An miR-143 promoter variant associated with essential hypertension.
ABSTRACT: MicroRNAs like miR-143 are increasingly linked to disease pathogenesis. miR-143 is enriched in vascular smooth muscle, and several single nucleotide polymorphisms have been identified in this miRNA. The aim of the current study was to explore a potential correlation between a polymorphism in the miR-143 promoter region, rs4705342, and essential hypertension (EH). Genotyping for miR-143 rs4705342 was performed from blood samples of 156 EH patients (case group) and 187 healthy individuals (control group) using a TaqMan assay. Participant demographic and clinical characteristics were also collected. Logistic regression was used to identify an association between genotype and EH, and odds ratios of EH risk were also determined. Frequencies of the CC, CT, and TT genotypes differed significantly between case (7.7%, 40.4%, 51.9%) and control (15.0%, 48.1%, 36.9%) groups (?(2) = 9.400, P = 0.009). Further, the frequency of the C allele was lower in the case group than in the control group (27.9% vs. 39.0%, P = 0.002). Compared with those having the TT genotype, patients carrying the CC and CT genotypes had a significantly reduced risk for EH (OR = 0.541, 95% CI = 0.351-0.834, P = 0.005), particularly for females, nonsmokers, and those not consuming alcohol (P < 0.05). Thus, the rs4705342 polymorphism in the miR-143 appears to be associated with essential hypertension, and further study is needed to understand the molecular mechanism producing this effect.
Project description:MiR-143 and miR-145 were down-regulated in papillary thyroid carcinoma (PTC) involving in cell proliferation, apoptosis, migration, invasion, and epithelial to mesenchymal transition. In this study, we aimed to investigate the association between 2 functional polymorphisms (ie, rs4705342 and rs353292) in the flanking region of miR-143/145 and risk of PTC.A case-control study including 316 PTC patients and 347 controls was performed. The rs4705342 and rs353292 were genotyped by using the TaqMan allelic discrimination. The results were confirmed by DNA sequencing.For the rs4705342, a reduced risk of PTC was observed in heterozygous comparison, dominant genetic model and allele comparison (CC vs TT: adjusted OR?=?0.37, 95% CI?=?0.19-0.74, P?=?.003; CT/CC vs TT: adjusted OR?=?0.64, 95% CI?=?0.47-0.87, P?=?.005;?C vs T: adjusted OR?=?0.66, 95% CI?=?0.52-0.85, P?=?.001, respectively). No significant difference was found in the genotypic distributions of the rs353292 between cases and controls.These findings indicate that the rs4705342 in the flanking region of miR-143/145 may be a protective factor against the occurrence of PTC. Further study is therefore required to investigate the correlation between the genotype and V-raf murine sarcoma viral oncogene homolog B1 V600E, rat sarcoma viral oncogene homolog mutations, rearranged in transformation/PTC1 and rearranged in transformation/PTC3.
Project description:The expression of miR-143/miR-145 was up-regulated in ischemic stroke (IS), which may be used as biomarkers and/or therapeutic targets for IS. We aimed to investigate the association of rs4705342 and rs4705343 polymorphisms in the promoter of miR-143/145 with risk of IS. The study population comprised 445 patients with IS and 518 controls. The rs4705342 genotype was analyzed by using a TaqMan Assay and the rs4705343 genotype was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. Relative expression of miR-143/miR-145 was measured by quantitative real-time PCR. We found that the rs4705342 was associated with a decreased risk of IS (TC vs. TT: adjusted OR?=?0.74, 95% CI, 0.57-0.97; CC vs. TT: adjusted OR?=?0.53, 95% CI, 0.34-0.83). Haplotype analysis showed that the TC haplotype was associated with an increased risk of IS risk (OR?=?1.33, 95% CI, 1.01-1.75), whereas the CT haplotype was associated with a decreased risk of IS risk (OR?=?0.68, 95% CI, 0.50-0.92). Importantly, patients carrying the rs4705342TC/CC genotypes had a lower level of miR-145 (P?=?0.03). We found for the first time that the rs4705342 CC was a protective factor for IS, probably by reducing the level of miR-145.
Project description:MicroRNAs (miRs)-143/145 are involved in various biological processes related to aneurysm formation and are downregulated in patients with intracranial aneurysm (IA). We aimed to determine whether two functional polymorphisms (i.e. rs4705342 and rs4705343) in the promoter of miR-143/145 are related to IA risk. A case-control study was undertaken to examine the association of rs4705342 and rs4705343 with IA risk, including 565 patients with IA and 622 age- and gender-matched controls. rs4705342 was analysed by TaqMan Assay, and rs4705343 was genotyped using polymerase chain reaction-restriction fragment length polymorphism. miR-143/145 expression was quantified using RT-PCR. rs4705342 was associated with a significantly lower risk of IA, with adjusted ORs of 0.74 (95% CI: 0.58-0.95) for TC genotype carriers and 0.74 (95% CI: 0.59-0.94) for TC/CC genotypes carriers. Individuals carrying the rs4705342 C allele had a reduced risk of IA (adjusted OR?=?0.82; 95% CI: 0.68-0.98). Haplotype of the two loci of rs4705342 and rs4705343 showed that the CT haplotype carried a lower IA risk and higher miR-143 level. Moreover, the rs4705342 CC/CT genotypes were associated with higher miR-143 levels. Thus, the rs4705342C-rs4705343T haplotype in the promoter of miR-143/145 cluster may be related to IA development.
Project description:BACKGROUND:Cardiovascular benefits by reversing environmental risks factors for essential hypertension (EH) and dyslipidemia could be weaken by high genetic risk. We investigated possible associations between ACE2 polymorphisms and dyslipidemia in patients with EH. METHODS:Four hundred and two hypertensive patients were enrolled in an EH group and 233 normotensive individuals were enrolled as control group from the Xinjiang region of China. Fourteen ACE2 polymorphisms were genotyped by Matrix-assisted laser desorption ionization time-of-flight mass spectrometry. RESULTS:Participants carrying T allele (TT?+?CT) of rs2074192 (P?=?0.006), rs4646155 (P?=?0.030) and rs4646188 (P?<?0.001), C allele (CT?+?CT or CC?+?CG) of rs4240157 (P?=?0.012), rs4830542 (P?=?0.020) and rs879922 (P?<?0.001) and TT genotype of rs2106809 (P?=?0.012) were associated with EH. Meanwhile,ACE2 SNPs also exhibited association with dyslipidemia but exhibited obvious heterogeneity. rs1978124 (TT?+?CT, P?=?0.009), rs2106809 (TT, P?=?0.045), rs233575 (CC?+?CT, P?=?0.018), rs4646188 (CC, P?=?0.011) and rs879922 (CC?+?CG, P?=?0.003) were association with increased LDL-C (?1.8 mmol/L). rs2106809 (CC?+?CT, P?<?0.001), rs2285666(TT?+?CT, P?=?0.017), rs4646142(CC?+?CG, P?=?0.044), rs4646155(TT?+?CT, P?<?0.001) and rs4646188(TT?+?CT, P?=?0.033) were association with decreased HDL-C (<?1.0 mmol/L). rs2074192 (TT?+?CT, P?=?0.012), rs4240157 (CC?+?CT, P?=?0.027), rs4646156 (AA+AT, P?=?0.007), rs4646188 (TT?+?CT, P?=?0.005), rs4830542 (CC?+?CT, P?=?0.047) and rs879922 (CC?+?CG, P?=?0.001) were association with increased TC (?5.2 mmol/L). rs2106809 (P?=?0.034) and rs4646188 (P?=?0.013) were associated with hypertriglyceridemia. Further, ischemic stroke was more prevalent with rs4240157 (CC?+?CT, P?=?0.043), rs4646188 (CC?+?CT, P?=?0.013) and rs4830542 (CC?+?CT, P?=?0.037). In addition, rs2048683 and rs6632677 were not association with EH, dyslipidemia and ischemic stroke. CONCLUSION:The ACE2 rs4646188 variant may be a potential and optimal genetic susceptibility marker for EH, dyslipidemia and its related ischemic stroke.
Project description:Essential hypertension (EH) is a principal contributing factor in worldwide cardiovascular disease mortality. Although interventions that minimize environmental risk factors for EH are associated with reduced cardiovascular disease, such approaches are limited for individuals with high genetic EH risk. In this study, we investigated possible associations between ACE2 polymorphisms and hypertension-related target organ damages in south Xinjiang, China. Four hundred and two hypertensive patients were enrolled as study participants in an EH group, and 233 normotensive individuals were enrolled as control subjects. Participants were recruited from the south Xinjiang region. Fourteen ACE2 polymorphisms were genotyped by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Risk genotypes of rs2074192 (TT+CT, OR?=?1.72, 95% CI: 1.17-2.53), rs2106809 (TT, OR?=?1.71, 95% CI: 1.13-2.58), rs4240157 (CC+CT, OR?=?1.99, 95% CI: 1.17-3.41), rs4646155 (TT+CT, OR?=?1.94, 95% CI: 1.06-3.54), rs4646188 (TT+CT, OR?=?3.25, 95% CI: 1.95-5.41), rs4830542 (CC+CT, OR?=?1.88, 95% CI: 1.10-3.23), and rs879922 (CC+CG, OR?=?4.86, 95% CI: 2.74-8.64) were associated with EH. Hypertensive patients carrying the control genotype of rs2074192 (CC, OR?=?2.37, 95% CI: 1.28-4.39) were associated with CAS ?50%, while those carrying a high-EH-risk genotype of rs4240157 (OR?=?2.62, 95% CI: 1.24-5.54), rs4646155 (OR?=?2.44, 95% CI: 1.16-5.10), or rs4830542 (CC+CT, OR?=?2.20, 95% CI: 1.03-4.69) were associated with atrial fibrillation (AF), larger left atrial diameter, and higher levels of renin-angiotensin-aldosterone system (RAAS) activation (renin and angiotensin I/II). In conclusion, the ACE2 variant rs2074192 was associated with EH and EH with CAS ?50%, while 3 ACE2 variants (rs4240157, rs4646155, and rs4830542) were associated with EH- and hypertension-related AF and left atrial remodeling in south Xinjiang, China.
Project description:<b>Background:</b> Corin is a transmembrane serine protease that activates pro-forms of atrial and brain natriuretic peptides. Numerous studies have indicated that corin played an important role in cardiovascular diseases (CVDs). However, there have been few studies about the correlation between single-nucleotide polymorphisms (SNPs) in the 3' untranslated region (3'UTR) of <i>CORIN</i> and CVDs. The aims of this study were to investigate the associations of three SNPs (rs3749585, rs4695253, and rs12641823) in the 3'UTR of <i>CORIN</i> with CVDs and to find the seed regions of microRNAs (miRNAs) that bind to SNPs of <i>CORIN</i>. <b>Methods and Results:</b> A case-control study (<i>n</i> = 3,537) was performed in a Han population of northeastern China. CVDs included essential hypertension (EH), atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD). Genotyping was performed using high-resolution melt analysis. In the EH-control study, rs3749585<sup>T</sup> was significantly associated with the risk of EH after adjusting for sex and age in allelic (<i>p</i> <sub><i>adj</i></sub> = 0.049; <i>OR</i>: 1.113) and dominant (<i>p</i> <sub><i>adj</i></sub> = 0.015, <i>OR</i>: 1.233) models. Rs4695253<sup>T</sup> was significantly associated with the risk of EH in the recessive model after adjusting for sex and age (<i>p</i> <sub><i>adj</i></sub> = 0.005, <i>OR</i>: 2.084). Rs3749585<sup>T</sup> was significantly and negatively associated with AF in the dominant and additive models after adjusting for sex, age, EH, HF, T2DM, and CAD (dominant: <i>p</i> <sub><i>adj</i></sub> = 0.009, <i>OR</i>: 0.762; additive: <i>p</i> <sub><i>adj</i></sub> = 0.048, <i>OR</i>: 0.873). In the HF-control study and CAD-control study, none of the three SNPs was associated with HF and CAD after adjusting for covariates in any models (<i>p</i> <sub><i>adj</i></sub> > 0.05). The levels of high-density lipoprotein (HDL) in rs4695253<sup>CC+CT</sup> were lower than the levels of HDL in rs4695253<sup>TT</sup> (42.47 ± 10.30 vs. 48.0 ± 10.24 mg/dl, <i>p</i> <sub><i>adj</i></sub> = 0.008). The levels of total cholesterol (TC) in rs4695253<sup>CC+CT</sup> were lower than the levels of TC in rs4695253<sup>TT</sup> (164.01 ± 49.15 vs. 180.81 ± 43.92 mg/dl, <i>p</i> <sub><i>adj</i></sub> = 0.036). Luciferase assay revealed that the relative luciferase activity of rs3749585<sup>CC</sup>-transfected cells was significantly decreased by miR-494-3p, in comparison to cells transfected with rs3749585<sup>TT</sup> (<i>p</i> < 0.001). A significant decrease in the relative luciferase activity of rs3749585<sup>TT</sup> reporter was observed as compared with rs3749585<sup>CC</sup> reporter in the presence of miR-1323 or miR-548o-3p (<i>p</i> = 0.017 and 0.012, respectively). <b>Conclusions:</b> We found significant associations between rs3749585<sup>T</sup> and rs4695253<sup>T</sup> and EH, between rs4695253<sup>T</sup> and the levels of TC and HDL, and between rs3749585<sup>T</sup> and AF. Hsa-miR-494-3p may serve as a potential therapeutic target for EH and AF patients in the future.
Project description:BACKGROUND:Genetic and environment play a significant role in the etiology of essential hypertension (EH). Recently STK39 rs3754777, ATP2B1 rs2681472 and rs17249754 have been associated with BP variation and hypertension. In this study we aimed to determine firstly whether index variants were associated with the risk of developing EH in Burkina Faso and secondly to characterize cardiovascular risk markers. METHODS:We conducted a case-control study with 380 participants including 180 case subjects with EH and 200 control subjects with normal BP. We used TaqMan genotyping assays with probes from Applied Biosystems to genotype polymorphisms using the 7500 Real-Time PCR System. Biochemical parameters were measured using chemistry analyzer COBAS C311. RESULTS:T-test showed that cardiovascular risk markers such as body mass index, waist circumference, blood sugar, total cholesterol and triglycerides were significantly higher in hypertensive compared to normotensive (all p?<? 0.05). Binary logistic regression analysis revealed in decreasing order that overweight, family history of hypertension, central obesity and alcohol intake increased the risk of developing EH (all OR?>?3.8; all p?<? 0.001). In genetic level we observed that individuals carrying the AA+AG genotype of ATP2B1 rs17249754 had a low risk of developing EH than those carrying the GG genotype (OR?=?0.48 [95% CI: 0.31-0.75] p?=?0.001) and the A allele frequency in the cases was significantly lower than that of the controls (OR?=?0.56 [95% CI: 0.38-0.82] p?=?0.003). We also observed that ATP2B1 rs17249754 was significantly associated with higher SBP and DPB in case and control groups (GG versus AG?+?AA; p?<? 0.05), ATP2B1 rs2681472 was significantly associated with higher SBP only in case and control group (AA versus AG?+?GG; p?<? 0.05), STK39 rs3754777 was not significantly associated with any of the BP traits (CC versus CT?+?TT; p?>?0.05). CONCLUSION:Our results confirmed the significant association of ATP2B1 rs17249754 with the risk of developing EH in Burkinabe and showed an increase of cardiovascular risk markers levels in subjects with EH.
Project description:Background: Cervical cancer is the second major female cancer in India and constitutes one-fourth of the world's burden. Human Papilloma Virus (HPV) infection is an essential but insufficient cause for cervical cancer. Genetic variants in microRNAs (miRNAs/miRs) play an important role in the susceptibility of various types of cancers.Objective: To evaluate the association of Single Nucleotide Polymorphisms (SNPs) in miR-146a (rs2910164), miR-196a2 (rs11614913), and miR-499 (rs3746444), with cervical cancer susceptibility in Indian population.Methods: Three hundred samples were genotyped by Polymerase chain reaction (PCR)-Restriction fragment length polymorphism (RFLP). Both patients and controls were also screened for the presence of HPV DNA.Results: In this case-control study, 125 (83.3%) cervical cancer cases were found to be infected with HPV DNA. The frequency of miR-146a C allele was higher in controls than in cases [odds ratio (OR) (95% confidence interval (CI)) = 0.81 (0.57-1.14), P-value = 0.258]. miR-196a2 T allele was found to be associated with the decreased risk of cervical cancer [OR (95% CI) = 0.36 (0.26-0.50), P-value<0.0001]. Approximately 1.22-fold increased risk has been observed in individuals carrying miR-499 TT genotypes [OR (95% CI) = 1.22 (0.63-2.36), P-value = 0.617]. Interaction studies for miR-196a2/miR-499 loci showed that women carrying TT/CC and TT/CT genotypes were less likely to develop cervical cancer than CC/CC combination [P<0.05]. Likewise, miR-146a/miR-196a2 genotypic combinations (CC/TT, CG/TT, GG/TT) followed the similar trend [P<0.05], exhibited the protective effect against cervical cancer with reference to CC/CC group. Combined genotypes of miR-146a/miR-499 [CC/CT, CG/CC, CG/CT, CG/TT, GG/CC, GG/CT, GG/TT] demonstrated a non-significant trend toward higher cervical cancer risk [OR > 1.00, P>0.05].Conclusion: Polymorphisms in miR-146a, miR-196a2, and miR-499 individually or collectively have the prospective to emerge as biomarkers for cervical cancer.
Project description:BACKGROUND:The present study sought to explore the relationship of common cardiovascular disease risk factors and noncoding RNAs with essential hypertension (EH). METHODS:A total of 402 EH patients and 402 gender- and age-frequency matched healthy controls were enrolled in this study. Each participant received a questionnaire survey, physical examination and laboratory tests. Quantitative real-time polymerase chain reaction (qPCR) was performed to assess relative expression levels of six noncoding RNAs (NR_027032, NR_034083, NR_104181, miR-126, miR-143 and miR-145) in peripheral blood leucocytes. Multiple logistic regression analysis was used to estimate the risk of having EH between hypertensive and non-hypertensive patients. RESULTS:Analysis showed that participants with anxiety, high body mass index, abdominal obesity and family history of hypertension had higher risk for EH, whereas those with bland diet and occupational physical activities had lower risk for EH. qPCR assays showed that NR_027032 (P?= 0.015) and NR_034083 (P?= 0.004) were significantly reduced in EH patients compared with controls, whereas NR_104181 (P?= 0.007), miR-143 (P?= 0.005) and miR-145 (P?= 0.015) were significantly elevated. After controlling the cardiovascular risk factors, multivariate analysis showed that lower expression levels of NR_034083 and higher expression levels of NR_104181 and miR-143 were risk factors for EH. CONCLUSIONS:EH is a result of environmental and epigenetic factors. Strikingly, NR_034083, NR_104181 and miR-143 may be correlated with the risk for EH development; therefore, epigenetic markers could be used to measure hypertension levels to help elucidate the pathogenesis of EH.
Project description:The present study aimed to investigate the function of the single nucleotide polymorphism (SNP) rs41291957 in the prognosis of intracerebral hemorrhage (ICH). In addition, the molecular mechanisms underlying the role of microRNA (miR)?143, Toll?like receptor 2 (TLR2) and interleukin?16 (IL?16) were studied in patients with ICH that carried different alleles in the locus of the rs41291957 SNP. Kaplan?Meier survival curves were calculated for 182 patients with ICH, genotyped as CC, presenting a cytosine in both chromosome, CT, presenting both variants, and TT, presents a thymine in both chromosomes. In addition, the possible regulatory relationships between miR?143 and TLR2/IL?16 were studied using computational analysis, luciferase assays and western blot assay. In addition, the inflammatory profiles of cerebrospinal fluid (CSF) and serum samples collected from the subjects were compared. The patients genotyped as TT presented the lowest survival rate, while patients genotyped as CC presented the highest survival rate. TLR2 mRNA was identified as a potential target of miR?143, while IL?16 showed no direct interaction with miR?143. The above regulatory relationships were further investigated using cells transfected with miR?143 precursor or TLR2 small interfering RNA. In addition, the expression levels of inflammatory factors, such as tumor necrosis factor ?, interferon, IL?6, IL?10 and NF?L?6, were highest in the CSF/serum samples collected from patients genotyped as TT and lowest in patients genotyped as CC. By contrast, the expression levels of miR?143 showed an opposite trend in the expression of the above inflammatory factors. The rs41291957 SNP, located in the promoter region of miR?143, reduced the expression of miR?143 and upregulated the expression of the pro?inflammatory factor TLR2, eventually leading to a poorer prognosis in patients with ICH.