H19 Polymorphisms Research Articles

Effects of Long Noncoding RNA H19 Polymorphisms on Urothelial Cell Carcinoma Development.

Urothelial cell carcinoma (UCC) is one of the major malignancies of the genitourinary tract, and it is induced by carcinogenic epidemiological risk factors. H19 is one of the most crucial long noncoding RNAs (lncRNAs) and is involved in various types of bladder cancer. In this study, we examined H19 single-nucleotide polymorphisms (SNPs) to investigate UCC susceptibility and clinicopathological characteristics. Using real-time polymerase chain reaction, we analyzed five SNPs of H19 in 431 UCC patients and 431 controls without cancer. The results showed that patients with UCC carrying the H19 rs217727 CT + TT and rs2107425 CT + TT genetic variants had a high risk of developing muscle invasive tumors (pT2–T4) (p = 0.030; p = 0.025, respectively). With a median follow up of 39 months, CT+TT polymorphisms of rs2107425 were associated with worse disease-specific survival (adjusted hard ratio (AHR) = 2.043, 95% confidence interval (CI) = 1.029-4.059) in UCC patients aged older than 65 years. In conclusion, our results indicate that patients with UCC carrying the H19 rs217727 CT + TT and rs2107425 CT + TT genetic variants have a high risk of developing muscle invasive tumors. Thus, H19 polymorphisms may be applied as a marker or therapeutic target in UCC treatment.

The clinicopathological characteristic associations of long non-coding RNA gene H19 polymorphisms with uterine cervical cancer.

The purposes of the current study were conducted to explore the relationships among long non-coding RNA gene H19 (LncRNA H19) polymorphisms and clinicopathological characteristics of uterine cervical cancer, and patient prognosis in Taiwan. Five genetic variants of LncRNA H19 rs3024270, rs2839698, rs3741219, rs2107425 and rs217727 were recruited from one hundred and thirty-four patients with invasive cancer, 101 with high-grade cervical intraepithelial neoplasia (CIN) of uterine cervix and 325 controls and their genetic distributions were determined. It indicated no associations of these LncRNA H19 genetic variants with development of cervical cancer. CC/CT in LncRNA H19 rs2839698 exhibited less risk to have pelvic lymph node metastasis [Odds ratio (OR): 0.19, 95% Confidence interval (CI):0.04-0.82, p=0.028)], as compared with TT. Meanwhile, cervical cancer patients with AA/AG in rs3741219 also had less risk to develop pelvic lymph node metastasis (OR: 0.17, 95% CI: 0.05-0.63, p=0.008), large tumor (OR: 0.17, 95% CI: 0.04-0.82, p=0.014) as well as parametrium (OR: 0.26, 95% CI: 0.07-0.95, p=0.045) and vagina invasion (OR: 0.25, 95% CI: 0.07-0.91, p=0.041, as compared to those with GG. However, only positive pelvic lymph node metastasis was related to worse recurrence-free survival and poor overall survival. Conclusively, it indicated no association of LncRNA H19 SNPs with cervical carcinogensis in Taiwanese women. Although genotypes TT in LncRNA H19 rs2839698 and GG in rs3741219 are related to some poor clinicopathological parameters of cervical cancer, only pelvic lymph node status could predict 5 year patient survival significantly.

Long non-coding RNA H19 and MALAT1 gene variants in patients with ischemic stroke in a northern Chinese Han population

Objectives Long non-coding RNAs (lncRNAs) have been identified as key regulators in the development of atherosclerosis, which is a major cause of ischemic stroke. However, to date, there are no reports on the association between lncRNA gene variation and the risk of ischemic stroke. Therefore, we assessed the association between H19 and MALAT1 gene polymorphisms and susceptibility to ischemic stroke in a northern Chinese Han population. Methods In our study, we genotyped four genetic variations in lncRNA-H19 and -MALAT1 (rs217727, rs2251375, rs619586, and rs3200401) in a case–control study of 567 ischemic stroke patients and 552 control subjects. Results We found that the TT genotype of the rs217727 polymorphism within H19 was significantly associated with increased risk of ischemic stroke in our northern Chinese Han population (odds ration (OR) = 1.519, 95% confidence interval (CI) = 1.072–2.152, p = 0.018). Stratified analysis based on stroke subtype revealed that the increased risk was more evident in small vessel ischemic stroke (OR = 1.941, 95% CI = 1.260–2.992, p = 0.02). Individuals with the TT genotype had a 1.941 times higher risk of small vessel ischemic stroke when compared with the subjects of CC + CT. These correlations remained after adjusting for confounding risk factors of stroke (OR = 1.913, 95% CI = 1.221–2.998, p = 0.005). However, there was no significant association between H19 rs2251375 or MALAT1 rs3200401 and ischemic stroke in either total population analysis or subgroup analysis. Conclusion In conclusion, our findings suggest that the H19 rs217727 gene polymorphism contributes to small vessel ischemic stroke susceptibility in the Chinese Han population and may serve as a potential indicator for ischemic stroke susceptibility.

Association between lncRNA H19 (rs217727, rs2735971 and rs3024270) polymorphisms and the risk of bladder cancer in Chinese population.

The Long non-coding RNA (lncRNA) H19 is involved in carcinogenesis, progression, and metastasis. However, the association between genetic variants in H19 and bladder cancer susceptibility has not been reported. This case-control study assessed the association between H19 genetic variants and susceptibility to bladder cancer in a Chinese Han population. In this study, 200 patients with bladder cancer and 200 healthy controls were surveyed and compared for frequencies of the genotypes of the H19 gene. Logistic regression analysis and the chi-square test were employed as statistical methods. Odds ratio (OR) and its corresponding 95% confidence interval (95% CI) were calculated to estimate the strength of association between H19 polymorphisms and risk of bladder cancer. We analyzed the frequency of three lncRNA H19 SNPs in 200 bladder cancer patients and 200 healthy controls. Carriers of variant rs217727 heterozygous genotype showed increased bladder cancer risk (P=0.008). Further stratified analyses revealed that the association between bladder cancer risk and variant genotypes of rs217727 was more profound in smokers. Furthermore, decreased risk of invasive bladder cancer was found in carrying rs3024270 CC patients. Our results provided the evidence that rs217727 in H19 was associated with elevated risk of bladder cancer, which may be a potential biomarker for predicting bladder cancer susceptibility. Furthermore, invasive bladder cancer in carrying rs3024270 CC genotype maybe have a good prognosis.

The long non-coding RNA H19 rs217727 polymorphism is associated with PE susceptibility.

H19 is an imprinted gene transcribing a long noncoding RNA which was previously reported to be involved in some diseases. However, the association between the H19 polymorphisms and Pre-eclampsia (PE) susceptibility has remained elusive. This study aimed to evaluate the association between three H19 haplotype SNPs (rs3741219, rs217727, and rs2107425) and the risk of PE. The present case control study consisted of 193 PE women and 201 controls. The H19 rs3741219 and rs217727 polymorphisms were genotyped with PCR-RFLP (Polymerase chain reaction-restriction fragment length polymorphism) and the H19 rs2107425 polymorphism with ARMS-PCR (Amplification refractory mutation system) methods. The frequency of alleles and genotypes of H19 rs3741219 and rs2107425 polymorphisms did not differ between PE women and controls. The frequency of the H19 rs217727T allele was significantly higher in PE women (P < 0.0001). The H19 rs217727 polymorphism was associated with higher PE susceptibility in the Co-dominant (OR = 12.1, 95% CI = 5.7-24.5, P < 0.0001 for CT genotype and OR = 29.7, 95% CI = 12.9-68.1, P < 0.0001 for TT genotype), Dominant (OR = 15.1, 95% CI = 7.5-30.3, P = P < 0.0001), Recessive (OR = 4.5, 95% CI = 2.6-7.9, P = < 0.0001), and Over-dominant (OR = 2.1, 95% CI = 1.4-3.1, P = 0.0006) models. Furthermore, the CCC, TCT, TCC, and CCT haplotypes of H19 rs3741219, rs217727, rs2107425 were associated with lower risk of PE; however, the CTC, TTC, and TTT haplotypes were associated with higher risk of PE. In conclusion, the present study found the relationship between H19 rs217727 but not rs3741219 and rs2107425 polymorphisms and PE susceptibility. In addition, the CTC, TTC, and TTT haplotypes were associated with the higher risk of PE.

No association of single nucleotide polymorphisms within H19 and HOX transcript antisense RNA (HOTAIR) with genetic susceptibility to systemic lupus erythematosus, rheumatoid arthritis, and primary Sjögren's syndrome in a Chinese Han population.

The H19 (rs2839698, rs3741219) and HOTAIR (rs920778) polymorphisms were related to many kinds of cancers. However, these polymorphisms have been scarcely explored in different autoimmune diseases. Here, we aimed to examine the association of the polymorphisms with susceptibility to or protection against systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren's syndrome (pSS) among Chinese Han patients. We conducted a case-control study including 800 patients (300 with SLE, 350 with RA, and 150 with pSS) and 350 healthy control individuals. The polymorphisms were specified from genomic DNA using TaqMan genotyping assay on a 7300 real-time reverse transcription polymerase chain reaction system. H19 rs2839698 was not associated with SLE susceptibility and was not associated with RA and pSS, respectively (P>0.05). Similarly, we did not find significant differences of allele or genotype frequencies between SLE, RA, and pSS patients and healthy controls for H19 gene rs3741219 polymorphism (P>0.05). In addition, no significant evidence was detected for the relationship of HOTAIR rs920778 polymorphism with risk of these diseases. Our results suggested that H19 rs2839698, rs3741219, and HOTAIR rs920778 polymorphisms may not be involved in the genetic background of SLE, RA, and pSS in Chinese.

Genetic variants in long noncoding RNA &lt;em&gt;H19 &lt;/em&gt;contribute to the risk of breast cancer in a southeast China Han population

The long noncoding RNA (lncRNA) H19 is a maternally expressed imprinted gene that plays important roles in tumorigenesis, progression, and metastasis. However, the association between polymorphisms on H19 and breast cancer (BC) susceptibility has remained obscure. In this case–control study, we assessed the interaction between two lncRNA H19 single-nucleotide polymorphisms (SNPs) (rs217727 C>T, rs2839698 C>T) and the risk of BC in a Chinese Han population. In total, 1,005 BC cases and 1,020 healthy controls were enrolled in this study. Correlations between genotypes and BC risk were evaluated by multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). False-positive report probability calculation was also utilized to identify false-positive associations. We observed that the rs217727 T variant was consistently significantly associated with an increased risk of BC in both codominant and dominant models (CT vs CC, OR 1.25, 95% CI 1.03–1.51; TT vs CC, OR 1.56, 95% CI 1.15–2.09; CT + TT vs CC, OR 1.31, 95% CI 1.09–1.57), and all associations remained significant after Bonferroni correction (P<0.025). Subsequent stratified analyses also revealed that associations between BC risk and rs217727 genotypes were more profound in patients with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, and hormone receptor-positive–HER2-negative molecular subtypes (all passed the threshold for Bonferroni correction, P<0.005). These findings extend available data on the association of H19 polymorphisms and BC susceptibility. Based on these results, we encourage further large-scale studies and functional research to confirm our findings and better elucidate the underlying biological mechanisms.

Significant association between lncRNA H19 polymorphisms and cancer susceptibility: a meta-analysis.

Previous epidemiological research suggests polymorphisms in long non-coding RNA (lncRNA) H19 are associated with an increased risk of cancer, but the results are inconsistent. We therefore conducted a meta-analysis to more accurately determine the association between lncRNA H19 polymorphisms and cancer risk. The PubMed, Embase, and Science Citation Index online databases were searched and 11 relevant studies involving a total of 33,209 participants were identified. Odds ratios (ORs) and corresponding 95% confidence interval (CIs) from these studies were used to detect associations between H19 polymorphisms and cancer risk using five genetic models. The pooled result suggested that the rs2839698 G>A polymorphism was associated with digestive cancer risk in all five models. Moreover, a protective effect against cancer development was observed for the T allele variant of the rs2107425 C>T polymorphism, especially in Caucasian patient populations. No significant associations were found between lncRNA H19 rs217727 G>A polymorphism and cancer risk. In summary, the rs2839698 G>A and rs2107425 C>T polymorphisms in lncRNA H19 may therefore play opposing roles during cancer development, and their effects may vary depending on cancer type and patient ethnicity.

Quantitative assessment of polymorphisms in H19 lncRNA and cancer risk: a meta-analysis of 13,392 cases and 18,893 controls.

H19 refers to a long non-coding RNA (lncRNA) that functions as an oncogenic molecule in different cancer cells. Genetic variants of H19 may affect the activity of certain regulatory factors, which subsequently regulate the aberrant expression of H19. This feedback loop might be one of the underlying mechanisms influencing tumour susceptibility and prognosis. Although there have been several recent studies that examined possible links between polymorphisms in H19 and cancer risk, the results have been inconclusive. Thus, we performed a meta-analysis to estimate the associations between H19 polymorphisms (rs2107425, rs2839698 and rs217727) and cancer risk. Ten studies comprising 13,392 cases and 18,893 controls were included in the study. Overall, the variant T allele of rs2107425 correlated with a significantly decreased risk of developing cancer (dominant model: OR = 0.86; 95% CI = 0.76–0.98). In addition, a marginally significant association between the rs2839698 and cancer risk was observed (dominant model: OR = 1.09; 95% CI = 0.99–1.20). After stratification for ethnicity, it became apparent that Asians with the variant A allele of rs2839698 exhibited a significantly higher risk of developing cancer (dominant model: OR = 1.11; 95% CI = 1.01–1.23). Interestingly, the rs2839698 variant was also significant associated with an increased risk of cancers of the digestive system (dominant model: OR = 1.23; 95% CI = 1.08–1.41). These findings provided evidence that H19 rs2107425 may modify general cancer susceptibility, while rs2839698 may modify cancer susceptibility based on ethnicity and type. Further experimental studies to evaluate the limits of this hypothesis are warranted, and future functional studies are required to clarify the possible mechanisms.

Association of genetic variants in lncRNA H19 with risk of colorectal cancer in a Chinese population.

ObjectiveThe long non-coding RNA (lncRNA) gene, H19, has been involving in multiple biological functions, which also plays a vital role in colorectal cancer carcinogenesis. However, the association between genetic variants in H19 and colorectal cancer susceptibility has not been reported. In this study, we aim to explore whether H19 polymorphisms are related to the susceptibility of colorectal cancer.MethodsWe conducted a case-control study to evaluate the association between four selected single nucleotide polymorphisms (SNPs) (rs2839698, rs3024270, rs217727, and rs2735971) in H19 and the risk of colorectal cancer in a Chinese population.ResultsWe found that individuals with rs2839698 A allele had a significantly increased risk of colorectal cancer, compared to those carrying G allele [odds ratio (OR) = 1.20, 95% confidence interval (CI) = 1.05–1.36 in additive model]. Further stratified analyses revealed that colon tumor site, well differentiated grade and Duke's stage of C/D were significantly associated with colorectal cancer risk (P < 0.05). Additionally, bioinformatic analysis showed that rs2839698 may change the crucial folding structures and alter the target microRNAs of H19.ConclusionsOur results provided the evidence that rs2839698 in H19 was associated with elevated risk of colorectal cancer, which may be a potential biomarker for predicting colorectal cancer susceptibility.

Genetic Polymorphisms in Long Noncoding RNA H19 Are Associated With Susceptibility to Breast Cancer in Chinese Population.

H19, a maternally expressed imprinted gene transcribing a long noncoding RNA, has previously been reported to be involved in tumorigenesis and cancer progression. However, the association between the H19 polymorphisms and breast cancer (BC) susceptibility has remained elusive. The aim of this study was to evaluate the associations between 2 H19 haplotype tagging SNPs (rs3741219 T>C, rs217727 C>T) and the risk of breast cancer.Our study comprised 464 BC patients and 467 cancer-free controls in China. rs3741219 and rs217727 were genotyped with polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) and created restriction site PCR (CRS-RFLP) assays, respectively. False-positive report probability (FPRP) was calculated to test the false-positive association.On performing univariate analysis, no significant association between H19 polymorphisms (rs3741219 and rs217727) and BC was observed. However, in further stratified analyses, CT+TT genotypes of rs217727 had a significantly lower risk of breast cancer among women with number of pregnancy >2 (OR = 0.79; 95% CI = 0.55–0.97). CT genotype of rs217727 was associated with ER positivity (OR = 2.19; 95 % CI = 1.07–4.45) and HER-2 positivity (OR = 1.34; 95 % CI = 1.05–2.12). It was proved that our results were less likely to be false positives according to false-positive report probability calculation.Our findings extend available data on the association of H19 polymorphisms and BC susceptibility. Further validation in large population or cohort studies is needed.

WITHDRAWN: Associations of the polymorphisms in long non-coding RNA H19 with hepatocellular carcinoma risk in a Southern Chinese population

// Zhifeng Lin 1, 2, * , Junguo Zhang 1, * , Xiaohui Ji 1 , Lucheng Pi 1 , Nana Tian 1 , Xinqi Lin 1 , Li Liu 1 , Sidong Chen 1 , Xinfa Yu 3 and Yanhui Gao 1 1 Department of Epidemiology and Health Statistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China 2 Medical Record Department of The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China 3 Shunde Hospital of Southen Medical University, Guangzhou, China * These authors contributed equally to this work Correspondence to: Yanhui Gao, email: gao_yanhui@163.com Xinfa Yu, email: yuxfa@126.com Keywords: hepatocellular carcinoma; HCC; LncRNA; H19; polymorphisms Received: September 15, 2017 Accepted: October 25, 2017 Published: January 02, 2018 ABSTRACT Background: Overexpression of H19 long non-coding RNA (lncRNA) has been observed in hepatocellular carcinoma (HCC), however, the role of H19 polymorphisms in the development of HCC was still unclear. Therefore, in this study, we aimed to explore whether the H19 polymorphisms were related to the susceptibility of HCC. Materials and Methods: A case-control study of 625 cases and 621 controls was conducted to investigate genetic associations of three potentially functional variants in H19 (rs2839702, rs2067051 and rs2075745) with HCC risk in a Southern Chinese population. Results: After adjustment for age, gender, smoking status, drinking status, HBsAg status, and family history of cancers, three H19 polymorphisms were not associated with HCC risk under any genetic models. The odds ratio (OR) per risk allele for HCC was 1.03 (95% confidence interval [95% CI] = 0.94–1.13) for rs2839702, 1.05 (95% CI = 0.96–1.16) for rs2067051, and 1.04 (95% CI = 0.95–1.14) for rs2075745, respectively. No significant associations were also observed in the stratified analysis, haplotype analysis and combined effect analysis. Conclusions: Our study indicated that no association of polymorphisms (rs2839702, rs2067051 and rs2075745) in long non-coding RNA H19 with HCC. Further larger population-based case-control study and a global view to the genetic component of H19 would be required to identify the causal genetic polymorphisms for HCC.

Association of polymorphisms in long non-coding RNA H19 with coronary artery disease risk in a Chinese population

H19 is an imprinted gene transcribing a long non-coding RNA and is downregulated postnatally. Re-expression of H19 has been observed in patients with atherosclerosis. However, to date, no data has been published on the association of H19 polymorphisms with the risk of coronary artery disease (CAD). In this study, four polymorphisms, rs217727, rs2067051, rs2251375, rs4929984, were analyzed in 701 CAD patients and 873 age- and sex-matched control subjects. Polymorphisms were genotyped by TaqMan technology. Our data showed that the T variant of rs217727 was associated with an increased risk of CAD [additive model: odds ratio (OR)=2.05, 95%CI=1.35–3.12; dominant model: OR=1.46, 95% confidence interval (CI)=1.12–1.90; recessive model: OR=1.75, 95%CI=1.18–2.58], while A variant of rs2067051 was associated with a decreased risk of CAD (additive model: OR=0.66, 95%CI=0.45–0.96; recessive model: OR=0.71, 95%CI=0.50–0.99). Combined analysis showed that subjects carrying 3 or 4 risk alleles had a significantly increased risk of CAD, relative to those with 0–2 risk alleles (OR=1.61, 95%CI=1.20–2.15). Moreover, CAD patients with 3 or 4 risk alleles also had significantly higher Gensini scores than those with 0–2 risk alleles (P=0.001). Further haplotype-based analysis revealed that individuals with C-G-C-C, T-G-A-A, and T-A-A-A haplotypes indicated a higher prevalence of CAD (OR=1.88, 95%CI=1.03–3.43; OR=2.26, 95%CI=1.19–4.31; OR=2.66, 95%CI=1.34–5.25, respectively), compared to individuals with the most common C-G-A-C haplotype. In conclusion, our study demonstrates for the first time that common polymorphisms of H19 are associated with the risk and severity of CAD in a Chinese population. Future studies are needed to explore the underlying mechanisms of our findings.

Investigation of IGF2/ ApaI and H19/ RsaI polymorphisms in patients with cutaneous melanoma

Objective The etiology of cutaneous melanoma is complex, involving both heterogeneous genetic and environmental components. The aim of our study was to verify if single polymorphic sites within IGF2 and H19 genes and their consequent haplotypes influence risk and/or prognosis of familial melanoma. Design Twenty one patients with clinical criteria of hereditary melanoma (early onset, presence of multiple primary melanoma, and/or one or more affected first- or second-degree relatives) and previously screened for CDKN2A mutations were genotyped by IGF2/ ApaI and H19/ RsaI PCR-RFLPs. Data were compared between patients and a control group (100 healthy young individuals) using Chi-square and Fisher's exact tests. We also investigated if these polymorphic sites could be microRNAs potential targets, using RegRNA software. Results Although the IGF2 and H19 genotypes/haplotypes were not significantly associated with melanoma, two of the most severe cases (very early onset or multiple melanomas) showed to be heterozygous for both genes. We found an overlap between IGF2/ ApaI and miR-615-5p, and between H19/ RsaI and miR-574-3p. Conclusions Some studies have shown H19, and IGF2 genes (or related genes or protein, for example, IGF2R and IMP-3) differential expression in melanoma. However, no study has attempted to examine markers across this cluster in relation to melanoma until now. Since the base change may impair the pairing of microRNA and its binding site, our results suggest a new window for future studies of IGF2 and H19 genetic variability and posttranscriptional regulation. Due to the importance and based on the present results, we suggest that the genotype/haplotype analysis of IGF2 and H19 polymorphisms should be better investigated in large populations with cutaneous melanoma, attempting to tie the association with progression of the disease.