Patients Carrying TT Genotype Research Articles

ABCB1 C1236T, G2677TA and C3435T Genetic Polymorphisms and Antidepressant Response Phenotypes: Results from a Portuguese Major Depressive Disorder Cohort.

P-glycoprotein (P-GP) is a transporter molecule expressed on the apical surface of capillary endothelial cells of the Blood-Brain Barrier (BBB), whose activity heavily influences drug distribution, including antidepressants. This transporter is encoded by ABCB1 gene, and genetic variations within ABCB1 gene have been proposed to affect drug efflux and have been previously associated with depression. In this context, we aimed to evaluate the role of C1236T, G2677TA and C3435T ABCB1 genetic polymorphisms in antidepressant treatment phenotypes from a cohort of patients harboring Major Depressive Disorder. Patients enrolled in the study consisted of 80 individuals with Major Depressive Disorder, who took part in a 27-month follow-up study at HML, Portugal. To investigate the correlation between ABCB1 polymorphisms and antidepressant response phenotypes, DNA was extracted from peripheral blood, and C1236T, C3435T and G2677TA polymorphisms were genotyped with TaqMan® SNP Genotyping Assays. Despite the fact that the evaluated polymorphisms (C1236T, C3435T and G2677TA) were not associated with treatment resistant depression, or relapse, we observed that patients carrying TT genotype of the C3435T polymorphism remit earlier than the ones carrying CC or CT genotypes (10.2 weeks vs. 14.9 and 21.3, respectively, p = 0.028, Log-rank test). Since we found an association with C3435T and time to remission, and not to the absence of remission, we suggest that this polymorphism could have an impact on antidepressant drug distribution, and thus influence on the time to remission will occur, without influencing the risk of remission itself.

VEGF single nucleotide polymorphisms predict improved outcome in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy

We aimed to investigate the prognostic role of genetic variants of VEGF in advanced NSCLC patients treated with platinum-based chemotherapy. A total of 196 patients with advanced NSCLC treated with first-line platinum-based chemotherapy were enrolled. We evaluated the relationship between VEGF polymorphisms and efficacy outcomes and chemotherapy toxicity. We found that rs699947, rs833061 and rs1005230 were in full linkage disequilibrium. Patients with CC genotype of rs833061 had a significant longer PFS than TT genotype (CC vs TT, HR = 1.67, 95%CI = 1.01−2.76, P = 0.043). Patients harbouring CC genotype had longer PFS compared with CT genotype (P < 0.001). Moreover, CC genotypes conferred a significantly increased PFS compared to CT and TT genotype in dominant model (CC vs CT + TT, HR = 1.95, 95%CI = 1.23−3.10, P = 0.005). Patients carrying TT genotype of rs833061 had improved both ORR (HR = 0.54, 95%CI = 0.30−0.98, P = 0.041) and DCR (HR = 0.37, 95%CI = 0.20−0.66, P = 0.001) than non-TT patients. Furthermore, no association was found between any rs833061 alleles and adverse events (P = 0.425), but patients carrying rs1570360 AA genotype were more likely to experience grade 3−4 toxicities (P = 0.004) (GG vs AA, HR = 3.16, 95%CI = 1.26−7.94, P = 0.015). In conclusion, the variant homozygote CC of rs833061 exhibited a better prognosis based on association analysis. The present study provides reference for the future study of platinum-based chemotherapy response and toxicity.

Genetic Factors of Renin-Angiotensin System Associated with Major Bleeding for Patients Treated with Direct Oral Anticoagulants.

The purpose of this study was to identify the renin–angiotensin system (RAS)-related genetic factors associated with bleeding and develop the bleeding risk scoring system in patients receiving direct oral anticoagulants (DOACs). This study was a retrospective analysis of prospectively collected samples from June 2018 to May 2020. To investigate the associations between RAS-related genetic factors and major bleeding, we selected 16 single nucleotide polymorphisms (SNPs) from five genes (namely, AGT, REN, ACE, AGTR1, and AGTR2). Multivariable logistic regression analysis was employed to investigate the independent risk factors for bleeding and to develop a risk scoring system. A total of 172 patients were included in the analysis, including 33 major bleeding cases. Both old age (≥65 years) and moderate to severe renal impairment (CrCl < 50 mL/min) increased the risk of bleeding in the multivariable analysis. Among RAS-related polymorphisms, patients carrying TT genotype of rs5050 and A allele of rs4353 experienced a 3.6-fold (95% CI: 1.4–9.3) and 3.1-fold (95% CI: 1.1–9.3) increase in bleeding, respectively. The bleeding risk increased exponentially with a higher score; the risks were 0%, 2.8%, 16.9%, 32.7%, and 75% in patients with 0, 1, 2, 3, and 4 points, respectively. Although this study is limited to a retrospective study design, this is the first study to suggest RAS-related genetic markers and risk scoring systems, including both clinical and genetic factors, for major bleeding in patients receiving DOAC treatment.

The Effects of WISP1 Polymorphisms on the Prognosis of Lung Cancer Patients with Platinum-Based Chemotherapy.

PurposeTo investigate the relationships between Wnt1 inducible signaling pathway protein 1 (WISP1) polymorphisms and the prognosis of platinum-based chemotherapy in lung cancer patients.Patients and MethodsA total of 363 lung cancer patients were recruited in this study. All of them received at least two cycles of platinum-based chemotherapy. We used unconditional logistic regression analysis to assess the associations of 39 single nucleotide polymorphisms in WISP1 gene with platinum-based chemotherapy prognosis.ResultsThe results indicated that patients carried rs2929973 GT or GG genotypes had increased risk of disease progression (HR = 0.712, 95% CI = 0.553–0.916, P = 0.015). Patients with rs2977551 TT genotype had a significantly decreased risk of progression-free survival than patients carrying CT or CC genotype (HR = 0.723, 95% CI = 0.561–0.932, P = 0.032) and overall survival (HR = 0.725, 95% CI = 0.552–0.913, P = 0.045). For rs2977549, patients carrying TT genotype had a significantly longer progression-free survival than patients with CC or CT genotypes (HR = 0.708, 95% CI = 0.550–0.912, P = 0.017). Among of them, rs16904853, rs10956697, rs2929965, rs2929973, rs7828685, rs2977551 and rs2977549 were related to progression-free survival, and rs10956697 and rs2977551 were related to overall survival in subgroup analyses, respectively.ConclusionWISP1 rs2929973, rs2977551 and rs2977549 may be contributed to a potential candidate biomarker for prediction of platinum-based chemotherapy prognosis in lung cancer patients.

Exploring the Association Between Genetic Polymorphisms in Genes Involved in Craniofacial Development and Isolated Tooth Agenesis

Tooth agenesis is a common congenital anomaly in humans and is more common in oral cleft patients than in the general population. Many previous studies suggested that oral cleft and tooth agenesis share a similar genetic background. Therefore, this study explored the association between isolated tooth agenesis and genetic polymorphisms in genes that are crucial for craniofacial and tooth development. Panoramic radiographs, anamnesis, and genomic DNA from 273 patients were included. Patients were classified as tooth agenesis present, when at least one permanent tooth was congenitally missing. Patients with syndromes and oral cleft were excluded. Only unrelated patients were included. The genetic polymorphisms in BMP2 (rs235768 and rs1005464), BMP4 (rs17563), RUNX2 (rs59983488 and rs1200425), and SMAD6 (rs3934908 and rs2119261) were genotyped by real-time polymerase chain reaction. Genotype and allele distributions were compared between the tooth agenesis phenotypes and controls by Chi-square test. Haplotype and diplotype analysis were also performed, in addition to multivariate analysis (alpha of 0.05). A total of 86 tooth agenesis cases and 187 controls were evaluated. For the rs235768 in BMP2, patients carrying TT genotype have higher chance to present tooth agenesis [p < 0.001; prevalence ratio (PR) = 8.29; 95% confidence interval (CI) = 4.26–16.10]. The TT genotype in rs3934908 (SMAD6) was associated with higher chance to present third molar agenesis (p = 0.023; PR = 3.25; 95% CI = 1.17–8.99). BMP2 was also associated in haplotype and diplotype analysis with tooth agenesis. In conclusion, genetic polymorphisms in BMP2 and SMAD6 were associated with isolated tooth agenesis.

The HBG2 rs7482144 (C > T) Polymorphism is Linked to HbF Levels but not to the Severity of Sickle Cell Anemia.

Sickle cell anemia (SCA) is a severe disease characterized by anemia, acute clinical complications, and a relatively short life span. In this disease, abnormal hemoglobin makes the red blood cells deformed, rigid, and sticky. Fetal hemoglobin (HbF) is one of the key modulators of SCA morbidity and mortality. Interindividual HbF variation is a heritable trait that is controlled by polymorphism in genes linked and unlinked to the hemoglobin β gene (HBB). The genetic polymorphisms that determine HbF levels are known to ameliorate acute clinical events. About 190 well-characterized homozygous SCA patients were included in this study. Complete blood count (CBC), high-performance liquid chromatography (HPLC), and clinical investigations were obtained from patient's records. Severity scores were determined by using the combination of anemia, complications, total leucocyte count, and transfusion scores. HBG2 rs7482144 polymorphism was genotyped by using the polymerase chain reaction and restriction fragment length polymorphism. The association between HBG2 rs7482144 polymorphism and HbF levels as well as the disease severity of SCA were assessed. SCA patients carrying TT genotype were found to have higher HbF levels. In addition, SCA patients with increased severity showed significantly lower levels of hemoglobin, HbF, and hematocrit values. However, the genotypes of HBG2 rs7482144 polymorphism were not found to be associated with the risk of disease severity. In summary, this study demonstrated that HBG2 rs7482144 polymorphism is linked with HbF levels, but it does not affect disease severity. The sample sizes used and the pattern of association deduced from our small sample size prevents us from extrapolating our findings further.

Association of Hepatocyte Growth Factor Genetic Variation (S3735520) and Its Concentration in Autism Spectrum Disorders: A Case-control Study

Background: Hepatocyte Growth Factor (HGF) was shown to play a key role in synaptogenesis, survival, maturation, and reconstruction of neuron cells and was shown to be implicated in Autism Spectrum Disorder (ASD). Objectives: Assessing the relationship between HGF (rs3735520) gene polymorphism and its circulating levels in ASD. Materials &amp; Methods: A total of 140 ASD patients and 120 children healthy controls referred to Shahid Rajaei Hospital, Mazandaran, Iran from September 2017 to January 2019 were enrolled in the study. Genomic DNA was extracted from blood samples, HGF polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism and HGF serum concentration was measured by enzyme-linked immunosorbent assay. Statistical analysis was done by ANOVA and the Chi-square test, using χ² in MedCalc statistical software ver. 12.1.4. Results: Genotype frequencies of CC, CT, and TT in the ASD group were 25.71%, 52.86%, and 21.43%, and in controls were 26.67%, 68.33%, and 5%, respectively (P=0003) and C and T alleles frequencies in patients were 53% and 47% and in controls were 61% and 39%, respectively (P=0.046). Moreover, the Mean±SD serum HGF levels in the controls and ASD patients were 363.33±118.44 and 219.95±73.61 pg/mL, respectively (P=0.009). Furthermore, ASD patients carrying TT genotype had lower serum HGF levels than CT and TT carriers (CC, CT, and TT Mean±SD serum levels were 271.88±30.47, 217.77±33.59 and 156.33±22.72 pg/mL, respectively). Conclusion: There was a significant relationship between HGF gene polymorphism and its serum levels with ASD in an Iranian population. We also suggest that TT genotype may be associated with a decrease in HGF circulation levels in ASD.

Investigation of carbonic anhydrase 6 gene polymorphism rs2274327 in relation to the oral health status and salivary composition in type 2 diabetic patients

Objective The aim of the present study was to investigate the oral manifestations and salivary composition in type 2 diabetics with periodontitis and to evaluate their association with CA6 gene polymorphism rs2274327. Methods Oral examination was performed by a single periodontist for 300 type 2 diabetics. Whole unstimulated saliva and blood were collected. The salivary pH, buffer capacity and flow rate were later measured. Immunoglobulin A and electrolytes were assessed using an autoanalyzer. CA6 gene polymorphism rs2274327 was screened by PCR-RFLP assay. The statistical analysis was performed using the SPSS 20.0 version. Results The salivary pH, buffer capacity and flow rate were significantly lower in the patients carrying TT genotype compared to CC and CT genotype carriers (p < .05). Furthermore, the DMFT index, OHI-s, PI, PPD and CAL were significantly higher in the subjects with TT genotype (p < .05). Carrying at least one T allele seemed to increase the risk of dental caries (OR = 2.59, p < .001), xerostomia (OR = 2.11, p=.003) and taste impairment (OR = 1.97, p < .05). Conclusion CA6 gene polymorphism rs2274327 seemed to increase the risk of developing, dental caries, periodontitis, xerostomia and taste impairment in type 2 diabetics.

Ceramide/sphingosine-1-phosphate imbalance is associated with distinct inflammatory phenotypes of uncontrolled asthma.

Asthma is associated with inflammatory dysregulation, but the underlying metabolic signatures are unclear. This study aimed to classify asthma inflammatory phenotypes based on cellular and metabolic features. To determine cellular and metabolic profiles, we assessed inflammatory cell markers using flow cytometry, sphingolipid (SL) metabolites using LC-MS/MS, and serum cytokines using ELISA. Targeted gene polymorphisms were determined to identify genetic predispositions related to the asthma inflammatory phenotype. In total, 137 patients with asthma and 20 healthy controls (HCs) were enrolled. Distinct cellular and metabolic profiles were found between them; patients with asthma showed increased expressions of inflammatory cell markers and higher levels of SL metabolites compared to HCs (P<.05 for all). Cellular markers (CD66+ neutrophils, platelet-adherent eosinophils) and SL metabolic markers (C16:0 and C24:0 ceramides) for uncontrolled asthma were also identified; higher levels were observed in uncontrolled asthma compared to controlled asthma (P<.05 for all). Asthmatics patients with higher levels of CD66+ neutrophils had lower FEV1(%), higher ACQ (but lower AQLO) scores, and higher sphingosine and C16:0 ceramide levels compared to those with low levels of CD66+ neutrophils. Asthmatics patients with higher levels of platelet-adherent eosinophils had higher S1P levels compared to those with lower levels of platelet-adherent eosinophils. Patients carrying TT genotype of ORMDL3 had more CD66+ neutrophils; those with AG/ GG genotypes of SGMS1 exhibited higher platelet-adherent eosinophils. Patients with uncontrolled asthma possess distinct inflammatory phenotypes including increased CD66+ neutrophils and platelet-adherent eosinophils, with an imbalanced ceramide/S1P rheostat, potentially involving ORMDL3 and SGMS1 gene polymorphisms. Ceramide/S1P synthesis could be targeted to control airway inflammation.

The calcineurin regulatory subunit polymorphism and the treatment efficacy of tacrolimus for idiopathic membranous nephropathy

Tacrolimus is considered to be one of the main therapeutic options for idiopathic membranous nephropathy (IMN). This study aimed to investigate the association of variants in genes encoding the binding protein and the drug target (calcineurin) of tacrolimus with the efficacy in IMN patients and the potential mechanism. Sixty-seven IMN patients treated with tacrolimus were enrolled retrospectively. Sanger sequencing was performed to search for variants in all exons of the genes in 8 IMN patients and genotype for the detected variants in the other 59 patients. The molecular mechanism underlying the relationship between the variants and the efficacy was explored in human peripheral blood mononuclear cells (PBMCs) and other cell lines. Single nucleotide polymorphism rs875 (T > C) in the 3′untranslated region (3′UTR) of PPP3R1 encoding calcineurin regulatory subunit was found to be associated with the treatment efficacy of tacrolimus for IMN. Patients carrying TT genotype had a significantly higher remission rate than those carrying TC/CC genotype (83% vs. 47%, P = 0.008). Western blot showed that the TT genotype carriers exhibited reduced PPP3R1 protein levels in PBMCs (P = 0.02). Compared with C allele, T allele displayed increased binding affinity for miR-582-5p in the luciferase reporter assay (P < 0.001). Moreover, knockdown of PPP3R1 in Jurkat T cell line enhanced the immunosuppressive effect of tacrolimus. Our study revealed the association of PPP3R1 3′UTR polymorphism rs875 with the efficacy of tacrolimus in IMN patients. The functional polymorphism might alter PPP3R1 expression via modulating the interaction of miR-582-5p with PPP3R1, which further affected the immunosuppressive effect of tacrolimus.

PMH9 - Association of Cyp2e1 Gene Polymorphisms with the Risk of Schizophrenia in the Bangladeshi Population

Among mental disorders, schizophrenia (SCZ) is the most disabling disease. The genetic polymorphisms of CYP2E1 gene are reported to be related to the development of several mental diseases. The purpose of this present study was to examine the association between the CYP2E1 (rs2070673) gene polymorphisms and schizophrenia in the Bangladeshi population. Genotyping of this gene was done by extracting DNA from 101 Schizophrenic patients and 101 healthy volunteers, after than polymerase chain reaction (PCR) was carried out for amplification of extracted DNA. After amplification, the respective DNA fragments were digested by restriction enzyme BspMI and finally expected DNA fragments were observed by agarose gel electrophoresis technique. We found that patients carrying AT genotype had shown a significantly higher risk (p<0.05) for the development of schizophrenia in compared to patients carrying TT genotype. Whereas patients carrying AA genotype revealed a higher risk for the development of schizophrenia in compared to patients carrying TT genotype and this result was found statistically significant (p<0.05). For combined model i.e. patients carrying AT+AA genotype had shown a similar scenario of higher risk for the development of schizophrenia in compared to patients carrying TT genotype (p<0.05). So, in the context of Bangladeshi Schizophrenia patients, our result indicates that allele rs2070673 (CYP2E1*7) is associated with the higher risk of schizophrenia. As we have identified the genetic basis of the Bangladeshi schizophrenia patients, we hope it will be helpful for the treatment selection of schizophrenia patients.

Protein C genetic variation was associated with the susceptibility to acute respiratory distress syndrome in Chinese Han population

Objective To investigate the genetic variants in the protein C (PC) and endothelial protein C receptor (EPCR) genes associated with the risk and outcome of acute respiratory distress syndrome (ARDS) patients in Chinese Han race. Methods Five tagSNPs (single nucleotide polymorphism, SNP) in the PC and EPCR genes were genotyped in patients with ARDS (n =275) and non-ARDS (n=337) in order to find the association between them in this case-control study. The SNPs were genotyped by SNPstream Beckman platform. Then, the correlation between the associated SNPs and plasma levels of activated protein C (APC) in patients with ARDS was investigated. The APC levels were measured using enzyme linked immunosorbent assay (ELISA) method. Results Association analysis revealed that two PC SNPs in perfect linkage disequilibrium, rs1799809 and rs1158867, were significantly associated with susceptibility to ARDS. T allele frequency of rs1799809 in ARDS patients was significantly higher than that in non-ARDS patients (OR=1.569, 95%CI: 1.192-2.066). And the genotype frequencies of rs1799809 were also significantly different between these two groups (P=0.007). The association remained significant after adjustment for multiple comparisons. Haplotype consisting of three SNPs in the PC gene was also associated with susceptibility to ARDS. The frequency of haplotype CCC in the ARDS samples was significantly lower than that in the non-ARDS group (P<0.01). Moreover, ARDS patients carrying rs1799809 TT genotype showed lower serum levels of APC than patients with TC and CC genotypes (Padj=0.02). However, genotype and allele analyses of EPCR did not show any significant difference between ARDS and non-ARDS patients. Conclusions These findings indicated that common genetic variation in the PC gene was significantly associated with susceptibility to ARDS in Chinese Han race. The PC genetic variation influenced plasma concentration of APC in patients with ARDS. Key words: PC; APC; EPCR; Genetic variation; SNPs; ARDS; Susceptibility; Prognosis

Influence of CYP3A4 and CYP3A5 polymorphisms on tacrolimus and sirolimus exposure in stable kidney transplant recipients.

Polymorphisms in genes encoding for drug-metabolizing enzymes and drug transporters are among multiple factors that modulate the pharmacokinetic variability of tacrolimus (TAC) and sirolimus (SRL). This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) on TAC and SRL dose-adjusted concentrations (C0/D) in stable kidney transplant recipients. This is an exploratory and prospective study, which includes 46 stable kidney transplant recipients. These patients were monitored from the 3rd to the 24th month after transplantation. The SRL group consisted of 25 patients receiving TAC, prednisone (PRED), and mycophenolate sodium (MPS), which were converted from TAC to SRL at 3rd month after transplantation. The TAC group consisted of 21 patients who underwent treatment with TAC, PRED, and MPS. Both groups were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T), CYP2C8 rs10509681 (c.1196A>G) and ABCB1 rs1045642 (c.3435C>T), rs1128503 (c.1236C>T), and rs2032582 (c.2677G>T/A) polymorphisms. In the TAC group, CYP3A4 rs2242480 A allele carriers were associated with lower TAC C0/D. For CYP3A5 rs15524 SNP, C0/D was higher among patients carrying TT genotype when compared with CT and CC genotype carriers in the SRL and, more consistently, in the TAC groups. For ABCB1 rs1045642 SNP, TT genotype was associated with reduced SRL C0/D, but only at month 15. CYP3A4 rs2242480 and CYP3A5 rs15524 SNPs resulted in significant changes in SRL and TAC C0/D at different times after transplantation.

Association of calcitonin receptor gene (CALCR) polymorphism with kidney stone disease in the population of West Bengal, India

Kidney Stone Disease (KSD) is a complex urologic disorder with strong genetic constituent. Earlier association studies have indicated that the genetic polymorphisms are the potential cause of stone materialization; however unfortunately, the actual genetic signature is still unknown. Therefore, present study was aimed to investigate the potential contribution of two important polymorphisms of calcitonin receptor gene (CALCR): (i) rs1801197 (Leu447Pro) and (ii) rs1042138 (3′UTR+18C>T) in renal stone formation. Accordingly, we enrolled 152 patients registered with calcium-rich stone in kidney (case) and 144 corresponding age, sex and ethnicity matched healthy individuals (controls). Epidemiological and clinical data were recorded as well as peripheral blood sample was collected from each individual. Serum creatinine and urinary calcium level was found high in patients, compared to controls. Out of two studied polymorphisms, we have not found any significant association against the rs1042138 with KSD, nonetheless, significant high frequency (p=0.001; Odds ratio=1.81; 95% CI: 1.28–2.55) of risk allele T against the rs1801197 (T>C) in patient was noted. Moreover, significant association with KSD was noted by genotypic analysis of rs1801197 (Leu447Pro) in our population. Interestingly, male patients carrying TT genotype was found to be at high risk of stone formation, while no such association was observed in female patients. Altogether, present study indicated that the rs1042138 might not be used as a useful marker for susceptibility of kidney stone formation, whereas, the rs1801197 could definitely be considered as one of the risk factors for KSD in Indian population at least in West Bengal in particular.

Impact of matrix metalloproteinase 9 rs3918242 genetic variant on lipid-lowering efficacy of simvastatin therapy in Chinese patients with coronary heart disease

BackgroundGenetic variation of matrix metalloproteinase 9 (MMP-9) gene polymorphism has been suggested to modulate coronary heart diseases (CHD), yet the underlying mechanisms are not well understood.MethodsWe investigated the association of MMP9 rs3918242 single nucleotide polymorphism with inflammation and lipid-lowering efficacy after simvastatin treatment in Chinese patients with CHD. Fasting serum lipid profile and plasma inflammatory mediators were determined at baseline in 264 patients with CHD and 186 healthy control subjects, and after HMG-CoA reductase inhibitor simvastatin treatment (20 mg/day) for 12 weeks in CHD subjects.ResultsWe found that plasma MMP-9, TNF-α and IL-10 levels were significantly elevated in patients with CHD compared to control subjects before treatment. The plasma MMP9 in CHD patients carrying rs3918242 CC, CT and TT genotypes were comparable. Interestingly, CHD patients carrying TT genotype had significantly higher level of triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) than those carrying CC genotype (P <0.05). Simvastatin treatment significantly reduced LDL-C, TG and plasma inflammatory mediator levels in CHD patients. The reduction of LDL-C upon simvastatin therapy was significantly greater in patients carrying TT genotype than those carrying CC genotype (P <0.05).ConclusionsMMP9 rs3918242 TT genotype is associated with elevated serum TG and LDL-C, and enhanced LDL-C-lowering response upon simvastatin treatment in Chinese patients with CHD.Clinical trial registrationThis study was retrospectively registered at Chinese Clinical Trial Registry (Registration number: ChiCTR-ROC-17010971) on March 23rd 2017.

Correlations of AFAP1, GMDS and PTGFR gene polymorphisms with intra-ocular pressure response to latanoprost in patients with primary open-angle glaucoma.

Genomewide association studies have identified a number of genetic variants that are associated with the development of primary open-angle glaucoma (POAG). This study aimed to explore possible correlations of common single nucleotide polymorphisms (SNPs) in AFAP1, GMDS and PTGFR genes with intra-ocular pressure (IOP) response to latanoprost in POAG patients. From January 2012 to December 2014, 135 patients with POAG were enrolled into our study. Direct sequencing of polymerase chain reaction (PCR) products was used to analyse the distribution of allelic and genotypic frequencies of AFAP1 rs11723068 G>A and rs757253 T>C, GMDS rs9503012 C>T and rs17134549 T>A, and PTGFR rs3753380 C>T and rs3766355 A>C. After 1, 2 and 4 weeks of latanoprost treatment, the IOP of POAG patients decreased significantly (all P < 0·05). The genotype frequencies of six SNPs in AFAP1, GMDS and PTGFR genes were conformed to Hardy-Weinberg equilibrium (HWE). Before latanoprost treatment, the baseline IOP levels of POAG patients carrying CC+AC genotypes of PTGFR rs3766355 A>C were higher than those carrying AA genotype (P < 0·05). After 1, 2 and 4 weeks of latanoprost treatment, POAG patients carrying TT genotype of GMDS rs9503012 C>T showed better response to latanoprost than those carrying CC+CT genotype (P < 0·05). Similarly, POAG patients carrying AA genotype of PTGFR rs3766355 A>C showed better response to latanoprost than those carrying CC+AC genotypes (P < 0·05). Logistic regression analysis showed that age, CC+CT genotypes of GMDS rs9503012 C>T and CC+AC genotypes of PTGFR rs3766355 A>C were independent risk factors for poor response to latanoprost in POAG patients. GMDS rs9503012 C>T and PTGFR rs3766355 A>C may be associated with IOP response to latanoprost in POAG patients.

Association of GRM4 gene polymorphisms with susceptibility and clinicopathological characteristics of osteosarcoma in Guangxi Chinese population.

Osteosarcoma is the most frequent malignant primary bone tumor. GRM4 is expressed in human osteosarcoma cells, and high expression of mGluR4 in osteosarcoma tissues is related to poor prognosis. The aim of this study was to investigate the association between polymorphism of the GRM4 gene and the susceptibility to osteosarcoma in a Chinese population. In a case-control study, we investigated polymorphisms in the GRM4 gene (rs2229901, rs733457, and rs1906953) with a real-time quantitative polymerase chain reaction (PCR) assay (TaqMan). The study was conducted with 126 Chinese patients with osteosarcoma and 168 Chinese subjects in a control group. Unconditional logistic regression was used to analyze the correlation between single nucleotide polymorphisms (SNPs) and osteosarcoma risk. Different survival rates of different genotypic patients with osteosarcoma were analyzed through Kaplan-Meier. There were statistically significant differences in the distributions of the rs1906953 genotypes between the cases and control group (P = 0.034). However, there was no remarkable difference in the three genotypes of GRM4 gene rs2229901 locus between the patient group and control group (P = 0.369). Survival analysis for rs1906953 showed that the median survival time of osteosarcoma patients with the CC genotype was significantly shorter compared to the CT and TT genotypes; patients carrying CC genotype have apparently got a decrease in their recurrence-free survival time in comparison with patients carrying TT genotype. Our data suggest that GRM4 gene polymorphism is closely related to the morbidity and metastasis of osteosarcoma in a Chinese population.

Correlation between TGF-β1 gene 29 T > C single nucleotide polymorphism and clinicopathological characteristics of osteosarcoma.

Transforming growth factor (TGF)-β1 is the most abundant growth factor in human bone. Several polymorphisms have been described in the TGF-β1 gene. To explore the correlation between TGF-β1 gene single nucleotide polymorphism and the clinicopathological characteristics of osteosarcoma. TaqMAN PCR technique was used to detect the TGF-β1 gene polymorphism of 124 patients with osteosarcoma from last follow-up and 136 healthy controls. The difference of gender, age, and allele frequency between patient group and control group with χ (2) text were tested. The relationship between single nucleotide polymorphism and the risk of osteosarcoma with logistic regression and different survival rates of different genotypic patients with osteosarcoma through Kaplan-Meier were analyzed. There is no remarkable difference of the three genotypes in TGF-β1 gene 509C > T locus between the patient group and control group (P = 0.26). However, there are significant distributive differences in 29 T > C genotype (P = 0.04), which shows that patients carrying TT genotype have more risk to get osteosarcoma than patients carrying CC genotype (odds ratio (OR) = 2.10, 95 % confidence interval (CI) = 1.08-4.05). The percentage of T allele frequency of patient group, as 60.1 %, is larger than the control group, as 48.9 %. By comparing with patients carrying CC genotype, patients carrying TT genotype have two times risk of metastasis (OR = 2.30, 95 % CI = 1.05-5.06), and most of them are in the period of Enneking IIB (OR = 2.54, 95 % CI = 1.18-5.51). The survival analysis indicates that there is no any significant decrease when there is recurrence in patients carrying TT genotype. The morbidity and metastasis of osteosarcoma are relevant to TGF-β1 gene 29 T > C single nucleotide polymorphism.

CARD8 rs2043211 Polymorphism is Associated with Gout in a Chinese Male Population

Background &Aim: Previous studies have suggested genetic factors are involved in the development of gout. We performed a case-control study to investigate the genetic association between CARD8 rs2043211 polymorphism and gout. Methods: A total of 396 male patients with gout and 403 age- and sex- matched healthy controls were included in this study. Genotyping was performed using TaqMan SNP Genotyping Assays. An association analysis was carried out using the χ2 test. The genotype-phenotype analysis was also conducted. Results: The genotype distribution of CARD8 rs2043211 polymorphism confirmed to HWE in the controls (P = 0.27). There was an obvious difference in the genotype distribution of CARD8 rs2043211 polymorphism between cases and controls (P = 0.017). In addition, there was an obvious association between CARD8 rs2043211 polymorphism and gout under the recessive comparison model (AA vs. TT/TA: OR = 0.65, 95%CI 0.47-0.88, P = 0.006). Patients carrying genotype TT of CARD8 rs2043211 polymorphism had higher triglycerides levels compared to those carrying the AA genotype (2.77±2.08 mmol/L vs. 2.07±1.15 mmol/L, P = 0.01). Patients with the TT genotype also had significantly higher systolic blood pressure compared with those with the AA genotype (142.11±21.10 mmHg vs. 135.38±14.66 mmHg, P = 0.03). Patients carrying TT genotype also had an increased risk of renal calculus compared with those carrying the AA genotype. Conclusion: CARD8 rs2043211 polymorphism is significantly associated with susceptibility to gout in Chinese Han males.

Genetic variations in IL1A and IL1RN are associated with the risk of preeclampsia in Chinese Han population.

Preeclampsia (PE) is an excessive systemic inflammation response with dysfunction of endothelial. Our study was to investigate the association between genetic variations in IL-1 and the susceptibility to PE in Chinese Han population. 402 PE patients and 554 normal pregnant women of third trimester were enrolled. The polymorphisms of rs315952 in IL1RN and rs17561 in IL1A were genotyped by TaqMan allelic discrimination real-time PCR. Obviously statistic difference of the genotypic frequencies were found in both of IL1RN rs315952 and IL1A rs17561 between cases and controls (for rs315952, P = 0.001; for rs17561, P = 0.021.). For rs315952, the C allele was associated with development of PE (P = 0.003, OR = 1.319, 95%CI 1.099–1.583). Patients with CC or CT genotype were less likely to develop severe PE than patients carrying TT genotype(P < 0.001, OR = 0.24, 95%CI 0.15–0.40). For rs17561, the C allele was the risk factor for predisposition to PE (P = 0.012, OR = 1.496, 95%CI 1.089–2.055). Our results suggest IL1RN and IL1A may involve in the development of PE in Chinese Han population.