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Association between lncRNA H19 polymorphisms and cancer susceptibility based on a meta-analysis from 25 studies
Journal Pre-proofs Review Association between lncRNA H19 polymorphisms and cancer susceptibility based on a meta-analysis from 25 studies Chunhui Liu, Lusi Chen, Zonghao You, Yuqing Wu, Can Wang, Guangyuan Zhang, Bin Xu, Ming Chen PII: DOI: Reference:
S0378-1119(19)30976-X https://doi.org/10.1016/j.gene.2019.144317 GENE 144317
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Gene Gene
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1 September 2019 18 December 2019 20 December 2019
Please cite this article as: C. Liu, L. Chen, Z. You, Y. Wu, C. Wang, G. Zhang, B. Xu, M. Chen, Association between lncRNA H19 polymorphisms and cancer susceptibility based on a meta-analysis from 25 studies, Gene Gene (2019), doi: https://doi.org/10.1016/j.gene.2019.144317
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Association between lncRNA H19 polymorphisms and cancer susceptibility based on a meta-analysis from 25 studies Running title: H19 SNPs and cancer risk Chunhui Liu1,2, Lusi Chen3, Zonghao You1,2, Yuqing Wu1,2, Can Wang1,2, Guangyuan Zhang1,2, Bin Xu 1,2, Ming Chen1,2* 1Department
of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China; 2Surgical
Research Center, Institute of Urology, Southeast University Medical School, Nanjing, China; 3Department
of Epidemiology and Health statistics, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China *Correspondence: Ming Chen, Department of Urology, Zhongda Hospital, Southeast University, 87 Dingjia Bridge Hunan Road, Nanjing, 210009, China. Email: [email protected] Declarations of interest: None. Association between lncRNA H19 polymorphisms and cancer susceptibility based on a meta-analysis from 25 studies Running title: H19 SNPs and cancer risk Chunhui Liu1,2, Lusi Chen3, Zonghao You1,2, Yuqing Wu1,2, Can Wang1,2, Guangyuan Zhang1,2, Bin Xu 1,2, Ming Chen1,2* 1Department
of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China; 2Surgical
Research Center, Institute of Urology, Southeast University Medical School, Nanjing, China; 3Department
of Epidemiology and Health statistics, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China *Correspondence: Ming Chen, Department of Urology, Zhongda Hospital, Southeast University, 87 Dingjia Bridge Hunan Road, Nanjing, 210009, China. Email: [email protected]
Declarations of interest: None. Highlights: This is the first meta-analysis investigated the association between H19 polymorphism rs3741219 and cancer susceptibility. This meta-analysis also investigated the association between another five H19 polymorphism (rs2107425, rs217727, rs2735971, rs2839698, and rs3024270) and cancer susceptibility for an update based on the newest data until May 31, 2019. Our results showed H19 rs2107425, rs217727 and rs2839698 were associated with an increasing cancer susceptibility in Asian. H19 rs2107425 was associated with a decreasing risk and H19 rs2839698 was associated with an increasing risk in Caucasian. No significant association was found in H19 rs2735971, rs3024270 and rs3741219 polymorphisms and cancer susceptibility. Abstract Background: Long non-coding RNA H19 polymorphisms were reported to be related to cancer susceptibility. However, the results from individual studies have been controversial or inconsistent. To clarify the associations between H19 single nucleotide polymorphisms (rs2107425, rs217727, rs2735971, rs2839698, rs3024270, and rs3741219) and the cancer susceptibility more accurately. Methods: Relevant publications were searched from PubMed and EMBASE up to May 31, 2019, for studies in English only. The reference lists of the retrieved studies were also investigated. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to find out the relationship between the H19 polymorphisms and cancer susceptibility. All of the data were analyzed using Stata 12.0. Results: The results showed that rs2107425 polymorphisms was associated with an increasing cancer susceptibility in Asian (T vs C: OR 1.13, 95% CI 1.01-1.28; TT+CT vs CC: OR 1.21, 95% CI 1.03-1.44; CT vs CC: OR 1.21, 95% CI 1.01-1.44) and decreasing risk in Caucasian (T vs C: OR 0.90, 95% CI 0.84-0.97; TT+CT vs CC: OR 0.84, 95% CI 0.75-0.94; CT vs CC: OR 0.82, 95% CI 0.72-0.94). And rs217727 polymorphism was associated with an increasing cancer susceptibility in the Asian (A vs G: OR 1.09, 95% CI 1.02-1.17; AA+GA vs GG: OR 1.12, 95% CI 1.01-1.21; AA vs GG: OR 1.18, 95% CI 1.02-1.36). Additionally, rs2839698 polymorphism was associated with an increasing risk overall (A vs G: OR 1.18, 95% CI 1.06-1.31), in breast cancer (A vs G: OR 1.67, 95% CI 1.14-2.45; AA+AG vs GG: OR 1.98, 95% CI 1.20-3.25; AG vs GG: OR 1.89, 95% CI 1.16-3.07), in Asian (A vs G: OR 1.09, 95% CI 1.03-1.14; AA+AG vs GG: OR 1.11, 95% CI 1.04-1.21; AA vs AG+GG: OR 1.12, 95% CI 1.01-1.25; AA vs GG: OR 1.15, 95% CI 1.01-1.49; AG vs GG: OR 1.09, 95% CI 1.02-1.17), and in Caucasian (AA vs AG+GG: OR 1.81, 95% CI 1.25-2.61).
Conclusion: H19 rs2107425, rs217727 and rs2839698 were associated with an increasing cancer susceptibility in Asian. Rs2107425 was associated with a decreasing risk and rs2839698 was associated with an increasing risk in Caucasian. No significant association was found in H19 rs2735971, rs3024270 and rs3741219 polymorphisms and cancer susceptibility. Keywords: H19; cancer; polymorphism; susceptibility; meta-analysis 1. Introduction Cancer incidence and mortality are rapidly growing worldwide, which is considered to be the leading cause of death, as well as the single most significant barrier to increasing life expectancy globally in the contemporary society (Wild, 2019). Based on the date of International Agency for Research on Cancer, GLOBOCAN estimates that there would be 18.1 million new cancer cases and 9.6 million deaths in 2018 (Bray et al., 2018). There are varieties of elements related to the progression of cancer, such as genetic factors, environmental factors, unhealthy dietary practices and lifestyles, chronic inflammation and so on (Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015). Genetic factors are one of the common factors about the cancer which influence the susceptibility and pathophysiology of cancer (Dong et al., 2008). Long noncoding RNA (lncRNA), generally defined as a set of noncoding RNA which has more than 200 bases in length and is unable to be translated into proteins, plays critical roles in a broad range of biological processes, such as cell cycle regulation, cell differentiation regulation, cell proliferation regulation and stress response (Fatica and Bozzoni, 2014). LncRNA participate in those process through the regulation of gene expression at multiple levels, including transport, chromatin modification, RNA maturation, transcription and so on (Guttman and Rinn, 2012; Zhang et al., 2016). In recent years, the number of lncRNAs identified in the human genome has been over 50000 and the relationship between lncRNA and cancer has been comprehensively investigated with in-depth biological functional study of lncRNAs (UszczynskaRatajczak et al., 2018). LncRNA H19 is one of the most important lncRNAs in cancer. It is located on chromosome 11p15.5 and is 2.3 kb in length (Brannan et al., 1990). The H19 has been identified to be associated with many types of cancer including bladder cancer, gastric cancer, esophageal cancer, and hepatic carcinoma (Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019). As the most common genetic variation, single nucleotide polymorphisms (SNPs) are becoming more and more popular in cancer research. According to the previously studies, SNPs were found to be able to predict the risk and prognosis of cancer (Hincza et al., 2019; Yang et al., 2019a). From 2008, subsequent studies even two meta-analysis explored the possible role of H19 SNPs in cancer susceptibility. The findings are still
controversial and more than 10 studies were published in recent two years. Therefore, we conducted this update meta-analysis to find out the association between the cancer susceptibility and six common H19 polymorphisms (rs2107425, rs217727, rs2735971, rs2839698, rs3024270, and rs3741219). 2. Material and methods 2.1 Publication search Two investigators independently performed a systematic computerized search for English studies using PubMed and Embase up to May 31, 2019. The keywords used are as follow: “H19 or lncRNA H19 or long non-coding RNA H19”, “polymorphisms or variants or variation or SNP” and “cancer or carcinoma or tumor or neoplasm”. In addition, studies were identified through a manual search of reviews and retrieved studies. Studies were included according to the following criteria: 1) case-control study and 2) evaluation of the association between lncRNA H19 SNPs and cancer susceptibility. The exclusion criteria were: 1) duplication publication using the same population; and 2) no available data even contracted with authors. 2.2 Data extraction Data were extracted by two independent investigators from included studies. Divergence were solved after discussion on every item. The collected information from each articles were as follows: first author, publication year, region, cancer type, cases and controls number, source of control, genotype frequencies, genotyping method, and P value for Hardy–Weinberg equilibrium (HWE) of controls. Meanwhile, we categorized ethnicity as Caucasian, African or Asian. 2.3 Methodology quality assessment Two investigators independently evaluated the quality of the included articles. The quality score items were included: representativeness of the cases, source of the controls, genotyping examination, HWE in controls and association assessment (Li et al., 2017). The scores ranged 0–10. 2.4 Statistical Analysis The HWE for control subjects of each studies was evaluated by a chi-square test, and P < 0.05 was seen as significant disequilibrium. Odds ratios (ORs) and the 95% confidence intervals (95% CIs) was calculated to evaluate the association of the H19 SNPs and cancer susceptibility. The pooled ORs were executed for homozygote comparison, dominant and recessive models, allele comparison and heterozygote comparison. The heterogeneity was calculated using the chi-square-based I2 test and the Q test. The fixed-effect model (the Mantel-Haenszel method) was chosen to use when the I2 value is less than 50%. While the I2 is more than 50%, a random-effects model (DerSimonian and Laird method) was adopted. Moreover, the eligible study was sequentially removed in order to perform the sensitivity analysis. Publication bias were assessed by Begg’s rank correlation and Egger’s linear regression. The publication bias
was seen to be significant statistically when P<0.05. All of the statistical analyses were conducted by the STATA 12.0 (StataCorp, College Station, TX, USA), the P values were two-sided. 3. Results 3.1 Characteristics of studies A total of 183 potentially relevant publications were included in the systematic review after duplicates removed and 25 articles including 20,362 cancer patients and 26,709 controls were eligible for inclusion at the end (Figure 1) (Verhaegh et al., 2008; Quaye et al., 2009; Song et al., 2009; Barnholtz-Sloan et al., 2010; Butt et al., 2012; Yang et al., 2015; Gong et al., 2016; Hua et al., 2016; Li et al., 2016; Xia et al., 2016; Guo et al., 2017; Hassanzarei et al., 2017; He et al., 2017; Hu et al., 2017; Lin et al., 2017; Cui et al., 2018; Li et al., 2018; Yang et al., 2018; Yin et al., 2018; Yuan et al., 2018; Abdollahzadeh and Ghorbian, 2019; Hu et al., 2019; Li and Niu, 2019; Safari et al., 2019; Yang et al., 2019b). Among these 25 articles, 8 studies focused on Caucasian populations, 17 on Asian populations and only 1 on African populations (one article included both Caucasian and African population). For the control groups of these articles, 7 were hospital based, 17 were population based, and 1 did not described. The characteristics of the eligible studies are listed in Table 1. The distributions of genotype frequency among 12 SNPs in lncRNA H19 are listed in Table 2. After removal of those records for which PHWE < 0.05 and date not enough or available for meta-analysis, 6 SNPs (rs2107425, rs217727, rs2735971, rs2839698, rs3024270, and rs3741219) were finally included in our analysis. 3.2 Meta-analysis of the lncRNA H19 rs2107425 C>T polymorphism and cancer risk Nine studies including 11,107 cancer patients and 15,365 controls were used to examine the relation between the H19 rs2107425 C>T polymorphism and cancer susceptibility. No significant associations were shown between rs2107425 polymorphism and overall cancer risk or subgroup analyses by cancer type in all the five genetic models. However, subgroup analyses by race showed that rs2107425 C>T was related to an increasing risk in Asian (T vs C: OR 1.13, 95% CI 1.01-1.28; TT+CT vs CC: OR 1.21, 95% CI 1.03-1.44; CT vs CC: OR 1.21, 95% CI 1.01-1.44) and decreasing risk in Caucasian (T vs C: OR 0.90, 95% CI 0.84-0.97; TT+CT vs CC: OR 0.84, 95% CI 0.75-0.94; CT vs CC: OR 0.82, 95% CI 0.72-0.94) (Figure 2A and Table 3). Heterogeneity was shown to exist in the allelic, dominant and heterozygote comparison of overall, Caucasian and breast subgroup according to the results (Table 3 and Supplement Table 1). Sensitivity analysis results indicated that the pooled ORs of rs2107425 C>T polymorphisms were not materially altered by the contribution of any individual study (Figure 3A and Supplement Table 2). No significant publication bias was observed in the studies about rs2107425 polymorphism (Table 4).
3.3 Meta-analysis of the lncRNA H19 rs217727 G>A polymorphism and cancer risk Eighteen studies including 9,625 cancer patients and 11,667 controls were used to examine the association between the H19 rs217727 G>A polymorphism and cancer susceptibility. An increasing risk of rs217727 G>A polymorphism were only found in the Asian subgroup (A vs G: OR 1.09, 95% CI 1.02-1.17; AA+GA vs GG: OR 1.12, 95% CI 1.01-1.21; AA vs GG: OR 1.18, 95% CI 1.02-1.36, Figure 2B). No significant associations were found between this SNP and cancer risk among overall, bladder cancer, breast cancer or Caucasian group in any of the five genetic models (Table 3). Heterogeneity results showed that heterogeneity existed in all group of the five genetic models expect the bladder group of allelic model (Table 3 and Supplement Table 1). Sensitivity analysis results showed that the pooled ORs of rs217727 G>A polymorphisms were only slightly altered when the data from Safari’s study was removed in allelic model (Figure 3B and Supplement Table 2). No significant publication bias were observed in the studies about rs2107425 polymorphism (Table 4). 3.4 Meta-analysis of the lncRNA H19 rs2839698 G>A polymorphism and cancer risk Thirteen studies including 7,741 cancer patients and 8,656 controls were used to examine the association between the H19 rs2839698 G>A polymorphism and cancer risk. An increased risk was identified between rs2839698 polymorphism and overall cancer risk (A vs G: OR 1.18, 95% CI 1.06-1.31). Besides that, the increased risk was also found in breast cancer group (A vs G: OR 1.67, 95% CI 1.14-2.45; AA+AG vs GG: OR 1.98, 95% CI 1.20-3.25; AG vs GG: OR 1.89, 95% CI 1.16-3.07; Figure 2C), in Asian (A vs G: OR 1.09, 95% CI 1.03-1.14; AA+AG vs GG: OR 1.11, 95% CI 1.041.21; AA vs AG+GG: OR 1.12, 95% CI 1.01-1.25; AA vs GG: OR 1.15, 95% CI 1.011.49; AG vs GG: OR 1.09, 95% CI 1.02-1.17), and in Caucasian (AA vs AG+GG: OR 1.81, 95% CI 1.25-2.61, Figure 2D) (Table 3). It showed that heterogeneity existed in allelic, dominant, homozygote and heterozygote models of overall group and in all five genetic models of breast subgroup. No heterogeneity was found in Asian group. The heterogeneity just was not identified in recessive model of Caucasian group. In bladder subgroup, the heterogeneity was only found in heterozygote genetic model (Table 3 and Supplement Table 1). Sensitivity analysis results showed that the statistically significant was altered when the data from Hassanzarei’s and Safari’s studies were removed in heterozygote model and the data from Li’s study was removed in homozygote model (Figure 3C and 3D and Supplement Table2). No significant publication bias were observed in the studies about rs2839698 polymorphism (Table 4). 3.5 Meta-analysis of the lncRNA H19 rs2735971 T>C, rs3024270 C>G and rs3741219 A>G polymorphisms and cancer risk
The association between the H19 rs2735971 T>C, rs3024270 C>G and rs3741219 A>G polymorphisms and cancer risk were separately examined in 6 studies involving 3,515 patients and 4,386 healthy controls, 8 studies involving 4,244 patients and 5,628 healthy controls, and 6 studies involving 3,266 patients and 3,415 healthy controls. There were no significant associations found between those three SNPs and cancer risk among all overall and subgroup in any of the five genetic models (Table 3 and Supplement Figure 1). Results of heterogeneity test showed that in rs2735971 overall group, the heterogeneity existed in allelic, recessive and homozygote models. In rs3024270 overall group and bladder subgroup and rs3741219 Asian group, no heterogeneity was found. In rs3741219 overall group and breast subgroup, the heterogeneity just was not identified in recessive model (Table 3 and Supplement Table 1). No substantial changes were observed in rs2735971 and rs3741219 polymorphism. However, a slight change were found when Hua’s data was removed in allelic, recessive and homozygote models of rs3024270 (Supplement Figure 2 and Supplement Table 2). No significant publication bias were observed in the studies about these three polymorphism (Table 4). 4. Discussion Various studies have been conducted to examine whether H19 polymorphism can affect cancer susceptibility, and two meta-analysis including 5 SNPs of H19 was performed in 2017 (Li et al., 2017; Lv et al., 2017). However, the findings are still controversial even in those two meta-analysis. For example, rs2839698 was found to be associated with overall cancer risk in Lv’s study. However, Li found that it was only associated with digestive cancer risk (Li et al., 2017; Lv et al., 2017). Moreover, another 10 studies on H19 were published in last two years. Therefore, it is necessary to conduct this updated meta-analysis. In this study, we collected all of relevant published data up to May 31, 2019, detected the associations between lncRNA H19 rs2107425, rs217727, rs2839698, rs2735971, rs3024270 and rs3741219 polymorphisms and cancer risk. We obtained some new conclusions. For rs2107425 C>T polymorphism, the same conclusion with previous study was obtained that it’s related to a decrease risk in Caucasian group (Li et al., 2017). However, we also found it was related to an increasing risk in Asian. For rs217727 G>A polymorphism, it was found no association with cancer risk in previous meta-analysis, but in our study it was related to an increasing risk in the Asian (Li et al., 2017; Lv et al., 2017). For rs2839698 G>A polymorphism, our study found a similar result with Lv’s study that it was associated with an increased cancer risk in overall and in Asian group(Lv et al., 2017). Moreover, we found it was also associated with an increased cancer risk in Caucasian group in recessive model and in breast cancer group in allelic, dominant, recessive and heterozygote models. For rs2735971 T>C and rs3024270 C>G polymorphisms, they were found be associated with decreased overall risk of cancer when compared with the wild type in Lv’s study (Lv et al., 2017). However, in our study no significant association was found. For rs3741219 A>G
polymorphism, this is the first meta-analysis about cancer risk, and no significant association was found. In recent studies, H19 was found over-expressed in various cancers, such as breast cancer, thyroid cancer, hepatic cancer and gastric cancer (Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018). It belongs to a highly conserved imprinted gene and has three transcript variants, and all of them have five exons and four introns (Gabory et al., 2010). The reasons H19 polymorphisms affect cancer risk were not clearly understood. Previous studies showed that 75% of the SNPs have influence on the lncRNA expression (Kumar et al., 2013). One research found the rs217727 GG carriers had much higher H19 expression than GA and AA carriers in hepatocellular carcinoma, this means rs217727 G>A may regulate the expression of H19, but the detail mechanism was not described(Ge et al., 2019). Besides that, we should pay attention to the location of SNPs when dissecting the mechanisms of SNPs (Gao and Wei, 2017). For example, SNPs located at the promoter can regulated the transcriptional activity, and SNP located at the exons can change the secondary structure of lncRNA (Yuan et al., 2016; Wang et al., 2019). In this study, six H19 SNPs were investigated in meta-analysis (rs2107425, rs217727, rs2839698, rs2735971, rs3024270 and rs3741219), and their relative locations are shown in Figure 4. We can see two SNPs (rs217727 and rs3741219) locate in the exons and one (rs3024270) in the introns of all three transcript variants, two SNPs (rs2107425 and rs2735971) locate in the introns of transcript variant 3 and the promoter of transcript variant 1 and 2, and one SNP (rs2839698) locate in the in the introns of transcript variant 3 and the exons of transcript variant 1 and 2. The location of rs2107425 is inconsistent, that’s means the mechanism of this SNP may be more complex. It may regulate the transcription of transcript variant 1 and 2, however this is not verified. Rs217727 locates in the exons of all transcript variants, which means it may change gene structure and function. Additionally, the LncRNASNP2 database (http://bioinfo.life.hust.edu.cn/lncRNASNP#!/) showed that the rs217727 and rs2839698 can alter the interaction of miRNAs and H19 but there is no direct verification. Heterogeneities were found in almost all of the polymorphisms in this meta-analysis. Stratified analyses suggested that patient ethnicity and cancer location might have contributed to the heterogeneities. And ethnicity may be the more important factor for heterogeneities especially in rs2107425 C>T polymorphism, because completely different genotype frequencies in Asian and Caucasian were observed. Several limitations should be taken into account in this meta-analysis. First, environmental factors and patients’ characteristics were not considered in this study, so the roles of gene environment interactions could not be assessed. Second, all of the data included in this study mainly focused on the Asian and Caucasian population. It remains unclear that whether these results can be promoted and applied on other populations or
not. Third, heterogeneity existed in almost all of the six polymorphism and could not be totally eliminated by subgroup analysis, this may influence our results. 5. Conclusion Our meta-analysis results showed that H19 rs2107425 C>T was associated with an increase risk in Asian and decrease risk in Caucasian, rs217727 G>A polymorphism was related to an increasing risk in the Asian, rs2839698 G>A polymorphism was associated with an increased risk in Asian and Caucasian. No significant association was found in H19 rs2735971, rs3024270 and rs3741219 polymorphisms and cancer risk. Further studies equipped with different ethnicities, as well as a large population size, are still needed. Acknowledgments The authors would like to thank Xiaoyue Zhu, for her discussion the statistical methods with authors. Conflict of interest The authors declare that they have no competing of interests. Funding This study was funded by The National Natural Science Foundation of China (No. 81872089, 81370849, 81672551, 81300472, 81070592, 81202268, 81202034), Natural Science Foundation of Jiangsu Province (BK20161434, BL2013032, BK20150642 and BK2012336), Six talent peaks project in Jiangsu Province, Jiangsu Provincial Medical Innovation Team (CXTDA2017025), Jiangsu Provincial Medical Talent (ZDRCA2016080), and Basic scientific research Funding of Southeast University (2242019K40239). Author Contributions Chunhui Liu and Bin Xu conceived and designed the study. Chunhui Liu and Lusi Chen collected the data. Chunhui Liu and Zonghao You evaluated the quality of the studies. Chunhui Liu and Can Wang analyzed the data. Chunhui Liu and Yuqing Wu wrote the paper. Guangyuan Zhang and Ming Chen revised the paper. All authors read and approved the final manuscript prior to submission. References Abdollahzadeh, S. and Ghorbian, S. Association of the study between LncRNA-H19 gene polymorphisms with the risk of breast cancer. J Clin Lab Anal, 2019;33, e22826. Barnholtz-Sloan, J.S., Shetty, P.B., Guan, X., Nyante, S.J., Luo, J., Brennan, D.J. and Millikan, R.C. FGFR2 and other loci identified in genome-wide association
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Urothelial Cell Carcinoma Development. Int J Environ Res Public Health, 2019b;16. Yin, Z., Cui, Z., Li, H., Li, J. and Zhou, B. Polymorphisms in the H19 gene and the risk of lung Cancer among female never smokers in Shenyang, China. BMC Cancer, 2018;18, 893. Yoshimura, H., Matsuda, Y., Yamamoto, M., Kamiya, S. and Ishiwata, T. Expression and role of long non-coding RNA H19 in carcinogenesis. Front Biosci (Landmark Ed), 2018;23, 614-625. Yuan, H., Liu, H., Liu, Z., Owzar, K., Han, Y., Su, L., Wei, Y., Hung, R.J., McLaughlin, J., Brhane, Y., et al. A Novel Genetic Variant in Long Noncoding RNA Gene NEXN-AS1 is Associated with Risk of Lung Cancer. Sci Rep, 2016;6, 34234. Yuan, Z., Yu, Y., Zhang, B., Miao, L., Wang, L., Zhao, K., Ji, Y., Wang, R., Ma, H., Chen, N., et al. Genetic variants in lncRNA H19 are associated with the risk of oral squamous cell carcinoma in a Chinese population. Oncotarget, 2018;9, 23915-23922. Zhang, S., Zhang, G. and Liu, J. Long noncoding RNA PVT1 promotes cervical cancer progression through epigenetically silencing miR-200b. APMIS, 2016;124, 649-58. Figure legends： Figure 1. Flow diagram for study selection Figure 2. Forest plot for the H19 polymorphism and cancer susceptibility. A: rs2107425, B: rs217727, C: rs2839698 subgroup analysis by cancer, D: rs2839698 subgroup by ethnicity. Figure 3. Sensitivity analyses for the H19 polymorphism and cancer susceptibility. A: rs2107425 in allelic model, B: rs217727 in allelic model, C: rs2839698 in heterozygote model, D: rs2839698 in homozygote model. Figure 4. The sketch map of the studied SNPs’ location in the H19 gene. Supplement Figure 1: Forest plot for the H19 polymorphism and cancer susceptibility. A: rs2735971, B: rs3024270, C: rs3741219. Supplement Figure 2: Sensitivity analyses for the H19 polymorphism and cancer susceptibility. A: rs2735971, B: rs3024270, C: rs3741219. Table 1 Characteristics of eligible studies. Table 2 Genotype frequency distributions of of H19 in included studies.
Table 3 Meta-analysis results of the association between H19 SNPs and cancer risk. Table 4 The results of publication bias from Begg’s and Egger’s test. Supplement Table 1 The P value of heterogeneity from Q test. Supplement Table 2 ORs (95% CI) of sensitivity analysis.
Abbreviations: Long noncoding RNA (lncRNA) Single nucleotide polymorphisms (SNPs) Hardy–Weinberg equilibrium (HWE) Odds ratios (ORs) 95% confidence intervals (95% CIs)
Abstract Background: Long non-coding RNA H19 polymorphisms were reported to be related to cancer susceptibility. However, the results from individual studies have been controversial or inconsistent. To clarify the associations between H19 single nucleotide polymorphisms (rs2107425, rs217727, rs2735971, rs2839698, rs3024270, and rs3741219) and the cancer susceptibility more accurately. Methods: Relevant publications were searched from PubMed and EMBASE up to May 31, 2019, for studies in English only. The reference lists of the retrieved studies were also investigated. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to find out the relationship between the H19 polymorphisms and cancer susceptibility. All of the data were analyzed using Stata 12.0. Results: The results showed that rs2107425 polymorphisms was associated with an increasing cancer susceptibility in Asian (T vs C: OR 1.13, 95% CI 1.01-1.28; TT+CT vs CC: OR 1.21, 95% CI 1.03-1.44; CT vs CC: OR 1.21, 95% CI 1.01-1.44) and decreasing risk in Caucasian (T vs C: OR 0.90, 95% CI 0.84-0.97; TT+CT vs CC: OR 0.84, 95% CI 0.75-0.94; CT vs CC: OR 0.82, 95% CI 0.72-0.94). And rs217727 polymorphism was associated with an increasing cancer susceptibility in the Asian (A vs G: OR 1.09, 95% CI 1.02-1.17; AA+GA vs GG: OR 1.12, 95% CI 1.01-1.21; AA vs GG: OR 1.18, 95% CI 1.02-1.36). Additionally, rs2839698 polymorphism was
associated with an increasing risk overall (A vs G: OR 1.18, 95% CI 1.06-1.31), in breast cancer (A vs G: OR 1.67, 95% CI 1.14-2.45; AA+AG vs GG: OR 1.98, 95% CI 1.20-3.25; AG vs GG: OR 1.89, 95% CI 1.16-3.07), in Asian (A vs G: OR 1.09, 95% CI 1.03-1.14; AA+AG vs GG: OR 1.11, 95% CI 1.04-1.21; AA vs AG+GG: OR 1.12, 95% CI 1.01-1.25; AA vs GG: OR 1.15, 95% CI 1.01-1.49; AG vs GG: OR 1.09, 95% CI 1.02-1.17), and in Caucasian (AA vs AG+GG: OR 1.81, 95% CI 1.25-2.61). Conclusion: H19 rs2107425, rs217727 and rs2839698 were associated with an increasing cancer susceptibility in Asian. Rs2107425 was associated with a decreasing risk and rs2839698 was associated with an increasing risk in Caucasian. No significant association was found in H19 rs2735971, rs3024270 and rs3741219 polymorphisms and cancer susceptibility. Keywords: H19; cancer; polymorphism; susceptibility; meta-analysis
Conflict of interest The authors declare that they have no competing of interests.
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Highlights: This is the first meta-analysis investigated the association between H19 polymorphism rs3741219 and cancer susceptibility. This meta-analysis also investigated the association between another five H19 polymorphism (rs2107425, rs217727, rs2735971, rs2839698, and rs3024270) and cancer susceptibility for an update based on the newest data until May 31, 2019. Our results showed H19 rs2107425, rs217727 and rs2839698 were associated with an increasing cancer susceptibility in Asian. H19 rs2107425 was associated with a decreasing risk and H19 rs2839698 was associated with an increasing risk in Caucasian. No significant association was found in H19 rs2735971, rs3024270 and rs3741219 polymorphisms and cancer susceptibility.
Table 1 Characteristics of eligible studies First author
Year
Cancer type
Country
Ethnicity
Sample size
Source of
Genotypin
control Case
Control
method
Verhaegh
2008
Bladder
Netherlands
Caucasian
177
204
PB
PCR-RFL
Quaye
2009
Ovarian
Mix
Caucasian
1457
2463
PB
TaqMan
Song
2009
Ovarian
Mix
Caucasian
5366
8538
PB
TaqMan
Sloan
2010
Breast
USA
African
737
658
PB
GoldenGa
USA
Caucasian
1225
1118
PB
GoldenGa
Butt
2012
Breast
Sweden
Caucasian
679
1355
PB
MassArra
Yang
2015
Gastric
China
Asian
500
500
HB
TaqMan
Gong
2016
Breast
China
Asian
479
203
HB
TaqMan
Hua
2016
Bladder
China
Asian
1046
1394
HB
TaqMan
Li
2016
Colorectal
China
Asian
1147
1203
PB
TaqMan
Xia
2016
Breast
China
Asian
464
467
PB
PCR-RFL
Guo
2017
Oral
China
Asian
461
739
PB
BeadChip
Hassanzarei
2017
Breast
India
Caucasian
230
240
ND
PCR-RFL
He
2017
Osteosarcoma
China
Asian
193
383
HB
TaqMan
Hu
2017
Pancreatic
China
Asian
416
416
PB
TaqMan
Lin
2017
Breast
China
Asian
1005
1020
HB
Genesky
Cui
2018
Breast
China
Asian
1488
1675
PB
TaqMan
Li
2018
Lung
China
Asian
555
618
PB
TaqMan
Yang
2018
Hepatocellular
China
Asian
465
465
HB
KASP
Yin
2018
Lung
China
Asian
556
395
HB
Illumina
Yuan
2018
Oral
China
Asian
431
984
PB
MassARR
Abdollahzadeh
2019
Breast
Iran
Caucasian
150
100
PB
PCR-RFL
Hu
2019
Neuroblastoma
China
Asian
393
810
PB
TaqMan
Li
2019
Bladder
China
Asian
200
200
PB
TaqMan
Safari
2019
Breast
Iran
Caucasian
111
130
PB
4P-ARMS
Yang
2019
Bladder
China
Asian
431
431
PB
TaqMan
PB: Population or Healthy based; HB: Hospital based; ND: Not described; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism.
Table 2 Genotype frequency distributions of of H19 in included studies First author
Verhaegh
Year
2008
Type of cancer
Bladder
Country
Netherlan
SNP
Case
Control
N
AA
Aa
Aa
N
AA
rs2107425C/T
177
92
65
20
204
89
rs217727T/C
177
114
59
4
204
115
rs2839698C/T
177
54
74
49
204
52
rs2735469C/T
177
119
51
7
204
136
rs17658052G/A
177
151
26
0
204
181
ds
Quaye
2009
Ovarian
Mix
rs2107425C/T
1457
764
544
149
2463
1118
Song
2009
Ovarian
Mix
rs2107425C/T
5366
2619
2192
555
8538
4029
Sloan
2010
Breast
USA
rs2107425C/T
737
161
390
186
658
170
USA
rs2107425C/T
1225
604
516
105
1118
521
Butt
2012
Breast
Sweden
rs2107425C/T
679
361
250
68
1355
637
Yang
2015
Gastric
China
rs217727C/T
500
160
252
88
500
193
rs2839698C/T
500
250
195
55
500
284
Gong
Hua
Li
Xia
Guo
Hassanzarei
2016
2016
2016
2016
2017
2017
Breast
Bladder
Colorectal
Breast
Oral
Breast
China
China
China
China
China
India
rs3741216A/T
500
380
102
18
500
379
rs3741219T/C
500
260
187
53
500
268
rs2107425C/T
479
181
235
63
203
79
rs2839698G/A
496
237
220
39
206
99
rs217727G/A
1046
431
467
148
1394
573
rs2735971C/T
1049
704
302
43
1396
928
rs2839698G/A
1049
552
418
79
1337
729
rs3024270G/C
1047
346
527
174
1395
447
rs2839698G/A
1147
583
462
102
1203
666
rs3024270C/G
1147
385
527
235
1203
420
rs217727G/A
1147
480
514
153
1203
456
rs2735971C/T
1147
773
334
40
1203
765
rs217727C/T
464
160
156
148
467
139
rs3741219T/C
464
238
186
40
467
245
rs2735971C/T
461
191
141
129
739
351
rs217727G/A
362
101
181
80
737
252
rs2839698G/A
362
58
171
133
741
120
rs3024270G/C
362
104
183
75
740
245
rs3741219T/C
230
63
126
41
240
109
rs217727C/T
230
71
132
27
240
125
rs2839698T/C
230
166
64
0
240
222
rs3741216T/A
230
204
26
0
240
175
He
2017
Osteosarcoma
China
rs2735971C/T
193
88
94
11
383
169
rs217727G/A
193
79
102
12
383
195
rs2839698G/A
193
83
98
12
383
178
rs3024270G/C
193
85
91
17
383
173
Hu
2017
Pancreatic
China
rs217727C/T
416
133
200
83
416
128
Lin
2017
Breast
China
rs217727 C/T
1005
403
471
131
1020
465
rs2839698C/T
1005
452
440
113
1020
484
rs217727 G/A
1488
611
692
185
1675
685
rs2071095C/A
1492
792
580
120
1674
786
rs2251375C/A
1491
504
704
283
1677
569
rs2839698G/A
1677
875
673
129
1491
801
rs2839701C/G
1490
762
600
128
1677
801
rs3741219A/G
1491
782
582
127
1677
832
Cui
2018
Breast
China
Li
2018
Lung
China
rs217727 G/A
555
210
250
95
618
246
Yang
2018
Hepatocellular
China
rs2735971G/A
465
327
126
12
465
313
rs2839698C/T
466
215
211
40
462
245
rs3024270G/C
471
151
225
95
466
170
rs217727 C/T
556
204
264
88
395
165
rs2107425C/T
556
161
266
129
395
140
rs2735469C/T
556
507
46
3
395
359
rs17658052G/A
556
507
47
2
395
371
rs217727 C/T
431
186
194
51
984
488
Yin
Yuan
2018
2018
Lung
Oral
China
China
Abdollahzadeh
Hu
2018
2019
Li
2019
Safari
2019
Yang
2019
Breast
Iran
Neuroblastoma
Bladder
Breast
Bladder
China
China
Iran
China
rs2839701C/G
444
205
188
51
984
507
rs217727 C/T
150
116
29
5
100
86
rs3741219 T/C
150
119
24
7
100
80
rs2839698G/A
393
179
175
39
810
365
rs3024270C/G
393
99
203
91
810
213
rs217727 G/A
393
186
164
43
810
382
rs217727 G/A
200
51
140
9
200
84
rs2735971C/T
200
128
62
10
200
126
rs3024270G/C
200
83
101
16
200
81
rs2839698C/T
111
15
57
39
130
53
rs217727 C/T
111
79
30
2
130
64
rs217727 C/T
431
185
202
44
431
191
rs2107425C/T
431
152
213
66
431
171
rs2839698C/T
431
206
170
55
431
192
rs3024270C/G
431
114
210
107
431
120
rs3741219A/G
431
192
181
58
431
185
AA: Homozygote; Aa: Common heterozygote; aa: Homozygote variant of case; aa: rare homozygote
Table 3 Meta-analysis results of the association between H19 SNPs and cancer risk SNP
N
Allelic model OR(95% CI)
Dominant model I2 (%)
OR(95% CI)
Recessive model I2 (%)
OR(95% CI)
Homozygot I2 (%)
OR(95%
rs2107425 Overall
9
0.98(0.90-1.06)a
69.4
0.95(0.84-1.08)a
74.5
1.04(0.96-1.12)
13.2
1.00(0.92-1
Breast
4
0.96(0.84-1.10)a
67.8
0.96(0.79-1.77)a
68.3
0.96(0.83-1.11)
27.9
0.95(0.72-1
Asian
3
1.13(1.01-1.28)
26.7
1.21(1.03-1.44)
0.0
1.12(0.91-1.40)
39.0
1.24(0.98-1
Caucasian
5
0.90(0.84-0.97) a
51.0
0.84(0.75-0.94) a
64.8
1.01(0.92-1.10)
8.4
0.94(0.86-1
Overall
18
1.07(0.99-1.16)a
69.7
1.08(0.97-1.21)a
71.5
1.11(0.95-1.29)a
64.2
1.14(0.97-1
Bladder
4
1.03(0.94-1.13)
38.2
1.10(0.80-1.52)a
78.9
0.73(0.40-1.32)a
79.9
0.89(0.59-1
Breast
5
1.00(0.80-1.25)a
84.0
0.94(0.70-1.25)a
82.6
1.13(0.81-1.58)a
69.8
1.06(0.73-1
Asian
15
1.09(1.02-1.17)a
56.0
1.12(1.01-1.24)a
65.2
1.14(0.99-1.31)a
63.6
1.18(1.02-1
Caucasian
3
0.82(0.39-1.73)a
86.7
0.77(0.36-1.64)a
83.1
0.58(0.12-2.90)a
61.3
0.54(0.09-3
6
1.09(0.90-1.32)a
81.9
1.01(0.90-1.12)
8.8
1.40(0.86-2.28)a
86.8
1.32(0.78-2
Overall
13
1.18(1.06-1.31) a
77.8
1.21(1.04-1.40) a
78.0
1.16(1.05-1.29)
31.8
1.24(1.03-1
Asian
10
1.09(1.03-1.14)
18.2
1.11(1.04-1.21)
1.1
1.12(1.01-1.25)
1.2
1.15(1.01-1
Caucasian
3
2.16(0.96-4.86) a
92.5
2.50(0.71-8.84) a
93.7
1.81(1.25-2.61)
22.8
2.38(0.52-1
Bladder
3
1.01(0.92-1.12)
0.0
1.00(0.87-1.14)
32.3
1.07(0.86-1.32)
0.0
1.00(0.80-1
Breast
4
1.67(1.14-2.45) a
93.2
1.98(1.20-3.25) a
92.9
1.27(0.84-1.93) a
69.4
1.67(0.86-3
rs217727
rs2735971 Overall rs2839698
rs3024270
Overall
8
1.05(0.99-1.11)
0.0
1.06(0.97-1.15
0.0
1.07(0.96-1.19)
19.2
1.10(0.98-1
Bladder
3
0.96(0.88-1.06)
0.0
0.98(0.85-1.13)
0.0
0.91(0.77-1.07)
0.0
0.91(0.75-1
Overall
6
1.09(0.93-1.27) a
68.3
1.10(0.89-1.37) a
74.2
1.12(0.95-1.32)
0.0
Breast
4
1.14(0.88-1.47) a
80.2
1.19(0.82-1.73) a
84.1
1.11(0.91-1.35)
0.0
1.30(0.83-2
Asian
4
0.98(0.91-1.06)
0.0
0.95(0.86-1.05)
0.0
1.07(0.89-1.27)
0.0
1.03(0.86-1
rs3741219
1.13(0.95-1
OR, odds ratio; CI, confidence interval. The results are in bold if P < 0.05. a P was calculated by random model.
Table 4 The results of publication bias from Begg’s and Egger’s test SNP
Allelic model
Dominant model
Recessive model
Homozygote vs w
P(Begg’s)
P(Egger’s)
P(Begg’s)
P(Egger’s)
P(Begg’s)
P(Egger’s)
P(Begg’s)
P(E
rs2107425
0.532
0.392
0.677
0.198
0.835
0.622
0.835
0.8
rs217727
0.520
0.611
0.733
0.872
0.472
0.124
0.622
0.2
rs2735971
0.851
0.415
0.573
0.716
0.573
0. 449
0.573
0.1
rs2839698
0.143
0.127
0.329
0.377
0.222
0.998
0.222
0.7
rs3024270
0.322
0.793
0.458
0.766
0.621
0.447
0.322
0.5
rs3741219
0.188
0.291
0.573
0.224
0.188
0.534
0.091
0.4
S0378-1119(19)30976-X https://doi.org/10.1016/j.gene.2019.144317 GENE 144317
To appear in:
Gene Gene
Received Date: Revised Date: Accepted Date:
1 September 2019 18 December 2019 20 December 2019
Please cite this article as: C. Liu, L. Chen, Z. You, Y. Wu, C. Wang, G. Zhang, B. Xu, M. Chen, Association between lncRNA H19 polymorphisms and cancer susceptibility based on a meta-analysis from 25 studies, Gene Gene (2019), doi: https://doi.org/10.1016/j.gene.2019.144317
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Association between lncRNA H19 polymorphisms and cancer susceptibility based on a meta-analysis from 25 studies Running title: H19 SNPs and cancer risk Chunhui Liu1,2, Lusi Chen3, Zonghao You1,2, Yuqing Wu1,2, Can Wang1,2, Guangyuan Zhang1,2, Bin Xu 1,2, Ming Chen1,2* 1Department
of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China; 2Surgical
Research Center, Institute of Urology, Southeast University Medical School, Nanjing, China; 3Department
of Epidemiology and Health statistics, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China *Correspondence: Ming Chen, Department of Urology, Zhongda Hospital, Southeast University, 87 Dingjia Bridge Hunan Road, Nanjing, 210009, China. Email: [email protected] Declarations of interest: None. Association between lncRNA H19 polymorphisms and cancer susceptibility based on a meta-analysis from 25 studies Running title: H19 SNPs and cancer risk Chunhui Liu1,2, Lusi Chen3, Zonghao You1,2, Yuqing Wu1,2, Can Wang1,2, Guangyuan Zhang1,2, Bin Xu 1,2, Ming Chen1,2* 1Department
of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China; 2Surgical
Research Center, Institute of Urology, Southeast University Medical School, Nanjing, China; 3Department
of Epidemiology and Health statistics, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China *Correspondence: Ming Chen, Department of Urology, Zhongda Hospital, Southeast University, 87 Dingjia Bridge Hunan Road, Nanjing, 210009, China. Email: [email protected]
Declarations of interest: None. Highlights: This is the first meta-analysis investigated the association between H19 polymorphism rs3741219 and cancer susceptibility. This meta-analysis also investigated the association between another five H19 polymorphism (rs2107425, rs217727, rs2735971, rs2839698, and rs3024270) and cancer susceptibility for an update based on the newest data until May 31, 2019. Our results showed H19 rs2107425, rs217727 and rs2839698 were associated with an increasing cancer susceptibility in Asian. H19 rs2107425 was associated with a decreasing risk and H19 rs2839698 was associated with an increasing risk in Caucasian. No significant association was found in H19 rs2735971, rs3024270 and rs3741219 polymorphisms and cancer susceptibility. Abstract Background: Long non-coding RNA H19 polymorphisms were reported to be related to cancer susceptibility. However, the results from individual studies have been controversial or inconsistent. To clarify the associations between H19 single nucleotide polymorphisms (rs2107425, rs217727, rs2735971, rs2839698, rs3024270, and rs3741219) and the cancer susceptibility more accurately. Methods: Relevant publications were searched from PubMed and EMBASE up to May 31, 2019, for studies in English only. The reference lists of the retrieved studies were also investigated. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to find out the relationship between the H19 polymorphisms and cancer susceptibility. All of the data were analyzed using Stata 12.0. Results: The results showed that rs2107425 polymorphisms was associated with an increasing cancer susceptibility in Asian (T vs C: OR 1.13, 95% CI 1.01-1.28; TT+CT vs CC: OR 1.21, 95% CI 1.03-1.44; CT vs CC: OR 1.21, 95% CI 1.01-1.44) and decreasing risk in Caucasian (T vs C: OR 0.90, 95% CI 0.84-0.97; TT+CT vs CC: OR 0.84, 95% CI 0.75-0.94; CT vs CC: OR 0.82, 95% CI 0.72-0.94). And rs217727 polymorphism was associated with an increasing cancer susceptibility in the Asian (A vs G: OR 1.09, 95% CI 1.02-1.17; AA+GA vs GG: OR 1.12, 95% CI 1.01-1.21; AA vs GG: OR 1.18, 95% CI 1.02-1.36). Additionally, rs2839698 polymorphism was associated with an increasing risk overall (A vs G: OR 1.18, 95% CI 1.06-1.31), in breast cancer (A vs G: OR 1.67, 95% CI 1.14-2.45; AA+AG vs GG: OR 1.98, 95% CI 1.20-3.25; AG vs GG: OR 1.89, 95% CI 1.16-3.07), in Asian (A vs G: OR 1.09, 95% CI 1.03-1.14; AA+AG vs GG: OR 1.11, 95% CI 1.04-1.21; AA vs AG+GG: OR 1.12, 95% CI 1.01-1.25; AA vs GG: OR 1.15, 95% CI 1.01-1.49; AG vs GG: OR 1.09, 95% CI 1.02-1.17), and in Caucasian (AA vs AG+GG: OR 1.81, 95% CI 1.25-2.61).
Conclusion: H19 rs2107425, rs217727 and rs2839698 were associated with an increasing cancer susceptibility in Asian. Rs2107425 was associated with a decreasing risk and rs2839698 was associated with an increasing risk in Caucasian. No significant association was found in H19 rs2735971, rs3024270 and rs3741219 polymorphisms and cancer susceptibility. Keywords: H19; cancer; polymorphism; susceptibility; meta-analysis 1. Introduction Cancer incidence and mortality are rapidly growing worldwide, which is considered to be the leading cause of death, as well as the single most significant barrier to increasing life expectancy globally in the contemporary society (Wild, 2019). Based on the date of International Agency for Research on Cancer, GLOBOCAN estimates that there would be 18.1 million new cancer cases and 9.6 million deaths in 2018 (Bray et al., 2018). There are varieties of elements related to the progression of cancer, such as genetic factors, environmental factors, unhealthy dietary practices and lifestyles, chronic inflammation and so on (Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015)(Romani et al., 2015). Genetic factors are one of the common factors about the cancer which influence the susceptibility and pathophysiology of cancer (Dong et al., 2008). Long noncoding RNA (lncRNA), generally defined as a set of noncoding RNA which has more than 200 bases in length and is unable to be translated into proteins, plays critical roles in a broad range of biological processes, such as cell cycle regulation, cell differentiation regulation, cell proliferation regulation and stress response (Fatica and Bozzoni, 2014). LncRNA participate in those process through the regulation of gene expression at multiple levels, including transport, chromatin modification, RNA maturation, transcription and so on (Guttman and Rinn, 2012; Zhang et al., 2016). In recent years, the number of lncRNAs identified in the human genome has been over 50000 and the relationship between lncRNA and cancer has been comprehensively investigated with in-depth biological functional study of lncRNAs (UszczynskaRatajczak et al., 2018). LncRNA H19 is one of the most important lncRNAs in cancer. It is located on chromosome 11p15.5 and is 2.3 kb in length (Brannan et al., 1990). The H19 has been identified to be associated with many types of cancer including bladder cancer, gastric cancer, esophageal cancer, and hepatic carcinoma (Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019)(Liu et al., 2019). As the most common genetic variation, single nucleotide polymorphisms (SNPs) are becoming more and more popular in cancer research. According to the previously studies, SNPs were found to be able to predict the risk and prognosis of cancer (Hincza et al., 2019; Yang et al., 2019a). From 2008, subsequent studies even two meta-analysis explored the possible role of H19 SNPs in cancer susceptibility. The findings are still
controversial and more than 10 studies were published in recent two years. Therefore, we conducted this update meta-analysis to find out the association between the cancer susceptibility and six common H19 polymorphisms (rs2107425, rs217727, rs2735971, rs2839698, rs3024270, and rs3741219). 2. Material and methods 2.1 Publication search Two investigators independently performed a systematic computerized search for English studies using PubMed and Embase up to May 31, 2019. The keywords used are as follow: “H19 or lncRNA H19 or long non-coding RNA H19”, “polymorphisms or variants or variation or SNP” and “cancer or carcinoma or tumor or neoplasm”. In addition, studies were identified through a manual search of reviews and retrieved studies. Studies were included according to the following criteria: 1) case-control study and 2) evaluation of the association between lncRNA H19 SNPs and cancer susceptibility. The exclusion criteria were: 1) duplication publication using the same population; and 2) no available data even contracted with authors. 2.2 Data extraction Data were extracted by two independent investigators from included studies. Divergence were solved after discussion on every item. The collected information from each articles were as follows: first author, publication year, region, cancer type, cases and controls number, source of control, genotype frequencies, genotyping method, and P value for Hardy–Weinberg equilibrium (HWE) of controls. Meanwhile, we categorized ethnicity as Caucasian, African or Asian. 2.3 Methodology quality assessment Two investigators independently evaluated the quality of the included articles. The quality score items were included: representativeness of the cases, source of the controls, genotyping examination, HWE in controls and association assessment (Li et al., 2017). The scores ranged 0–10. 2.4 Statistical Analysis The HWE for control subjects of each studies was evaluated by a chi-square test, and P < 0.05 was seen as significant disequilibrium. Odds ratios (ORs) and the 95% confidence intervals (95% CIs) was calculated to evaluate the association of the H19 SNPs and cancer susceptibility. The pooled ORs were executed for homozygote comparison, dominant and recessive models, allele comparison and heterozygote comparison. The heterogeneity was calculated using the chi-square-based I2 test and the Q test. The fixed-effect model (the Mantel-Haenszel method) was chosen to use when the I2 value is less than 50%. While the I2 is more than 50%, a random-effects model (DerSimonian and Laird method) was adopted. Moreover, the eligible study was sequentially removed in order to perform the sensitivity analysis. Publication bias were assessed by Begg’s rank correlation and Egger’s linear regression. The publication bias
was seen to be significant statistically when P<0.05. All of the statistical analyses were conducted by the STATA 12.0 (StataCorp, College Station, TX, USA), the P values were two-sided. 3. Results 3.1 Characteristics of studies A total of 183 potentially relevant publications were included in the systematic review after duplicates removed and 25 articles including 20,362 cancer patients and 26,709 controls were eligible for inclusion at the end (Figure 1) (Verhaegh et al., 2008; Quaye et al., 2009; Song et al., 2009; Barnholtz-Sloan et al., 2010; Butt et al., 2012; Yang et al., 2015; Gong et al., 2016; Hua et al., 2016; Li et al., 2016; Xia et al., 2016; Guo et al., 2017; Hassanzarei et al., 2017; He et al., 2017; Hu et al., 2017; Lin et al., 2017; Cui et al., 2018; Li et al., 2018; Yang et al., 2018; Yin et al., 2018; Yuan et al., 2018; Abdollahzadeh and Ghorbian, 2019; Hu et al., 2019; Li and Niu, 2019; Safari et al., 2019; Yang et al., 2019b). Among these 25 articles, 8 studies focused on Caucasian populations, 17 on Asian populations and only 1 on African populations (one article included both Caucasian and African population). For the control groups of these articles, 7 were hospital based, 17 were population based, and 1 did not described. The characteristics of the eligible studies are listed in Table 1. The distributions of genotype frequency among 12 SNPs in lncRNA H19 are listed in Table 2. After removal of those records for which PHWE < 0.05 and date not enough or available for meta-analysis, 6 SNPs (rs2107425, rs217727, rs2735971, rs2839698, rs3024270, and rs3741219) were finally included in our analysis. 3.2 Meta-analysis of the lncRNA H19 rs2107425 C>T polymorphism and cancer risk Nine studies including 11,107 cancer patients and 15,365 controls were used to examine the relation between the H19 rs2107425 C>T polymorphism and cancer susceptibility. No significant associations were shown between rs2107425 polymorphism and overall cancer risk or subgroup analyses by cancer type in all the five genetic models. However, subgroup analyses by race showed that rs2107425 C>T was related to an increasing risk in Asian (T vs C: OR 1.13, 95% CI 1.01-1.28; TT+CT vs CC: OR 1.21, 95% CI 1.03-1.44; CT vs CC: OR 1.21, 95% CI 1.01-1.44) and decreasing risk in Caucasian (T vs C: OR 0.90, 95% CI 0.84-0.97; TT+CT vs CC: OR 0.84, 95% CI 0.75-0.94; CT vs CC: OR 0.82, 95% CI 0.72-0.94) (Figure 2A and Table 3). Heterogeneity was shown to exist in the allelic, dominant and heterozygote comparison of overall, Caucasian and breast subgroup according to the results (Table 3 and Supplement Table 1). Sensitivity analysis results indicated that the pooled ORs of rs2107425 C>T polymorphisms were not materially altered by the contribution of any individual study (Figure 3A and Supplement Table 2). No significant publication bias was observed in the studies about rs2107425 polymorphism (Table 4).
3.3 Meta-analysis of the lncRNA H19 rs217727 G>A polymorphism and cancer risk Eighteen studies including 9,625 cancer patients and 11,667 controls were used to examine the association between the H19 rs217727 G>A polymorphism and cancer susceptibility. An increasing risk of rs217727 G>A polymorphism were only found in the Asian subgroup (A vs G: OR 1.09, 95% CI 1.02-1.17; AA+GA vs GG: OR 1.12, 95% CI 1.01-1.21; AA vs GG: OR 1.18, 95% CI 1.02-1.36, Figure 2B). No significant associations were found between this SNP and cancer risk among overall, bladder cancer, breast cancer or Caucasian group in any of the five genetic models (Table 3). Heterogeneity results showed that heterogeneity existed in all group of the five genetic models expect the bladder group of allelic model (Table 3 and Supplement Table 1). Sensitivity analysis results showed that the pooled ORs of rs217727 G>A polymorphisms were only slightly altered when the data from Safari’s study was removed in allelic model (Figure 3B and Supplement Table 2). No significant publication bias were observed in the studies about rs2107425 polymorphism (Table 4). 3.4 Meta-analysis of the lncRNA H19 rs2839698 G>A polymorphism and cancer risk Thirteen studies including 7,741 cancer patients and 8,656 controls were used to examine the association between the H19 rs2839698 G>A polymorphism and cancer risk. An increased risk was identified between rs2839698 polymorphism and overall cancer risk (A vs G: OR 1.18, 95% CI 1.06-1.31). Besides that, the increased risk was also found in breast cancer group (A vs G: OR 1.67, 95% CI 1.14-2.45; AA+AG vs GG: OR 1.98, 95% CI 1.20-3.25; AG vs GG: OR 1.89, 95% CI 1.16-3.07; Figure 2C), in Asian (A vs G: OR 1.09, 95% CI 1.03-1.14; AA+AG vs GG: OR 1.11, 95% CI 1.041.21; AA vs AG+GG: OR 1.12, 95% CI 1.01-1.25; AA vs GG: OR 1.15, 95% CI 1.011.49; AG vs GG: OR 1.09, 95% CI 1.02-1.17), and in Caucasian (AA vs AG+GG: OR 1.81, 95% CI 1.25-2.61, Figure 2D) (Table 3). It showed that heterogeneity existed in allelic, dominant, homozygote and heterozygote models of overall group and in all five genetic models of breast subgroup. No heterogeneity was found in Asian group. The heterogeneity just was not identified in recessive model of Caucasian group. In bladder subgroup, the heterogeneity was only found in heterozygote genetic model (Table 3 and Supplement Table 1). Sensitivity analysis results showed that the statistically significant was altered when the data from Hassanzarei’s and Safari’s studies were removed in heterozygote model and the data from Li’s study was removed in homozygote model (Figure 3C and 3D and Supplement Table2). No significant publication bias were observed in the studies about rs2839698 polymorphism (Table 4). 3.5 Meta-analysis of the lncRNA H19 rs2735971 T>C, rs3024270 C>G and rs3741219 A>G polymorphisms and cancer risk
The association between the H19 rs2735971 T>C, rs3024270 C>G and rs3741219 A>G polymorphisms and cancer risk were separately examined in 6 studies involving 3,515 patients and 4,386 healthy controls, 8 studies involving 4,244 patients and 5,628 healthy controls, and 6 studies involving 3,266 patients and 3,415 healthy controls. There were no significant associations found between those three SNPs and cancer risk among all overall and subgroup in any of the five genetic models (Table 3 and Supplement Figure 1). Results of heterogeneity test showed that in rs2735971 overall group, the heterogeneity existed in allelic, recessive and homozygote models. In rs3024270 overall group and bladder subgroup and rs3741219 Asian group, no heterogeneity was found. In rs3741219 overall group and breast subgroup, the heterogeneity just was not identified in recessive model (Table 3 and Supplement Table 1). No substantial changes were observed in rs2735971 and rs3741219 polymorphism. However, a slight change were found when Hua’s data was removed in allelic, recessive and homozygote models of rs3024270 (Supplement Figure 2 and Supplement Table 2). No significant publication bias were observed in the studies about these three polymorphism (Table 4). 4. Discussion Various studies have been conducted to examine whether H19 polymorphism can affect cancer susceptibility, and two meta-analysis including 5 SNPs of H19 was performed in 2017 (Li et al., 2017; Lv et al., 2017). However, the findings are still controversial even in those two meta-analysis. For example, rs2839698 was found to be associated with overall cancer risk in Lv’s study. However, Li found that it was only associated with digestive cancer risk (Li et al., 2017; Lv et al., 2017). Moreover, another 10 studies on H19 were published in last two years. Therefore, it is necessary to conduct this updated meta-analysis. In this study, we collected all of relevant published data up to May 31, 2019, detected the associations between lncRNA H19 rs2107425, rs217727, rs2839698, rs2735971, rs3024270 and rs3741219 polymorphisms and cancer risk. We obtained some new conclusions. For rs2107425 C>T polymorphism, the same conclusion with previous study was obtained that it’s related to a decrease risk in Caucasian group (Li et al., 2017). However, we also found it was related to an increasing risk in Asian. For rs217727 G>A polymorphism, it was found no association with cancer risk in previous meta-analysis, but in our study it was related to an increasing risk in the Asian (Li et al., 2017; Lv et al., 2017). For rs2839698 G>A polymorphism, our study found a similar result with Lv’s study that it was associated with an increased cancer risk in overall and in Asian group(Lv et al., 2017). Moreover, we found it was also associated with an increased cancer risk in Caucasian group in recessive model and in breast cancer group in allelic, dominant, recessive and heterozygote models. For rs2735971 T>C and rs3024270 C>G polymorphisms, they were found be associated with decreased overall risk of cancer when compared with the wild type in Lv’s study (Lv et al., 2017). However, in our study no significant association was found. For rs3741219 A>G
polymorphism, this is the first meta-analysis about cancer risk, and no significant association was found. In recent studies, H19 was found over-expressed in various cancers, such as breast cancer, thyroid cancer, hepatic cancer and gastric cancer (Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018)(Yoshimura et al., 2018). It belongs to a highly conserved imprinted gene and has three transcript variants, and all of them have five exons and four introns (Gabory et al., 2010). The reasons H19 polymorphisms affect cancer risk were not clearly understood. Previous studies showed that 75% of the SNPs have influence on the lncRNA expression (Kumar et al., 2013). One research found the rs217727 GG carriers had much higher H19 expression than GA and AA carriers in hepatocellular carcinoma, this means rs217727 G>A may regulate the expression of H19, but the detail mechanism was not described(Ge et al., 2019). Besides that, we should pay attention to the location of SNPs when dissecting the mechanisms of SNPs (Gao and Wei, 2017). For example, SNPs located at the promoter can regulated the transcriptional activity, and SNP located at the exons can change the secondary structure of lncRNA (Yuan et al., 2016; Wang et al., 2019). In this study, six H19 SNPs were investigated in meta-analysis (rs2107425, rs217727, rs2839698, rs2735971, rs3024270 and rs3741219), and their relative locations are shown in Figure 4. We can see two SNPs (rs217727 and rs3741219) locate in the exons and one (rs3024270) in the introns of all three transcript variants, two SNPs (rs2107425 and rs2735971) locate in the introns of transcript variant 3 and the promoter of transcript variant 1 and 2, and one SNP (rs2839698) locate in the in the introns of transcript variant 3 and the exons of transcript variant 1 and 2. The location of rs2107425 is inconsistent, that’s means the mechanism of this SNP may be more complex. It may regulate the transcription of transcript variant 1 and 2, however this is not verified. Rs217727 locates in the exons of all transcript variants, which means it may change gene structure and function. Additionally, the LncRNASNP2 database (http://bioinfo.life.hust.edu.cn/lncRNASNP#!/) showed that the rs217727 and rs2839698 can alter the interaction of miRNAs and H19 but there is no direct verification. Heterogeneities were found in almost all of the polymorphisms in this meta-analysis. Stratified analyses suggested that patient ethnicity and cancer location might have contributed to the heterogeneities. And ethnicity may be the more important factor for heterogeneities especially in rs2107425 C>T polymorphism, because completely different genotype frequencies in Asian and Caucasian were observed. Several limitations should be taken into account in this meta-analysis. First, environmental factors and patients’ characteristics were not considered in this study, so the roles of gene environment interactions could not be assessed. Second, all of the data included in this study mainly focused on the Asian and Caucasian population. It remains unclear that whether these results can be promoted and applied on other populations or
not. Third, heterogeneity existed in almost all of the six polymorphism and could not be totally eliminated by subgroup analysis, this may influence our results. 5. Conclusion Our meta-analysis results showed that H19 rs2107425 C>T was associated with an increase risk in Asian and decrease risk in Caucasian, rs217727 G>A polymorphism was related to an increasing risk in the Asian, rs2839698 G>A polymorphism was associated with an increased risk in Asian and Caucasian. No significant association was found in H19 rs2735971, rs3024270 and rs3741219 polymorphisms and cancer risk. Further studies equipped with different ethnicities, as well as a large population size, are still needed. Acknowledgments The authors would like to thank Xiaoyue Zhu, for her discussion the statistical methods with authors. Conflict of interest The authors declare that they have no competing of interests. Funding This study was funded by The National Natural Science Foundation of China (No. 81872089, 81370849, 81672551, 81300472, 81070592, 81202268, 81202034), Natural Science Foundation of Jiangsu Province (BK20161434, BL2013032, BK20150642 and BK2012336), Six talent peaks project in Jiangsu Province, Jiangsu Provincial Medical Innovation Team (CXTDA2017025), Jiangsu Provincial Medical Talent (ZDRCA2016080), and Basic scientific research Funding of Southeast University (2242019K40239). Author Contributions Chunhui Liu and Bin Xu conceived and designed the study. Chunhui Liu and Lusi Chen collected the data. Chunhui Liu and Zonghao You evaluated the quality of the studies. Chunhui Liu and Can Wang analyzed the data. Chunhui Liu and Yuqing Wu wrote the paper. Guangyuan Zhang and Ming Chen revised the paper. All authors read and approved the final manuscript prior to submission. References Abdollahzadeh, S. and Ghorbian, S. Association of the study between LncRNA-H19 gene polymorphisms with the risk of breast cancer. J Clin Lab Anal, 2019;33, e22826. Barnholtz-Sloan, J.S., Shetty, P.B., Guan, X., Nyante, S.J., Luo, J., Brennan, D.J. and Millikan, R.C. FGFR2 and other loci identified in genome-wide association
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Urothelial Cell Carcinoma Development. Int J Environ Res Public Health, 2019b;16. Yin, Z., Cui, Z., Li, H., Li, J. and Zhou, B. Polymorphisms in the H19 gene and the risk of lung Cancer among female never smokers in Shenyang, China. BMC Cancer, 2018;18, 893. Yoshimura, H., Matsuda, Y., Yamamoto, M., Kamiya, S. and Ishiwata, T. Expression and role of long non-coding RNA H19 in carcinogenesis. Front Biosci (Landmark Ed), 2018;23, 614-625. Yuan, H., Liu, H., Liu, Z., Owzar, K., Han, Y., Su, L., Wei, Y., Hung, R.J., McLaughlin, J., Brhane, Y., et al. A Novel Genetic Variant in Long Noncoding RNA Gene NEXN-AS1 is Associated with Risk of Lung Cancer. Sci Rep, 2016;6, 34234. Yuan, Z., Yu, Y., Zhang, B., Miao, L., Wang, L., Zhao, K., Ji, Y., Wang, R., Ma, H., Chen, N., et al. Genetic variants in lncRNA H19 are associated with the risk of oral squamous cell carcinoma in a Chinese population. Oncotarget, 2018;9, 23915-23922. Zhang, S., Zhang, G. and Liu, J. Long noncoding RNA PVT1 promotes cervical cancer progression through epigenetically silencing miR-200b. APMIS, 2016;124, 649-58. Figure legends： Figure 1. Flow diagram for study selection Figure 2. Forest plot for the H19 polymorphism and cancer susceptibility. A: rs2107425, B: rs217727, C: rs2839698 subgroup analysis by cancer, D: rs2839698 subgroup by ethnicity. Figure 3. Sensitivity analyses for the H19 polymorphism and cancer susceptibility. A: rs2107425 in allelic model, B: rs217727 in allelic model, C: rs2839698 in heterozygote model, D: rs2839698 in homozygote model. Figure 4. The sketch map of the studied SNPs’ location in the H19 gene. Supplement Figure 1: Forest plot for the H19 polymorphism and cancer susceptibility. A: rs2735971, B: rs3024270, C: rs3741219. Supplement Figure 2: Sensitivity analyses for the H19 polymorphism and cancer susceptibility. A: rs2735971, B: rs3024270, C: rs3741219. Table 1 Characteristics of eligible studies. Table 2 Genotype frequency distributions of of H19 in included studies.
Table 3 Meta-analysis results of the association between H19 SNPs and cancer risk. Table 4 The results of publication bias from Begg’s and Egger’s test. Supplement Table 1 The P value of heterogeneity from Q test. Supplement Table 2 ORs (95% CI) of sensitivity analysis.
Abbreviations: Long noncoding RNA (lncRNA) Single nucleotide polymorphisms (SNPs) Hardy–Weinberg equilibrium (HWE) Odds ratios (ORs) 95% confidence intervals (95% CIs)
Abstract Background: Long non-coding RNA H19 polymorphisms were reported to be related to cancer susceptibility. However, the results from individual studies have been controversial or inconsistent. To clarify the associations between H19 single nucleotide polymorphisms (rs2107425, rs217727, rs2735971, rs2839698, rs3024270, and rs3741219) and the cancer susceptibility more accurately. Methods: Relevant publications were searched from PubMed and EMBASE up to May 31, 2019, for studies in English only. The reference lists of the retrieved studies were also investigated. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to find out the relationship between the H19 polymorphisms and cancer susceptibility. All of the data were analyzed using Stata 12.0. Results: The results showed that rs2107425 polymorphisms was associated with an increasing cancer susceptibility in Asian (T vs C: OR 1.13, 95% CI 1.01-1.28; TT+CT vs CC: OR 1.21, 95% CI 1.03-1.44; CT vs CC: OR 1.21, 95% CI 1.01-1.44) and decreasing risk in Caucasian (T vs C: OR 0.90, 95% CI 0.84-0.97; TT+CT vs CC: OR 0.84, 95% CI 0.75-0.94; CT vs CC: OR 0.82, 95% CI 0.72-0.94). And rs217727 polymorphism was associated with an increasing cancer susceptibility in the Asian (A vs G: OR 1.09, 95% CI 1.02-1.17; AA+GA vs GG: OR 1.12, 95% CI 1.01-1.21; AA vs GG: OR 1.18, 95% CI 1.02-1.36). Additionally, rs2839698 polymorphism was
associated with an increasing risk overall (A vs G: OR 1.18, 95% CI 1.06-1.31), in breast cancer (A vs G: OR 1.67, 95% CI 1.14-2.45; AA+AG vs GG: OR 1.98, 95% CI 1.20-3.25; AG vs GG: OR 1.89, 95% CI 1.16-3.07), in Asian (A vs G: OR 1.09, 95% CI 1.03-1.14; AA+AG vs GG: OR 1.11, 95% CI 1.04-1.21; AA vs AG+GG: OR 1.12, 95% CI 1.01-1.25; AA vs GG: OR 1.15, 95% CI 1.01-1.49; AG vs GG: OR 1.09, 95% CI 1.02-1.17), and in Caucasian (AA vs AG+GG: OR 1.81, 95% CI 1.25-2.61). Conclusion: H19 rs2107425, rs217727 and rs2839698 were associated with an increasing cancer susceptibility in Asian. Rs2107425 was associated with a decreasing risk and rs2839698 was associated with an increasing risk in Caucasian. No significant association was found in H19 rs2735971, rs3024270 and rs3741219 polymorphisms and cancer susceptibility. Keywords: H19; cancer; polymorphism; susceptibility; meta-analysis
Conflict of interest The authors declare that they have no competing of interests.
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Highlights: This is the first meta-analysis investigated the association between H19 polymorphism rs3741219 and cancer susceptibility. This meta-analysis also investigated the association between another five H19 polymorphism (rs2107425, rs217727, rs2735971, rs2839698, and rs3024270) and cancer susceptibility for an update based on the newest data until May 31, 2019. Our results showed H19 rs2107425, rs217727 and rs2839698 were associated with an increasing cancer susceptibility in Asian. H19 rs2107425 was associated with a decreasing risk and H19 rs2839698 was associated with an increasing risk in Caucasian. No significant association was found in H19 rs2735971, rs3024270 and rs3741219 polymorphisms and cancer susceptibility.
Table 1 Characteristics of eligible studies First author
Year
Cancer type
Country
Ethnicity
Sample size
Source of
Genotypin
control Case
Control
method
Verhaegh
2008
Bladder
Netherlands
Caucasian
177
204
PB
PCR-RFL
Quaye
2009
Ovarian
Mix
Caucasian
1457
2463
PB
TaqMan
Song
2009
Ovarian
Mix
Caucasian
5366
8538
PB
TaqMan
Sloan
2010
Breast
USA
African
737
658
PB
GoldenGa
USA
Caucasian
1225
1118
PB
GoldenGa
Butt
2012
Breast
Sweden
Caucasian
679
1355
PB
MassArra
Yang
2015
Gastric
China
Asian
500
500
HB
TaqMan
Gong
2016
Breast
China
Asian
479
203
HB
TaqMan
Hua
2016
Bladder
China
Asian
1046
1394
HB
TaqMan
Li
2016
Colorectal
China
Asian
1147
1203
PB
TaqMan
Xia
2016
Breast
China
Asian
464
467
PB
PCR-RFL
Guo
2017
Oral
China
Asian
461
739
PB
BeadChip
Hassanzarei
2017
Breast
India
Caucasian
230
240
ND
PCR-RFL
He
2017
Osteosarcoma
China
Asian
193
383
HB
TaqMan
Hu
2017
Pancreatic
China
Asian
416
416
PB
TaqMan
Lin
2017
Breast
China
Asian
1005
1020
HB
Genesky
Cui
2018
Breast
China
Asian
1488
1675
PB
TaqMan
Li
2018
Lung
China
Asian
555
618
PB
TaqMan
Yang
2018
Hepatocellular
China
Asian
465
465
HB
KASP
Yin
2018
Lung
China
Asian
556
395
HB
Illumina
Yuan
2018
Oral
China
Asian
431
984
PB
MassARR
Abdollahzadeh
2019
Breast
Iran
Caucasian
150
100
PB
PCR-RFL
Hu
2019
Neuroblastoma
China
Asian
393
810
PB
TaqMan
Li
2019
Bladder
China
Asian
200
200
PB
TaqMan
Safari
2019
Breast
Iran
Caucasian
111
130
PB
4P-ARMS
Yang
2019
Bladder
China
Asian
431
431
PB
TaqMan
PB: Population or Healthy based; HB: Hospital based; ND: Not described; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism.
Table 2 Genotype frequency distributions of of H19 in included studies First author
Verhaegh
Year
2008
Type of cancer
Bladder
Country
Netherlan
SNP
Case
Control
N
AA
Aa
Aa
N
AA
rs2107425C/T
177
92
65
20
204
89
rs217727T/C
177
114
59
4
204
115
rs2839698C/T
177
54
74
49
204
52
rs2735469C/T
177
119
51
7
204
136
rs17658052G/A
177
151
26
0
204
181
ds
Quaye
2009
Ovarian
Mix
rs2107425C/T
1457
764
544
149
2463
1118
Song
2009
Ovarian
Mix
rs2107425C/T
5366
2619
2192
555
8538
4029
Sloan
2010
Breast
USA
rs2107425C/T
737
161
390
186
658
170
USA
rs2107425C/T
1225
604
516
105
1118
521
Butt
2012
Breast
Sweden
rs2107425C/T
679
361
250
68
1355
637
Yang
2015
Gastric
China
rs217727C/T
500
160
252
88
500
193
rs2839698C/T
500
250
195
55
500
284
Gong
Hua
Li
Xia
Guo
Hassanzarei
2016
2016
2016
2016
2017
2017
Breast
Bladder
Colorectal
Breast
Oral
Breast
China
China
China
China
China
India
rs3741216A/T
500
380
102
18
500
379
rs3741219T/C
500
260
187
53
500
268
rs2107425C/T
479
181
235
63
203
79
rs2839698G/A
496
237
220
39
206
99
rs217727G/A
1046
431
467
148
1394
573
rs2735971C/T
1049
704
302
43
1396
928
rs2839698G/A
1049
552
418
79
1337
729
rs3024270G/C
1047
346
527
174
1395
447
rs2839698G/A
1147
583
462
102
1203
666
rs3024270C/G
1147
385
527
235
1203
420
rs217727G/A
1147
480
514
153
1203
456
rs2735971C/T
1147
773
334
40
1203
765
rs217727C/T
464
160
156
148
467
139
rs3741219T/C
464
238
186
40
467
245
rs2735971C/T
461
191
141
129
739
351
rs217727G/A
362
101
181
80
737
252
rs2839698G/A
362
58
171
133
741
120
rs3024270G/C
362
104
183
75
740
245
rs3741219T/C
230
63
126
41
240
109
rs217727C/T
230
71
132
27
240
125
rs2839698T/C
230
166
64
0
240
222
rs3741216T/A
230
204
26
0
240
175
He
2017
Osteosarcoma
China
rs2735971C/T
193
88
94
11
383
169
rs217727G/A
193
79
102
12
383
195
rs2839698G/A
193
83
98
12
383
178
rs3024270G/C
193
85
91
17
383
173
Hu
2017
Pancreatic
China
rs217727C/T
416
133
200
83
416
128
Lin
2017
Breast
China
rs217727 C/T
1005
403
471
131
1020
465
rs2839698C/T
1005
452
440
113
1020
484
rs217727 G/A
1488
611
692
185
1675
685
rs2071095C/A
1492
792
580
120
1674
786
rs2251375C/A
1491
504
704
283
1677
569
rs2839698G/A
1677
875
673
129
1491
801
rs2839701C/G
1490
762
600
128
1677
801
rs3741219A/G
1491
782
582
127
1677
832
Cui
2018
Breast
China
Li
2018
Lung
China
rs217727 G/A
555
210
250
95
618
246
Yang
2018
Hepatocellular
China
rs2735971G/A
465
327
126
12
465
313
rs2839698C/T
466
215
211
40
462
245
rs3024270G/C
471
151
225
95
466
170
rs217727 C/T
556
204
264
88
395
165
rs2107425C/T
556
161
266
129
395
140
rs2735469C/T
556
507
46
3
395
359
rs17658052G/A
556
507
47
2
395
371
rs217727 C/T
431
186
194
51
984
488
Yin
Yuan
2018
2018
Lung
Oral
China
China
Abdollahzadeh
Hu
2018
2019
Li
2019
Safari
2019
Yang
2019
Breast
Iran
Neuroblastoma
Bladder
Breast
Bladder
China
China
Iran
China
rs2839701C/G
444
205
188
51
984
507
rs217727 C/T
150
116
29
5
100
86
rs3741219 T/C
150
119
24
7
100
80
rs2839698G/A
393
179
175
39
810
365
rs3024270C/G
393
99
203
91
810
213
rs217727 G/A
393
186
164
43
810
382
rs217727 G/A
200
51
140
9
200
84
rs2735971C/T
200
128
62
10
200
126
rs3024270G/C
200
83
101
16
200
81
rs2839698C/T
111
15
57
39
130
53
rs217727 C/T
111
79
30
2
130
64
rs217727 C/T
431
185
202
44
431
191
rs2107425C/T
431
152
213
66
431
171
rs2839698C/T
431
206
170
55
431
192
rs3024270C/G
431
114
210
107
431
120
rs3741219A/G
431
192
181
58
431
185
AA: Homozygote; Aa: Common heterozygote; aa: Homozygote variant of case; aa: rare homozygote
Table 3 Meta-analysis results of the association between H19 SNPs and cancer risk SNP
N
Allelic model OR(95% CI)
Dominant model I2 (%)
OR(95% CI)
Recessive model I2 (%)
OR(95% CI)
Homozygot I2 (%)
OR(95%
rs2107425 Overall
9
0.98(0.90-1.06)a
69.4
0.95(0.84-1.08)a
74.5
1.04(0.96-1.12)
13.2
1.00(0.92-1
Breast
4
0.96(0.84-1.10)a
67.8
0.96(0.79-1.77)a
68.3
0.96(0.83-1.11)
27.9
0.95(0.72-1
Asian
3
1.13(1.01-1.28)
26.7
1.21(1.03-1.44)
0.0
1.12(0.91-1.40)
39.0
1.24(0.98-1
Caucasian
5
0.90(0.84-0.97) a
51.0
0.84(0.75-0.94) a
64.8
1.01(0.92-1.10)
8.4
0.94(0.86-1
Overall
18
1.07(0.99-1.16)a
69.7
1.08(0.97-1.21)a
71.5
1.11(0.95-1.29)a
64.2
1.14(0.97-1
Bladder
4
1.03(0.94-1.13)
38.2
1.10(0.80-1.52)a
78.9
0.73(0.40-1.32)a
79.9
0.89(0.59-1
Breast
5
1.00(0.80-1.25)a
84.0
0.94(0.70-1.25)a
82.6
1.13(0.81-1.58)a
69.8
1.06(0.73-1
Asian
15
1.09(1.02-1.17)a
56.0
1.12(1.01-1.24)a
65.2
1.14(0.99-1.31)a
63.6
1.18(1.02-1
Caucasian
3
0.82(0.39-1.73)a
86.7
0.77(0.36-1.64)a
83.1
0.58(0.12-2.90)a
61.3
0.54(0.09-3
6
1.09(0.90-1.32)a
81.9
1.01(0.90-1.12)
8.8
1.40(0.86-2.28)a
86.8
1.32(0.78-2
Overall
13
1.18(1.06-1.31) a
77.8
1.21(1.04-1.40) a
78.0
1.16(1.05-1.29)
31.8
1.24(1.03-1
Asian
10
1.09(1.03-1.14)
18.2
1.11(1.04-1.21)
1.1
1.12(1.01-1.25)
1.2
1.15(1.01-1
Caucasian
3
2.16(0.96-4.86) a
92.5
2.50(0.71-8.84) a
93.7
1.81(1.25-2.61)
22.8
2.38(0.52-1
Bladder
3
1.01(0.92-1.12)
0.0
1.00(0.87-1.14)
32.3
1.07(0.86-1.32)
0.0
1.00(0.80-1
Breast
4
1.67(1.14-2.45) a
93.2
1.98(1.20-3.25) a
92.9
1.27(0.84-1.93) a
69.4
1.67(0.86-3
rs217727
rs2735971 Overall rs2839698
rs3024270
Overall
8
1.05(0.99-1.11)
0.0
1.06(0.97-1.15
0.0
1.07(0.96-1.19)
19.2
1.10(0.98-1
Bladder
3
0.96(0.88-1.06)
0.0
0.98(0.85-1.13)
0.0
0.91(0.77-1.07)
0.0
0.91(0.75-1
Overall
6
1.09(0.93-1.27) a
68.3
1.10(0.89-1.37) a
74.2
1.12(0.95-1.32)
0.0
Breast
4
1.14(0.88-1.47) a
80.2
1.19(0.82-1.73) a
84.1
1.11(0.91-1.35)
0.0
1.30(0.83-2
Asian
4
0.98(0.91-1.06)
0.0
0.95(0.86-1.05)
0.0
1.07(0.89-1.27)
0.0
1.03(0.86-1
rs3741219
1.13(0.95-1
OR, odds ratio; CI, confidence interval. The results are in bold if P < 0.05. a P was calculated by random model.
Table 4 The results of publication bias from Begg’s and Egger’s test SNP
Allelic model
Dominant model
Recessive model
Homozygote vs w
P(Begg’s)
P(Egger’s)
P(Begg’s)
P(Egger’s)
P(Begg’s)
P(Egger’s)
P(Begg’s)
P(E
rs2107425
0.532
0.392
0.677
0.198
0.835
0.622
0.835
0.8
rs217727
0.520
0.611
0.733
0.872
0.472
0.124
0.622
0.2
rs2735971
0.851
0.415
0.573
0.716
0.573
0. 449
0.573
0.1
rs2839698
0.143
0.127
0.329
0.377
0.222
0.998
0.222
0.7
rs3024270
0.322
0.793
0.458
0.766
0.621
0.447
0.322
0.5
rs3741219
0.188
0.291
0.573
0.224
0.188
0.534
0.091
0.4