


 > Acknowledgements Top


We appreciated Zhijun Li for his kind help in the control of the screening process. We also thank Hailong Liu for his excellent technical support.

 
 > References Top

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  [Table 1], [Table 2], [Table 3]



 

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