Publications by authors named "Chengming Zhou"

12 Publications

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NR4A1 knockdown confers hepatoprotection against ischaemia-reperfusion injury by suppressing TGFβ1 via inhibition of CYR61/NF-κB in mouse hepatocytes.

J Cell Mol Med 2021 Jun 3;25(11):5099-5112. Epub 2021 May 3.

Department of Intensive Care Unit, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.

Nuclear receptor subfamily 4, group A, member 1 (NR4A1) can aggravate ischaemia-reperfusion (I/R) injury in the heart, kidney and brain. Thus, the present study aimed to unravel the role of NR4A1 on hepatic I/R injury. For this purpose, the mouse hepatic I/R model and H/R-exposed mouse hepatocytes model were established to stimulate the hepatic and hepatocellular damage. Then, the levels of ALT and AST as well as TNF-α and IL-1β expression were measured in the mouse serum and supernatant of hepatocyte s, respectively. Thereafter, we quantified the levels of NR4A1, CYR61, NF-kB p65 and TGFβ1 under pathological conditions, and their interactions were analysed using ChIP and dual-luciferase reporter gene assays. The in vivo and in vitro effects of NR4A1, CYR61, NF-kB p65 and TGFβ1 on I/R-induced hepatic and H/R-induced hepatocellular damage were evaluated using gain- and loss-of-function approaches. NR4A1 was up-regulated in the hepatic tissues of I/R-operated mice and in H/R-treated hepatocytes. Silencing NR4A1 relieved the I/R-induced hepatic injury, as supported by suppression of ALT and AST as well as TNF-α and IL-1β. Meanwhile, NR4A1 knockdown attenuated the H/R-induced hepatocellular damage by inhibiting the apoptosis of hepatocyte s. Moreover, we also found that NR4A1 up-regulated the expression of CYR61 which resulted in the activation of the NF-κB signalling pathway, thereby enhancing the transcription of TGFβ1, which was validated to be the mechanism underlying the contributory role of NR4A1 in hepatic I/R injury. Taken together, NR4A1 silencing reduced the expression of CYR61/NF-κB/TGFβ1, thereby relieving the hepatic I/R injury.
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http://dx.doi.org/10.1111/jcmm.16493DOI Listing
June 2021

LINC00657 knockdown suppresses hepatocellular carcinoma progression by sponging miR-424 to regulate PD-L1 expression.

Genes Genomics 2020 11 29;42(11):1361-1368. Epub 2020 Sep 29.

Department of Liver & Laparoscopic Surgery, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, No. 137, Liyushan South Road, Xinshi District, Ürümqi, 830054, Xinjiang Uyghur Autonomous Region, China.

Background: Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed malignant tumor and the fourth leading cause of cancer-related deaths worldwide. As a novel non-coding RNA, LINC00657 was firstly identified as an oncogenic role in breast cancer. However, few research focus on the effect of LINC00657 on the progression of HCC.

Objectives: The purpose of this study was to investigate the effect of LINC00657 on HCC tissues and cells, and further explore the potential mechanism.

Methods: We first measured the expression of LINC00657 in HCC tissues and cell lines using qRT-PCR. Next we established LINC00657 knockdown in HCC cells. CCK-8 assay, cell invasion assay, flow cytometry analysis, qRT-PCR and western blotting were applied to assess the role of LINC00657 knockdown in the biological behavior of HCC cells. The bioinformatics analysis and the rescue experiment were devoted to the underlying mechanism.

Results: LINC00657 was remarkably overexpressed in HCC tissues and cell lines, associated with poor prognosis. LINC00657 knockdown repressed cell proliferation and invasion, promoted cell apoptosis of HCC cell lines. The bioinformatics analysis showed LINC00657 sponged miR-424 as a ceRNA. Besides, PD-L1 mimic rescued the suppression of si-LINC00657 in the biological behavior of HCC cells.

Conclusion: In a word, we observed LINC00657 regulated PD-L1 expression by sponging miR-424, thus affecting the developments of hepatocellular carcinoma. These findings LINC00657 may provide new evidence for therapeutic application in hepatocellular carcinoma.
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http://dx.doi.org/10.1007/s13258-020-01001-yDOI Listing
November 2020

A targeted sequencing approach to find novel pathogenic genes associated with sporadic aortic dissection.

Sci China Life Sci 2018 12 17;61(12):1545-1553. Epub 2018 Oct 17.

Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Aortic dissection (AD) is a heterogeneous genetic disease of the aorta with high mortality and poor prognosis. However, only few genetic causes of AD have been explored till date. After conducting a broad literature review focused on identifying potential pathogenic pathways, we designed a panel containing 152 AD-associated genes to conduct massively parallel targeted next-generation sequencing of 702 sporadic aortic dissection patients and 163 matched healthy controls. After validation by Sanger sequencing, we identified 21 definitely pathogenic and 635 likely pathogenic variants in 61.25% (430/702) of patients. In these patients, 34.88% (150/430) harbored more than one variant that was either definitely or likely to be pathogenic. Among the candidate genes, we identified 546 likely pathogenic variants in 47.72% (335/702) of patients. Importantly, we identified 94 loss-of-function (LOF) variants in 45 genes in AD patients, but only five LOF variants in the controls (P=1.34×10). With a burden test, we highlighted RNF213 as an important new gene for AD pathogenesis. We also performed transcriptome sequencing of human aorta tissues to evaluate the expression levels of these newly identified genes. Our study has compiled a comprehensive genetic map of sporadic AD in the Han Chinese population. We believe it will facilitate risk predicting and genetic diagnosis of this severe disease in the future.
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http://dx.doi.org/10.1007/s11427-018-9382-0DOI Listing
December 2018

Mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism.

Fertil Steril 2018 08;110(3):486-495.e5

Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, People's Republic of China; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, People's Republic of China. Electronic address:

Objective: To investigate the mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism (IHH) and discover new pathogenic genes that cause IHH.

Design: A gene panel, including 31 known IHH genes and 52 candidate genes, was used to perform semiconductor next-generation sequencing.

Setting: University hospital.

Patients: One hundred thirty-eight sporadic male IHH patients and 10 IHH families; 100 healthy men with normal fertility served as control subjects.

Interventions(s): None.

Main Outcome Measure(s): Targeted next-generation sequencing, polymerase chain reaction and sequencing, pedigree analysis, and bioinformatics analysis.

Result(s): Variants were distributed uniformly throughout 52 genes (52/83, 62.65%), including 16 (16/31, 51.61%) causal genes and 36 (36/52, 69.23%) candidate genes. Six new pathogenic variants and 52 likely pathogenic variants were identified in 16 genes known to cause nIHH/KS (normosmic IHH/Kallmann syndrome). In the 148 probands, PROKR2 (22/148, 14.86%), CHD7, FGFR1, and KAL1 had high mutation rates, and 8.78% (13/148) of the patients carried at least two variants in known genes. In addition, variants were identified in 36 candidate genes, and EGFR, ERBB4, PAX6, IGF1, SEMA4D, and SEMA7A should be prioritized for further research and genetic testing in IHH.

Conclusion(s): The mutation frequency of IHH-causal genes in Chinese HAN males was different from the data reported in white populations. Oligogenic inheritance was a common phenomenon in IHH. Our study expands the mutation profile for IHH, and the new likely pathogenic genes identified in our study warrant further research in GnRH neuronal networks.
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http://dx.doi.org/10.1016/j.fertnstert.2018.04.010DOI Listing
August 2018

Paclitaxel delivered by CD44 receptor-targeting and endosomal pH sensitive dual functionalized hyaluronic acid micelles for multidrug resistance reversion.

Colloids Surf B Biointerfaces 2018 Oct 18;170:330-340. Epub 2018 Jun 18.

Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China; Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, 750004, China.

The drug efflux mediated by P-glycoprotein (P-gp) transporter is a major factor responsible for multidrug resistance (MDR) of paclitaxel (PTX). The efficient intracellular PTX delivery is a promising strategy for overcoming the MDR of tumor cells. A CD44 receptor targeting and endosome-pH sensitive dual functionalized hyaluronic acid-deoxycholic acid-histidine (HA-DOCA-His) micellar formulation was developed to overcome MDR, and a CD44 receptor targeting hyaluronic acid-deoxycholic acid (HA-DOCA) micelles was used as a comparison. Compared with Taxol solution and HA-DOCA micelles, the cytotoxicity of PTX loaded in HA-DOCA-His micelles against drug-resistant tumor cells was improved significantly and possessed superior MDR-overcoming performance; this phenomenon is due to the increased intracellular PTX delivery by CD44 receptor-mediated endocytosis pathway and endosome-pH sensitivity-mediated PTX triggering release. Upon pharmacokinetic study, PTX/HA-DOCA-His micelles demonstrated longer blood circulation time, larger AUC, decreased V and CL than the Taxol solution. More importantly, PTX/HA-DOCA-His micelles were more effective in tumor growth inhibition in MCF-7/Adr tumor-bearing mice compared with PTX/HA-DOCA micelles and Taxol solution. Dual targeting strategy-functionalized HA-DOCA-His micelles demonstrated excellent MDR-reversing ability for therapeutic efficacy and improvement on MDR tumors, thereby providing an effective targeting strategy for PTX delivery of nano-drug delivery system in MDR cancer chemotherapy.
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http://dx.doi.org/10.1016/j.colsurfb.2018.06.024DOI Listing
October 2018

Mucus adhesion- and penetration-enhanced liposomes for paclitaxel oral delivery.

Int J Pharm 2018 Feb 27;537(1-2):245-256. Epub 2017 Dec 27.

Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China; Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, 750004, China.

Low aqueous solubility and intestinal permeability limit the oral chemotherapy efficacy of paclitaxel (PTX). Traditional nanodrug delivery systems show excellent aqueous solubility improved ability of PTX. However, gastrointestinal (GI) mucus limits the improvement of intestinal permeability in traditional nanodrug delivery systems. A novel mucus adhesion- and penetration-functionalized chitosan-thioglycolic acid-Pluronic F127 (CS-TGA-PF) liposome system was developed for PTX oral delivery. The optimized formulation of PTX-loaded CS-TGA-PF liposomes showed particle size of 121.4 nm and zeta potential of 50.2 mV. CS-TGA-PF liposomes were more stable than unmodified liposomes and demonstrated a sustained-release manner of PTX incubated in simulated gastric fluid and intestinal fluid. CS-TGA-PF liposomes absorbed a three-fold amount of mucin compared with that of unmodified liposomes, which would prolong the residence time of liposomes on the mucosal surface in the intestinal tract. The intestinal mucus adhesion- and penetration-enhanced efficacy of CS-TGA-PF liposomes for intestinal PTX delivery was studied by observing the intestinal absorption and distribution. Results exhibited increased liposome uptake by the GI mucosa and improved drug intestinal absorption. In conclusion, the dual functional CS-TGA-PF liposomes with mucus adhesion- and permeation-enhanced properties could be used as a promising nanodrug delivery system for PTX oral delivery.
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http://dx.doi.org/10.1016/j.ijpharm.2017.12.044DOI Listing
February 2018

FBN1 mutations largely contribute to sporadic non-syndromic aortic dissection.

Hum Mol Genet 2017 12;26(24):4814-4822

Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.

Mutations in FBN1 have been well identified in syndromic aortic dissection (AD) and familial thoracic aortic aneurysms and dissections. However, whether mutations of FBN1 contribute to sporadic non-syndromic AD and the characteristics of mutations remain unknown. Using next-generation-sequencing technology, FBN1 was sequenced in a total of 702 sporadic cases (including 687 of non-syndromic AD and 15 of sporadic Marfan syndrome with aortic event, and 527 normal controls). For the sporadic non-syndromic AD cohort, we found 26 variants in 27 patients (18 with missense, 2 frameshift, 1 initiation codon mutation, 3 nonsense and 3 splice site mutations). The prevalence of variants was significantly high in the sporadic non-syndromic AD cohort (27/687, 3.9%). The patients with FBN1 mutations were younger, suffered from fewer risk factors such as hypertension and smoking, and were less gender partitioned than non-FBN1-mutation AD patients. The mutations were spread along the FBN1 gene in our sporadic non-syndromic AD cohort and mutation locations are not different between non-syndromic and syndromic patients. These results demonstrate that the deleterious mutations in FBN1 largely contribute to pathogenesis of sporadic non-syndromic AD, which expands our knowledge of FBN1 variants and the genetic basis and pathology of AD.
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http://dx.doi.org/10.1093/hmg/ddx360DOI Listing
December 2017

Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection.

Sci China Life Sci 2017 Jan 13;60(1):57-65. Epub 2016 Dec 13.

Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Aortic dissection (AD) is a devastating, heterogeneous condition of aorta. The homeostasis between collagens and matrix metalloproteases (MMPs)/tissue inhibitors of MMPs (TIMPs) system in the extracellular matrix plays an important role for structure and functions of aorta. However, our knowledge on association between variants of genes in this system and pathogenesis of AD is very limited. We analyzed all yet known coding human genes of collagens (45 genes), MMPs/TIMPs (27 genes) in 702 sporadic AD patients and in 163 matched healthy controls, by using massively targeted next-generation and Sanger sequencing. To define the pathogenesis of potential disease-causing candidate genes, we performed transcriptome sequencing and pedigree co-segregation analysis in some genes and generated Col5a2 knockout rats. We identified 257 pathogenic or likely pathogenic variants which involved 88.89% (64/72) genes in collagens-MMPs/TIMPs system and accounted for 31.05% (218/702) sporadic AD patients. In them, 84.86% patients (185/218) carried one variant, 12.84% two variants and 2.30% more than two variants. Importantly, we identified 52 novel probably pathogenic loss-of-function (LOF) variants (20 nonsense, 16 frameshift, 14 splice sites, one stop-loss, one initiation codon) in 11.06% (50/452) AD patients, which were absent in 163 controls (P=2.5×10). Transcriptome sequencing revealed that identified variants induced dyshomeostasis in expression of collagens-TIMPs/MMPs systems. The Col5a2 rats manifested growth retardation and aortic dysplasia. Our study provides a first comprehensive map of genetic alterations in collagens-MMPs/TIMPs system in sporadic AD patients and suggests that variants of these genes contribute largely to AD pathogenesis.
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http://dx.doi.org/10.1007/s11427-016-0333-3DOI Listing
January 2017

CD44 Receptor Targeting and Endosomal pH-Sensitive Dual Functional Hyaluronic Acid Micelles for Intracellular Paclitaxel Delivery.

Mol Pharm 2016 12 31;13(12):4209-4221. Epub 2016 Oct 31.

Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University , No. 1160, Shengli Street, Yinchuan 750004, China.

A novel CD44 receptor targeting and endosome pH-sensitive dual functional hyaluronic acid-deoxycholic acid-histidine (HA-DOCA-His) micellar system was designed for intracellular paclitaxel (PTX) delivery. The HA-DOCA-His micelles exhibited desirable endosome pH (5.0-6.0)-induced aggregation and deformation behavior verified by size distribution, critical micellar concentration, and zeta potential changes. The HA-DOCA-His micelles presented excellent encapsulation efficiency and loading capacity of 90.0% and 18.9% for PTX, respectively. The PTX release from HA-DOCA-His micelles was pH-dependent, with more rapid PTX release at pH 6.0 and 5.0 than those at pH 7.4 and 6.5. The cellular uptake performance of HA-DOCA-His micelles was enhanced comparing with pH-insensitive HA-DOCA micelles by qualitative and quantitative measurements. HA-DOCA-His micelles could be taken up via CD44-receptor mediated endocytosis, transported into endosomes, and triggered drug release to cytoplasm. In vitro cytotoxicity study exhibited PTX-loaded HA-DOCA-His micelles were more active in tumor cell growth inhibition in MCF-7 cells at pH 5.8 than those at pH 6.8 and pH 7.4. A superior antitumor efficacy was demonstrated with HA-DOCA-His micelles in a MCF-7 breast tumor model. These indicated that the dual functional HA-DOCA-His micelles combined targeted intracellular delivery and endosomal release strategies could be developed as a promising nanocarrier for anticancer efficacy improvement of PTX.
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http://dx.doi.org/10.1021/acs.molpharmaceut.6b00870DOI Listing
December 2016

Association between variation in the genes DDAH1 and DDAH2 and hypertension among Uygur, Kazakh and Han ethnic groups in China.

Sao Paulo Med J 2016 Jan;134(3):205-10

MD. Head of Department, Department of Cardiology, First Affiliated Hospital, Shihezi Medical College, Shihezi University, Shihezi, China.

Context And Objective: Dimethylarginine dimethylaminohydrolase enzymes (DDAH), which are encoded by the genes DDAH1 and DDAH2, play a fundamental role in maintaining endothelial function. We conducted a case-control study on a Chinese population that included three ethnic groups (Han, Kazakh and Uygur), to systemically investigate associations between variations in the genes DDAH1 and DDAH2 and hypertension.

Design And Setting: Experimental study at the Department of Internal Medicine and Genetic Diagnosis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.

Methods: This case-control study included 1,224 patients with hypertension and 967 healthy unrelated individuals as controls. DDAH1 -396 4N (GCGT) del>ins, rs3087894, rs805304 and rs9267551 were genotyped using the TaqMan 5' nuclease assay.

Results: The G/C genotype of rs3087894 in DDAH1 was a risk factor for hypertension in the Kazakh group in the co-dominant model (G/C versus G/G) (OR 1.39; 95% CI: 1.02-1.88; P < 0.05), with the same result in the dominant model (G/C + C/C versus G/G) (OR 1.38; 95% CI: 1.03-1.84; P < 0.05). In contrast, the C/C genotype of rs3087894 seemed to be a protective factor against hypertension in the Uygur group in the recessive model (C/C versus G/G + G/C) (OR 0.62; 95% CI: 0.39- 0.97; P < 0.05). Similar findings for rs3087894 were also observed after adjusting the variable for the age covariate.

Conclusion: Our results indicated that the C-allele of rs3087894 in DDAH1 was a risk factor for hypertension in the Kazakh group but a protective factor in the Uygur group.
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http://dx.doi.org/10.1590/1516-3180.2015.01150108DOI Listing
January 2016

Development and evaluation of alginate-chitosan gastric floating beads loading with oxymatrine solid dispersion.

Drug Dev Ind Pharm 2016 30;42(3):456-63. Epub 2015 Sep 30.

a Department of Pharmaceutics , School of Pharmacy, Ningxia Medical University , Yinchuan , People's Republic of China .

Oxymatrine (OM) can be metabolized to matrine in gastrointestinal ileocecal valve after oral administration, which affects pharmacological activity and reduce bioavailability of OM. A type of multiple-unit alginate-chitosan (Alg-Cs) floating beads was prepared by the ionotropic gelation method for gastroretention delivery of OM. A solid dispersion technique was applied and incorporated into beads to enhance the OM encapsulation efficiency (EE) and sustain the drug release. The surface morphology and internal hollow structure of beads were evaluated using optical microscopy and scanning electron microscopy (SEM). The developed Alg-Cs beads were spherical in shape with hollow internal structure and had particle size of 3.49 ± 0.09 mm and 1.33 ± 0.09 mm for wet and dried beads. Over 84% of the optimized OM solid dispersion-loaded Alg-Cs beads were able to continuously float over the simulated gastric fluid for 12 h in vitro. The OM solid dispersion-loaded Alg-Cs beads showed drug EE of 67.07%, which was much higher than that of beads loading with pure OM. Compared with the immediate release of OM capsules and pure OM-loaded beads, the release of OM from solid dispersion-loaded Alg-Cs beads was in a sustained-release manner for 12 h. Prolonged gastric retention time of over 8.5 h was achieved for OM solid dispersion-loaded Alg-Cs floating beads in healthy rabbit in in vivo floating ability evaluated by X-ray imaging. The developed Alg-Cs beads loading with OM solid dispersion displayed excellent performance features characterized by excellent gastric floating ability, high drug EE and sustained-release pattern. The study illustrated the potential use of Alg-Cs floating beads combined with the solid dispersion technique for prolonging gastric retention and sustaining release of OM, which could provide a promising drug delivery system for gastric-specific delivery of OM for bioavailability enhancement.
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http://dx.doi.org/10.3109/03639045.2015.1088866DOI Listing
October 2016

Association Between Polymorphism in the Human Cathepsin L (CTSL1) Promoter with Hypertension in the Uygur, Kazak and Han Populations in China.

J Coll Physicians Surg Pak 2015 Sep;25(9):640-3

Department of Cardiology, The First Affiliated Hospital, Shihezi Medical College, Shihezi University, Shihezi, China.

Objective: To systemically investigate the association between the polymorphism (rs3118869) in cathepsin Lenzyme gene with hypertension in three ethnic groups (Han, Kazak and Uygur) in China.

Study Design: Case-control study.

Place And Duration Of Study: Department of Cardiology, The First Affiliated Hospital, Shihezi Medical College, Shihezi University and Department of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2013 to May 2014.

Methodology: This case-control study included 1224 patients (422 Uygur, 425 Kazak and 377 Han individuals) with hypertension and 967 healthy unrelated individuals (339 Uygur, 337 Kazak and 291 Han individuals) as controls. The participants came from three ethnic groups (Han, Kazak and Uygur) which were recruited from Xinjiang Province of China. The polymorphism (rs3118869) of the human cathepsin Lgene was genotyped using the TaqMan 5' nuclease assay. Binary logistic regression was built to determine the association of polymorphism with hypertension.

Results: The genotype distribution of polymorphism was not significantly different in three ethnic groups. The rs3118869 polymorphism was significantly associated with Essential Hypertension (EH) in co-dominant model (A/C vs. C/C) in total people (OR = 0.697, 95% CI = 0.520 -0.932, p = 0.015), the same result was obtained in recessive model (C/C + A/C vs. A/A) in total people (OR = 0.689, 95% CI = 0.522 -0.910, p = 0.009). Similar finding of rs3118869 in recessive model (C/C + A/C vs. A/A) was also observed after adjusting the variable to the covariates age (OR = 0.629, 95% CI = 0.464 0853, p = 0.003).

Conclusion: The study results indicate the A-allele of rs3118869 is a protective factor in hypertension.
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http://dx.doi.org/09.2015/JCPSP.640643DOI Listing
September 2015