A single-nucleotide polymorphism in lnc-LAMC2-1:1 interferes with its interaction with miR-128 to alter the expression of deleted in colorectal cancer and its effect on the survival rate of subjects with ovarian cancer

This study aimed to identify the association between lnc-LAMC2-1:1 polymorphism rs2147578 and the recurrence of ovary cancer, as well as to study the underlying mechanism of rs2147578 in ovary cancer. Real-time polymerase chain reaction, Western blot analysis, immunohistochemistry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Logrank test, and Kaplan-Meier analysis were carried out to explore the role of rs2147578 in ovary cancer. No obvious difference was observed concerning all clinical characteristics among 90 patients genotyped as CC (N = 28), CG (N = 38), and GG (N = 24) in their rs2147578 polymorphism. In addition, the subjects carrying the CC genotype had longer recurrence-free survival time and showed a lower level of malignancy compared with those carrying CG and GG genotypes. Lnc-LAMC2-1:1 and miR-128 were lowly expressed in the CC group, while deleted in colorectal cancer (DCC) was highly expressed in the CC group. Furthermore, DCC was identified as a target gene of miR-128, and miR-128 mimics decreased the luciferase activity of cells cotransfected with wild-type DCC 3′-untranslated region. Lnc-LAMC2:1-1 directly targeted and affected miR-128 expression, and the G allele in lnc-LAMC2-1:1 rs2147578 upregulated miR-128 expression. Transfection with a miR-128 precursor evidently downregulated the expression of lnc-LAMC2-1:1, miR-128, and DCC expression, but did not affect the expression of ABCC5 and body mass index. Finally, miR-128 precursor promoted cell proliferation and inhibited cell apoptosis. Compared with lnc-LAMC2-1:1 rs2147578C allele, the G allele increases the risk of ovarian cancer by reducing the binding between lnc-LAMC2-1:1 and miR-128-3p, which in turn further decreases the expression of DCC and inhibits cell apoptosis.     

Retracted: Rs11655237 polymorphism of LINC00673 affects the prognosis of cervical cancer by interfering with the interaction between LINC00673 and microRNA-1231

Single-nucleotide polymorphism (SNP) in long noncoding RNAs (lncRNAs) is known to disrupt the binding between lncRNAs and microRNAs. In this paper, we aimed to explore the role of LINC00673 rs11655237 SNP in the survival of cervical cancer (CC). Real-time polymerase chain reaction and western-blot analysis were used to detect expressions of LINC00673 and microRNA-1231 (miR-1231) in CC patients with different rs11655237 SNP genotypes. And the expression of LINC00673, miR-1231, and IFNAR1 was measured in mice and cells treated with exosomes carrying GG, GA, and AA rs11655237 genotypes. Compared with patients carrying the rs11655237 A allele of LINC00673 rs11655237 SNP, patients carrying the G allele showed higher overall survival and higher miR-1231 expression. In addition, the expression of miR-1231 was the highest in patients carrying the GG genotype and the lowest in patients carrying the AA genotype. Furthermore, the exosomes carrying GG, GA, and AA genotypes of LINC00673 rs11655237 SNP reduced tumor growth in mice, while the inhibitory effect of rs11655237 A allele was much stronger than that of the rs11655237 G allele. Additionally, exosome treatment upregulated the expression of LINC000673 and IFNAR1 while downregulating the expression of miR-1231. Interestingly, the A allele of rs11655237 generated a binding site for miR-1231 and subsequently affected the expression of IFNAR1, a target gene of miR-1231 containing a miR-1231 binding site in its 3′-untranslated region. Cells transfected with exosomes carrying GG, GA, and AA genotypes of LINC00673 rs11655237 SNP achieved higher LINC000673 and IFNAR1 expression along with lower miR-1231 expression. Therefore, rs11655237 can be used as a prognostic biomarker for CC.     

Is CD36 gene polymorphism in region encoding lipid-binding domain associated with early onset CAD?

CD36 is a fatty acid translocase in striated muscle cells and cardiomyocytes. Some study suggested that alterations in CD36 gene may be associated with coronary artery disease (CAD) risk. The aim of the current study was to compare the frequency of CD36 variants in region encoding lipid-binding domain in Caucasian patients with early-onset CAD, no-CAD adult controls and neonates. The study group comprised 100 patients with early onset CAD. The genetic control groups were 306 infants and 40 no-CAD adults aged over 70 years. Exons 4, 5 and 6 including fragments of flanking introns were studied using the denaturing high-performance liquid chromatography technique and direct sequencing. Changes detected in analyzed fragment of CD36: IVS3-6 T/C (rs3173798), IVS4-10 G/A (rs3211892), C311T (Thr104Ile, not described so far) in exon 5, G550A (Asp184Asn, rs138897347), C572T (Pro191Leu, rs143150225), G573A (Pro191Pro, rs5956) and A591T (Thr197Thr, rs141680676) in exon 6. No significant differences in the CD36 genotype, allele and haplotype frequencies were found between the three groups. Only borderline differences (p = 0.066) were found between early onset CAD patients and newborns in the frequencies of 591T allele (2.00% vs 0.50%) and CGCGCGT haplotype (2.00% vs 0.50%) with both IVS3-6C and 591T variant alleles. In conclusion, CD36 variants: rs3173798, rs3211892, rs138897347, rs5956, rs143150225 rs141680676 and C311T do not seem to be involved in the risk of early-onset CAD in Caucasian population.     

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val⁶⁶Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.     

Time to wake up: No impact of COMT Val158Met gene variation on circadian preferences,arousal regulation and sleep

Dopamine has been implicated in the regulation of sleep–wake states and the circadian rhythm. However, there is no consensus on the impact of two established dopaminergic gene variants: the catechol-O-methyltransferase Val158Met (COMT Val158Met; rs4680) and the dopamine D4 receptor Exon III variable-number-of-tandem-repeat polymorphism (DRD4 VNTR). Pursuing a multi-method approach, we examined their potential effects on circadian preferences, arousal regulation and sleep. Subjects underwent a 7-day actigraphy assessment (SenseWear Pro3), a 20-minute resting EEG (analyzed using VIGALL 2.0) and a body mass index (BMI) assessment. Further, they completed the Morningness–Eveningness Questionnaire (MEQ), the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI). The sample comprised 4625 subjects (19–82 years) genotyped for COMT Val158Met, and 689 elderly subjects (64–82 years) genotyped for DRD4 VNTR. The number of subjects varied across phenotypes. Power calculations revealed a minimum required phenotypic variance explained by genotype ranging between 0.5% and 1.5% for COMT Val158Met and between 3.3% and 6.0% for DRD4 VNTR. Analyses did not reveal significant genotype effects on MEQ, ESS, PSQI, BMI, actigraphy and EEG variables. Additionally, we found no compelling evidence in sex- and age-stratified subsamples. Few associations surpassed the threshold of nominal significance (p < .05), providing some indication for a link between DRD4 VNTR and daytime sleepiness. Taken together, in light of the statistical power obtained in the present study, our data particularly suggest no impact of the COMT Val158Met polymorphism on circadian preferences, arousal regulation and sleep. The suggestive link between DRD4 VNTR and daytime sleepiness, on the other hand, might be worth investigation in a sample enriched with younger adults.     

The genetic association study of TP53 polymorphisms in Saudi obese patients

Obesity is a multifactorial metabolic disorder characterized by low grade chronic inflammation. Rare and novel mutations in genes which are vital in several key pathways have been reported to alter the energy expenditure which regulates body weight. The TP53 or p53 gene plays a prominent role in regulating various metabolic activities such as glycolysis, lipolysis, and glycogen synthesis. Recent genome-wide association studies reported that tumor suppressor gene p53 variants play a critical role in the predisposition of type 2 diabetes and obesity. Till date, no reports are available from the Arabian population; hence the present study was intended to assess the association between p53 variants with risk of obesity development in the Saudi population. We have selected three p53 polymorphisms, rs1642785 (C > G), and rs9894946 (A > G), and rs1042522 (Pro72Arg; C > G) and assessed their association with obesity risk in the Saudi population. Phenotypic and biochemical parameters were also evaluated to check their association with p53 genotypes and obesity. Genotyping was carried out on 136 obese and 122 normal samples. We observed that there is significantly increased prevalence p52 Pro72Arg (rs1042522) polymorphism in obese persons when compared to controls at GG genotype in overall comparison (OR: 2.169, 95% CI: 1.086-4.334, p = 0.02716). Male obese subjects showed three-fold higher risk at GG genotype (OR: 3.275, 95% CI: 1.230-8.716, p = 0.01560) and two-fold risk at G allele (OR: 1.827, 95% CI: 1.128-2.958, p = 0.01388) of p53 variant Pro72Arg respectively. This variant has also shown significant influence on cholesterol, LDL level, and random insulin levels in obese subjects (p ≤ 0.05). In conclusion, p53 Pro72Arg variant is highly prevalent among obese individuals and may act as a genetic modifier for obesity development among Saudis.     

A single nuclear polymorphism in let-7g binding site affects the doubling time of thyroid nodule by regulating KRAS-induced cell proliferation

As an indicator for the malignancy of thyroid nodules (TN), the doubling time of TN was studied in this study to evaluate the effect of rs712 polymorphism on the progression of TN. In addition, we aimed to study the potential molecular mechanisms underlying the pathological effect of rs712 polymorphism upon TN. A Taqman method was used to genotype the patients according to their rs712 polymorphism. Real-time polymerase chain reaction, western blot, Terminal deoxynucleotidyl transferase dUTP nick end labeling assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay was conducted to study the correlation between KRAS expression and the pathological effect of rs712 polymorphism. In-silicon analysis and luciferase assay were utilized to establish the regulatory relationship between let-7g and KRAS. KRAS messenger RNA (mRNA)/protein levels in the GG group were upregulated with a decreased apoptosis index. KRAS mRNA was validated to be a virtual target of let-7g. In addition, the mRNA/protein level of KRAS as well as cell proliferation index was decreased in primary thyroid cancer cells genotyped as TT/TG and transfected with KRAS small interfering RNA (siRNA)/let-7g precursors. The cell apoptosis index was evidently elevated in the KRAS siRNA/let-7g precursors group compared with that in the scramble controls. Moreover, KRAS mRNA/protein only showed slight reduction when GG-genotyped primary thyroid cancer cells were transfected by let-7g precursors. Additionally, let-7g precursors exhibited no significant effect on cell proliferation index or cell apoptosis in GG cells. Rs712 polymorphism T>G in the 3′-untranslated region of KRAS interrupts the interactions between let-7g and KRAS mRNA, leading to a higher cell proliferation index and reduced doubling time of TN.     

PVT1 (rs13281615) and miR-146a (rs2910164) polymorphisms affect the prognosis of colon cancer by regulating COX2 expression and cell apoptosis

In this study, we aimed to investigate the potential correlation between rs13281615/rs2910164 polymorphisms and the prognosis of colon cancer (CC). Taqman was utilized to genotype the rs13281615/rs2910164 polymorphisms in recruited subjects. Kaplan–Meier survival curves were calculated to study the prognostic values of different genotypes of rs13281615/rs2910164 polymorphisms. Real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assays were conducted to establish a potential signaling pathway underlying the role of rs13281615/rs2910164 polymorphisms, whereas bioinformatics analysis and luciferase reporter assays were performed to identify plasmacytoma variant translocation 1 (PVT1) and cyclooxygenase-2 (COX2) as targets of microRNA-146a (miR-146a). No significant difference was observed in respect to clinical characteristics among subjects with different genotypes. However, patients genotyped as GG/CC + GC showed the lowest chance of survival, whereas patients of GA + AA/GG genotype showed the highest chance of survival. Moreover, the relative expressions of PVT1, prostaglandin E2 (PGE2), and COX2 were the lowest and the relative expression of miR-146a was the highest in GA + AA/GG subjects, validating the roles of PVT1, miR-146a, and COX2 in CC. In addition, both PVT1 and COX2 were identified as virtual targets of miR-146a, and the luciferase activities of cells cotransfected with wild-type PVT1/COX2 and miR-146a mimics were significantly reduced. Moreover, the presence of PVT1 decreased the level of miR-146a whereas increasing the messenger RNA and protein levels of COX2, thus establishing a PVT1/miR-146a/COX2 signaling pathway underlying the pathogenesis of CC. The presence of rs13281615 G > A polymorphism on PVT1 and the rs2910164 C > G polymorphism on miR-146a contributes to a favorable prognosis in CC patients via modulating the activity of the PVT1/miR-146a/COX2 signaling pathway.     

Association of TNF-308 G>A polymorphism located in tumor necrosis factor a with the risk of developing cervical cancer and results of pap smear

Tumor necrosis factor a (TNFa) is an inflammatory cytokine that plays a crucial role in the immune response and the progression of cervical lesions. There is a growing body of data evaluating the value of a genetic variant in the TNFa gene with the risk of developing cervical cancer. The aim of this study was to explore the association of a variant, TNF-308 G>A, residing in the TNFa gene with cervical cancer. A total of 91 women with cervical cancer and 161 women as the control group were recruited. DNA was extracted, and Taqman®-probes-based assay was used for genotyping. Our results showed that the minor allele frequency was 0.3 in total population, and the frequency of minor allele A was more in the case group compared with the control. The regression models in different genetic models also revealed that the allele A is a potential risk factor for the development of cervical cancer. In particular, in the dominant model, patients with AG and AA genotypes had a higher risk of developing cervical cancer with odds ratio (OR) of 2.75 (95% confidence interval [CI]: 1.57-4.83, <0.001) and OR of 7.27 (95%CI: 2.5-20.8, <0.001), compared with the GG genotype. Moreover, a similar outcome was obtained for smear test results. Our study demonstrated that TNF-308 G>A located on TNF-a was associated with the risk of cervical cancer, supporting further studies in a larger population and multicenter setting to show the value of emerging markers as risk stratification biomarkers in cervical cancer.