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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 2  |  Page : 581-586

Association of microRNA polymorphisms with gastric cancer risk in the North Chinese Han population


1 Central Laboratory, Institute of Medical Science, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
2 The Prenatal Diagnosis Center, Jinan Maternity and Child Care Hospital, Jinan, Shandong, China
3 Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
4 Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
5 Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
6 Department of Medical Genetics, Key Laboratory for Experimental Teratology of the Ministry of Education, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China

Date of Submission13-Jan-2021
Date of Acceptance09-Jul-2021
Date of Web Publication14-Jan-2022

Correspondence Address:
Cuihua Yi
Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Wenhua Xi Road 107, Jinan 250012, Shandong Province
China
Jisheng Li
Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Wenhua Xi Road 107, Jinan, 250012, Shandong Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_74_21

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 > Abstract 


Background and Aims: MicroRNA (miRNA) was found as a class of endogenous, important regulators of gene expression and involved in the regulation of many biological processes such as cell proliferation, apoptosis, and differentiation. Increasing studies have suggested that miR-146a, miR-196a2, and miR-499 play important roles in the development processes of gastric cancer (GC). The aim of our study is to investigate whether three common miRNA polymorphisms are associated with the susceptibility of GC.
Materials and Methods: MiR-146a rs2910164 (G > C), miR-196a2 rs11614913 (C > T), and miR-499 rs3746444 (A > G) were genotyped by Taq-man assays in the present case–control study (386 patients, 341 controls). The associations between the selected miRNA single-nucleotide polymorphisms (SNPs) and the risk of GC were estimated by odds ratio (OR) with 95% confidence interval using logistic regression analysis.
Results: Our results showed that none of the three SNPs was associated with the risk of GC in allelic frequencies and multiple genetic models. Further stratified analysis with regard to clinical-pathological parameters of GC patients indicated that miR-146a rs2910164 SNP was strongly associated with age (OR = 0.53, P = 0.001) and gender (OR = 0.61, P = 0.006).
Conclusions: The present study showed no association of the investigated miRNA SNPs with the risk of GC in the north Chinese population.

Keywords: Association study, gastric cancer, MicroRNA, polymorphism


How to cite this article:
Xin Q, Shan S, Ding E, Jin M, Li B, Li J, Liu Q, Yi C, Li J. Association of microRNA polymorphisms with gastric cancer risk in the North Chinese Han population. J Can Res Ther 2022;18:581-6

How to cite this URL:
Xin Q, Shan S, Ding E, Jin M, Li B, Li J, Liu Q, Yi C, Li J. Association of microRNA polymorphisms with gastric cancer risk in the North Chinese Han population. J Can Res Ther [serial online] 2022 [cited 2022 Jul 7];18:581-6. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/581/335484




 > Introduction Top


Gastric cancer (GC) is the fourth-most common malignant tumor worldwide, seriously endangering people's health.[1] The mortality rate of gastric cancer ranks second or third in all human cancers. Gastric cancer (GC) has turned out to be a complex and multifactorial disorder in which genetic and environmental factors are all contributors to disease onset. Previously, numerous studies have been conducted to elucidate the etiology mechanism of GC pathogenesis. Evidence have been identified GC is a result of many risk factors, including Helicobacter pylori infection, high-salt diet, smoking as well as heavy drinking. A majority of studies demonstrate that there is the obvious genetic predisposition of GC. Basic research in GC etiology found abnormal gene regulation and polymorphism play an important role in the pathogenesis of GC.

MicroRNAs (miRNAs) are a class of 18–24 nucleotides length, single-stranded noncoding RNAs, which could regulate target gene expression at the post-transcriptional level by binding its mRNA 3'-UTR region and lead to target mRNA decrease and degradation. It has been widely reported that miRNAs could participate in diversity biological processes, including cell apoptosis, proliferation, differentiation, inflammation reaction, and immune response.[2],[3] The role of miRNA in tumorigenesis has drawn researchers' high attention because more and more evidence suggest that miRNA abnormal expression and dysfunction may involve in tumorigenesis, progression, and cancer development.[4]

It is increasingly recognized that miRNAs might be involved in the pathogenesis of GC. Previous numerous case-control studies and meta-analysis have been performed to clarify whether miR-146a rs2910164, miR-196a2 rs11614913, and miR-499 rs3746444 single-nucleotide polymorphisms (SNPs) are relevant to the genetic susceptibility of GC.[5],[6],[7],[8],[9],[10],[11] There are studies that have verified that miR-146a rs2910164 and miR-196a2 rs11614913 polymorphisms are associated with GC susceptibility.[6],[12],[13],[14] Hou et al. have shown that deregulated miR-146a was related to increased tumor size and poor cell differentiation in GC tissues.[15],[16],[17],[18],[19],[20],[21] The other SNP investigated in this study is rs3746444 in miR-499, and rs3746444C was associated with a significantly increased risk for GC development in the Chinese population.[17] These data suggested potential values of miR-146a rs2910164, miR-196a2 rs11614913 and miR-499 rs3746444 in the diagnose and therapy of GC. However, a meta-analysis from Zhang et al. demonstrated that neither rs2910164 nor rs11614913 was associated with the susceptibility of human GC.[18] As for rs3746444, no association was observed between this polymorphism and GC in the Chinese or Romanian population.[9],[19] Since studies' conclusions are inconsistent and controversial even though the subjects of these researches are in the same ethnical background. We conducted this case-control study to investigate whether SNP sites of miR-146a, miR-196a2, and miR-499 SNPs are relevant to the genetic susceptibility of GC in the North Chinese Han cohort we collected.


 > Materials And Methods Top


Study population

We recruited 727 genetically unrelated subjects in this case–control study, including 386 GC patients from Qilu hospital and 341 age- and gender-matched healthy controls without evidence of malignancy or autoimmune disease. The diagnosis of all GC patients was histologically confirmed. The patients were followed up until August 2015 or death. The patients and controls were born and have been living in Shandong, an eastern coastal province of North China. The ethnic background of all subjects we enrolled are from Han population. The inclusion criteria for the GC group entailed those were histologically diagnosed as GC by postoperative pathological diagnosis. Patients who had a history of tumors, chronic diseases, severe metabolic diseases, or endocrine disorders were excluded in our study. Anticoagulation peripheral blood samples were taken with informed consent of patients and controls and the study was approved by the Ethics Committee of Qilu Hospital of Shandong University.

DNA extraction and single nucleotide polymorphism genotyping

Two milliliters of peripheral blood from subjects were drawn in Vacutainer tubes containing ethylenediaminetetraacetic acid (EDTA) anticoagulant tubes and stored at 2°C–8°C. Genomic DNA from fresh whole blood collected in EDTA were extracted using Wizard genomic DNA purification kit (Promega) according to the manufacturer's protocol. The concentration and purity of isolated genomic DNA were measured using the NanoDrop 2000 spectrophotometer (Thermo Scientific) and stored in −80°C. The genotyping experiment of rs2910164 (G > C), rs11614913 (C > T), rs3746444 (A > G) were carried out using the Taq-man genotyping assays on the LightCycler® 480 instrument (Roche). SNP genotyping probes for rs2910164 (Catalog number: 4351379), rs11614913 (Catalog number: 4351379), and rs3746444 (Catalog number: 4351379) were purchased from Thermo Fisher Scientific company. The polymerase chain reaction (PCR) reaction mixture (10 μL) contained the following: 5 mL 2 × Cycleave PCR Reaction Mix (Takara), 5–10 ng DNA sample, 0.2 μM Taqman probe (Invitrogen) and add distilled water to 10 μL. Real-time fluorescence quantitative PCR was performed with the following conditions: An initial denaturation at 95°C for 10~30 sec, followed by 45 cycles of denaturation at 95°C for 5 s, annealing at 60°C for 10 s, extension at 72°C for 10–15 s. All assays were carried out in 384-well arrays. Genotyping accuracy was verified by randomly selected samples. The data of genotype results were analyzed using the LightCycler®480 Gene Scanning software.

Statistical analysis

Main analyses were undertaken using the Statistical Package for the Social Sciences (SPSS) 16.0 statistical software (IBM Corp., Armonk, NY, USA). We first assessed Hardy–Weinberg equilibrium (HWE) of controls using the Chi-Square Goodness-of-Fit Test. Genotype frequencies were calculated by direct counting. Chi-square test was used to determine significance in the distribution of genotypes in cancer present or absent subjects. The odds ratio (OR) and 95% confidence interval (95% CI) values were calculated by logistic regression analysis. Confounding parameters such as “gender, smoking, drinking, and age” were adjusted in regression analysis. The Bonferroni-corrected threshold for multiple testing is used. The P value (P) lower than 0.05 (P < 0.05) was considered statistically significant.


 > Results Top


General characteristics of subjects

We enrolled about 727 individuals (386 GC patients and 341 healthy controls) in this case–control study. The demographic distributions of selected characteristics are demonstrated in [Table 1]. Statistical analysis indicates that no significant differences were observed in terms of gender and age distributions between cases and controls, suggesting that frequency matching on these two parameters was adequate (P > 0.05).
Table 1: Characteristics of cases and controls

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Genotypic distributions of rs2910164, rs11614913 and rs3746444 in case and control group from different genetic models

In the present study, we selected and genotyped three promising SNPs–miR-146a rs2910164, miR-196a2 rs11614913, and miR-499 rs3746444. The minor allele frequencies of all selected SNPs were more than 5% in the HapMap Chinese Han population. All the investigated SNPs genotype distributions of control group were consistent with HWE (P = 0.57 for rs2910164; P = 0.18 for rs11614913; P = 0.53 for rs3746444).

The locations of the identified SNPs are presented in [Table 2]. Participants were genotyped to explore the possible relation between rs2910164 in miR146a, rs11614913 in miR196a2, and GC susceptibility in this study. We analyzed the allele frequencies and genotypic distributions in codominant, dominant, recessive as well as overdominant models for these polymorphisms in GC between GC patients and healthy controls. We observed that no correlations between GC cases and healthy controls for miR-146a rs2910164, miR-196a2 rs11614913, and miR-499 rs3746444 SNPs (OR = 1.02, P = 0.87 for rs2910164; OR = 1.08, P = 0.46 for rs11614913; OR = 1.16, P = 0.32 for rs3746444). Furthermore, none of the three SNPs was associated with the risk of GC in any genetic model [Table 2].
Table 2: Basic information of genotyped single nucleotide polymorphisms and comparisons of gene polymorphisms between gastric cancer patients and healthy control

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Association between single-nucleotide polymorphisms in miRNAs and clinical parameters

To further evaluate whether these SNPs might influence the risk of GC, we further performed stratified analyses according to clinicopathologic parameters, including age, gender, Lauren classification, lymph node metastasis, clinical stage, and tumor size. The comparison results are summarized in [Table 3], [Supplementary Table 1], and [Supplementary Table 2], respectively. We found that miR-146a rs2910164G showed significant associations with age (OR = 0.53, P = 0.001). In addition, the frequencies of CG + GG genotypes of rs2910164 were apparently lower in the group aged 51–60 years than that under aged 50 years (OR = 0.51, P = 0.02). The gender-stratified analysis results indicated a lower prevalence of rs2910164G in the female GC group compared with that in the male GC group (OR = 0.61, P = 0.006) [Table 3]. There were not any significant differences between the rs2910164 and the remaining parameters in GC patients. Regarding rs11614913 and rs3746444 polymorphisms, no associations were found between the allele and genotype frequencies and clinical parameters in the stratified analyses.
Table 3: Stratified analysis for the association between rs2910164 and gastric cancer clinical characteristics

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 > Discussion Top


In this study, we performed a genetic case-control association study with 727 subjects (386 cases and 341 controls) to identify susceptibility loci of miR-146a rs2910164, miR-196a2 rs11614913, and miR-499 rs3746444 for GC. Our data suggested that no significant frequency difference was observed between these loci with GC susceptibility in the North Chinese Han populations.

MiR-146a is located in the human chromosome 5q34. Previous studies have showed miR-146a could be associated with different types of tumors, such as gastrointestinal cancer, lung cancer, breast cancer, colorectal cancer, hepatocellular carcinoma, ovarian cancer, and papillary thyroid carcinoma.[20],[21],[22],[23],[24],[25] MiR-146a was down-regulated in the development and progression of several kinds of cancers including the GC.[26] Researchers have identified that miR146a could directly bind to EGFR to regulate the signaling of EGFR and cell survival.[16] In addition, miR-146a could inhibit epithelial-mesenchymal transition by targeting insulin receptor substrate 2 in nonsmall-cell lung cancer.[27] Accumulating evidence suggests that aberrant regulation of miR-146a and its target genes could involve in the development progress of GC. rs2910164 variant, residing at the position 60 bases downstream from the first nucleotide of human pre-miR-146a, is located in the passenger strand. It was reported that the allele C variant resulted in a decrease stability of secondary structure and a decreased production of mature miR-146a.[28] Subsequently, rs2910164 G > C change reduced the inhibition of miR-146a target genes IRAK1 and TRAF6 in thyroid cells.[25] By contrast, other studies demonstrated that the C allele of rs2910164 could elevate the expression level of miR-146a in breast cancer cells and cervical cancer tissues.[28],[29] These findings suggested that the expression of mature miR-146a was differently regulated by the C allele of rs2910164 in different types of cancers.

MiR-196a2, located in the human chromosome12q13.13, is composed of two different mature miRNAs (miR-196a2-5p and miR-196a2-3p), which are processed from the same stem-loop. A majority of studies have reported that the polymorphism of miR-196a2 rs11614913 significantly associated with susceptibility of gastrointestinal cancers or GC. In addition, rs11614913 C allele and CC genotype increased the risk of GC.[5],[7],[8] Recently, it has been demonstrated genotypes for rs11614913 might be related to the susceptibility of preeclampsia.[30] rs11614913 is located at the pre-miRNA regions of human miR-196a2. The nucleotide change T >C may increase miR-196a2 expression and subsequently influence the carcinogenesis-related genes, such as HOX family, ANXA1, and HMGA1.[31] Based on the above evidence, it is reasonable to propose rs11614913 may affect the expression patterns of GC-related genes through regulating the expression level of miR-196a2.

Although the relationship between the rs3746444 variant in miR-499 and risk of GC has also been widely investigated, there are still different conclusions about the susceptibility with GC. Rong et al. have confirmed the association between and the risk of GC in Asians.[32] However, Wu et al.'s results have suggested this polymorphism is not associated with susceptibility to GC in the Chinese population.[19] rs3746444 is located in the seed sequence of miR-499a. Unlike rs2910164, rs3746444 did not affect the secondary structure of pre-miR-499. But it could regulate the maturation progress of miR-499a.[33] Further studies should be performed to reveal the biological role of this site in the development of GC.

In the current study, we did not find significant differences between the three SNPs and GC. Several potential limitations might exist and should be taken into account in our case–control study. First, the incidence of GC in men is much higher than that in women, and the male-to-female ratio is approximately 2.4:1.[34] In addition, the incidence of GC is closely related to age. The peak incidence of GC occurs in the eighth decade.[35] In the present study, no significant differences were observed in terms of gender and age distributions between cases and controls. The subjects we enrolled in our hospitals do not represent GC population well. Consequently, the admission rate bias is an important factor affecting the outcome in our study. Second, the relatively small sample size in our study may not have the statistical power to detect a small effect. Additional larger discovery sample size should be performed to validate the association relationship between rs2910164, rs11614913, and rs3746444 with GC susceptibility risk in further studies. Third, our collected information did not include H. pylori infection detection, family history of cancer, dietary situation, GC progression condition, lifestyle information, and other environmental factors. The adjustment for more environmental factors in the present study should be taken into consideration to reach convincing results. Fourth, although the association between both SNPs and GC have not been observed in our case–control study, further biological functional research should be performed to illustrate the potential role of both miRNAs during the process of GC development and progression because growing evidence suggested that the abnormal expression of miR-146a and miR-196a2 in various tumor genesis.


 > Conclusions Top


The main finding of this study suggested that none of the three variants, miR-146a rs2910164 (G > C), miR-196a2 rs11614913 (C > T), and miR-499 rs3746444 (A > G), was associated with GC risk in the North Chinese Han population. And the stratified association analysis revealed that miR-146a rs2910164 SNP was strongly associated with age and gender.

Financial support and sponsorship

This research was supported by the National Natural Science Foundation of China (81801613), China Postdoctoral Science Fund (2020M682188), Shandong Provincial Natural Science Foundation (ZR2020LZL018), Science and Technology Development Plan of Jinan (202019090), Clinical Research Center of Shandong University (2020SDUCRCC010) and Beijing Medical and Health Foundation Grant (YWJKJJHKYJJ-F1121A).

Conflict of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3]



 

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