CC Genotype Patients Research Articles

Uridine Glucuronosyltransferase 2B7 Polymorphism-Based Pharmacogenetic Dosing of Epirubicin in FEC Chemotherapy for Early-Stage Breast Cancer

BackgroundEpirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7). Patients homozygous for the minor allele (CC) in the UGT2B7 -161 promoter polymorphism have lower clearance and significantly higher rates of leukopenia compared to wild-type homozygote (TT) or heterozygote (CT) patients. This study was designed to determine if TT and CT genotype patients could tolerate a higher epirubicin dose compared to CC genotype patients. Patients and MethodsWe studied women with histologically confirmed non-metastatic, invasive breast cancer who were scheduled to receive at least three cycles of FE100C in the (neo)adjuvant setting. Patients received standard-dose FE100C during the first 21-day cycle. Based on genotype, the epirubicin dose was escalated in the second and third cycles to 115 and 130 mg/m2 or to 120 and 140 mg/m2 for CT and TT genotype patients, respectively. The main outcome measurements were myelosuppression and dose-limiting toxicity. These were analyzed for relationships with the three genotypes. ResultsForty-five patients were enrolled (10 CC, 21 CT, and 14 TT genotypes) and received 100 mg/m2 of epirubicin in the first cycle. Twelve and 10 TT patients were dose escalated at the second and third cycles, respectively; 16 CT patients were dose escalated at the second and third cycles. Leukopenia, but not febrile neutropenia, was genotype and dose dependent and increased in patients with CT and TT genotypes as their dose was increased. However, the third-cycle leukopenia rates were comparable to patients with the CC genotype receiving standard-dose epirubicin. ConclusionPharmacogenetically guided epirubicin dosing is well tolerated and allowed dose escalation without increased toxicity.

The association of genetic polymorphisms in interleukin-1 receptors type 1 and type 2 with sudden sensorineural hearing loss in a Taiwanese population: a case control study

BackgroundSudden sensorineural hearing loss (SSNHL) is a disease with an unknown etiology; damage to the auditory nerve from inflammation due to viral infection or vascular incidents has been implicated. According to several studies, cytokines, including interleukins, are associated with SSNHL in terms of serum expression and genetic polymorphisms. Interleukin-1 (IL-1) plays a key role in inflammation and may be associated with SSNHL. This study analyzed the association of single nucleotide polymorphisms (SNPs) of IL-1 receptor (IL-1R) genes with SSNHL in Taiwan.MethodsWe conducted a case–control study involving 401 patients with SSNHL and 730 healthy controls. Four SNPs (IL-1R type 1 gene [IL1R1] [rs3917225 and rs2234650] and IL-1R type 2 gene [IL1R2] [rs4141134 and rs2071008]) were selected. The genotypes were determined using the TaqMan assay. The Hardy–Weinberg equilibrium (HWE) was tested for each SNP, and genetic effects were evaluated.ResultsThe TT genotype of rs2234650 had an adjusted odds ratio (OR) of 2.988 (95% confidence interval [95% CI] 1.27–6.82) (P = 0.012) compared with the CC genotype in patients with SSNHL. The SNP rs2234650 was associated with SSNHL in the recessive model (TT vs. CC + CT, P = 0.0206, OR = 2.681). The CT genotype of rs4141134 had an adjusted OR of 3.860 (95% CI 2.01–7.44; P < 0.0001) compared with the TT genotype, in patients with SSNHL. The SNP rs4141134 was associated with SSNHL under the dominant model (CC + CT vs. TT, P < 0.0001, OR = 4.087).ConclusionThese findings suggest that IL1R1 and IL1R2 gene polymorphisms may contribute to an increased risk of SSNHL in Taiwan.

TIMP-2 gene rs4789936 polymorphism is associated with increased risk of breast cancer and poor prognosis in Southern Chinese women.

Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an endogenous inhibitor of matrix metalloproteinase-2, and an important regulator of cancer growth and metastasis. Here, we evaluated the relationship between TIMP-2 gene rs4789936 polymorphism and breast cancer risk and prognosis in Southern Chinese women. Analysis of 480 breast cancer cases and 530 healthy controls revealed that compared to the CC genotype, the TT/CT genotypes increased the risk of breast cancer (CT: odds ratio (OR)=1.46, 95%CI: 1.11-1.92; TT: OR=2.57, 95%CI: 1.76-3.77). Stratified and cross-over analyses indicated that the increased risk of the rs4789936 polymorphism was associated with age, smoking, drinking, and the body mass index. The TT and CT genotypes were more common than the CC genotype in patients with lymph node metastases (TT: OR=2.54, 95%CI: 1.54-4.18; CT: OR=2.10, 95%CI: 1.40-3.15), advanced stage (TT: OR=1.91, 95%CI: 1.17-3.14; CT: OR=1.80, 95%CI: 1.20-2.70), or progesterone receptor positive cancer (TT: OR=2.02, 95%CI: 1.23-3.32). Multivariate cox regression indicated the CT and TT genotypes (HR=4.65, 95%CI: 1.26-17.18, P=0.021; HR=6.62, 95%CI: 1.51-29.11, P=0.012) were associated with poor prognosis in breast cancer patients. Thus, the TIMP-2 gene rs4789936 polymorphism is associated with elevated breast cancer risk and may be an independent prognosis factor in breast cancer patients.

Effect of Estrogen Receptor- Alpha Gene Polymorphism (IVS1-397 T>C) on Microvascular Complications of Type 1 Diabetes Mellitus.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease whose etiology involves genetic predisposition as well as environmental factors. Polymorphisms of some genes are among the most important genetic factors that influence autoimmunity. Gender is another important factor affecting autoimmunity. Females are more susceptible to autoimmune diseases which may be due to the effect of sex hormones on the immune system activity. The metabolic effects of estrogen are mediated through its receptor - alpha. The exact mechanism is not well understood. A number of polymorphisms have been reported in the Estrogen Receptor- alpha (ER-alpha) IVS1 397 T>C gene which may be involved in the pathogenesis of diabetes. To assess the influence of Estrogen Receptor- alpha gene [IVS1-397 T>C] polymorphism on vascular complications of type1 diabetes mellitus in pubertal females and on the glycemic control. This cross-sectional case-control study included 40 pubertal regularly menstruating girls less than 18 years with type 1 diabetes mellitus recruited from the Pediatric Diabetes Clinic, Children's Hospital, Ain-Shams University and 20 healthy age-and sex-matched controls. Estrogen receptor alpha genotypes were analyzed by Restriction Fragment Length PCR and correlated with both clinical and laboratory parameters in the studied cases. ER-alpha was chosen as it might play a role in diabetes pathogenesis. The study revealed the TC genotype was the most prevalent genotype of the estrogen receptor. The TT genotype patients had a younger age of onset of T1DM. The prevalence of obesity was higher among TC and TT than in CC bearing patients. In addition, CC genotype patients had the least prevalence of microalbuminuria and had better glycemic control than other genotypes. Our findings suggest that Estrogen receptor- alpha gene may be affecting the age of onset of Type1 diabetes mellitus in pubertal girls as well as the glycemic control of these patients, where CC bearing girls had better glycemic control than other genotypes and less incidence of microalbuminuria.

MiR-618 rs2682818 C&amp;gt;A polymorphism decreases Hirschsprung disease risk in Chinese children

MicroRNAs (miRNAs) are endogenous non-coding small RNAs that play an important role in the development of many malignant tumors. In addition, recent studies have reported that single nucleotide polymorphisms (SNPs) located in the miRNA functional region was inextricably linked to tumor susceptibility. In the present study, we investigated the susceptibility between miR-618 rs2682818 C>A and Hirschsprung disease (HSCR) in the Southern Chinese population (1470 patients and 1473 controls). Odds ratios (ORs) and 95% confidence intervals (CIs) were used for estimating the strength of interrelation between them. We found that the CA/AA genotypes of miR-618 rs2682818 were associated with a decreased risk of HSCR when compared with the CC genotype (OR = 0.84, 95% CI = 0.72–0.99, P=0.032). Based on the stratified analysis of HSCR subtypes, the rs2682818 CA/AA genotypes were able to significantly lessen the risk of HSCR compared with CC genotype in patients with long-segment HSCR (adjusted OR = 0.70, 95% CI = 0.52–0.93, P=0.013). In conclusion, our results indicated that the miR-618 rs2682818 C>A polymorphism was associated with a reduced risk of HSCR in Chinese children, especially in patients with long-segment HSCR (L-HSCR) subtype.

Association of PTEN Gene SNPs rs2299939 With PFS in Patients With Small Cell Lung Cancer Treated With Early Radiotherapy.

Lung cancer has higher morbidity and mortality than most cancers. It is common that there are some phenomenons of secondary drug resistance, radiotherapy resistance and poor prognosis during the treatment of small cell lung cancer (SCLC). Recent studies revealed that the single-nucleotide polymorphisms (SNPs) are associated with the curative effect among patients with the same pathological type and stage. Our study analyzed the start time of radiotherapy and the relationship between PTEN gene rs2299939 polymorphisms and survival time among 116 SCLC patients. The results showed that early radiotherapy significantly improved the time of survival in patients compared with late radiotherapy (P = 0.029). Simultaneously, the study found that patients with the rs2299939 AA genotype showed significant sensitivity to both early and late radiotherapy, but early radiotherapy is better. The median survival time of CC genotype patients was 12 months in the early radiotherapy group while it was 9 months in the late radiotherapy group, thus recommending early radiotherapy among these patients. In addition, it was found that rs2299939 could regulate the expression of related genes in peripheral blood and lung tissues by eQTL analysis. This study revealed that the early radiotherapy could prolong the PFS of SCLC and shall be performed in SCLC treatment.

Single nucleotide polymorphisms associated with elevated alanine aminotransferase in patients receiving asunaprevir plus daclatasvir combination therapy for chronic hepatitis C.

AimsDrug-induced liver damage characterized by serum alanine aminotransferase (ALT) elevation often occurs in direct-acting antiviral (DAA) combination therapy for chronic hepatitis C virus (HCV) infection. This study explored single nucleotide polymorphisms (SNPs) at drug metabolism- or transport-related genes that were associated with ALT elevation in asunaprevir plus daclatasvir therapy.MethodsSubjects were 185 Japanese patients with chronic HCV genotype 1b infection who received asunaprevir plus daclatasvir therapy. Tag SNPs at possible metabolizing enzyme and transporter genes, which were involved in the pharmacokinetics of asunaprevir and daclatasvir, were selected.ResultsAmong the tag SNPs analyzed, CYP3A4 rs4646437 was significantly associated with ALT elevation (p = 0.013): maximum ALT values in patients with genotype CC were higher than those in patients with genotype non-CC (allele T). The proportion of grades 2–4 in genotype CC patients were significantly greater than those in genotype non-CC patients (p = 0.028). No patients with genotype non-CC showed grade ≥2 ALT elevation. In multivariate analysis, rs4646437 genotype CC and cirrhosis were significant, independent factors associated with grade ≥1 ALT elevation (odds ratio, 2.83 and 1.88; p = 0.040 and 0.045, respectively). In exploratory analyses, although serum concentrations of asunaprevir and daclatasvir were not correlated with maximum ALT values or rs4646437 genotypes, asunaprevir concentrations in patients with grade ≥1 ALT elevation were significantly higher than those in patients with grade <1 ALT elevation (P = 0.023).ConclusionsCYP3A4 rs4646437 was found to be significantly and independently associated with ALT elevation in Japanese patients receiving ASV plus DCV therapy. Notably, none of the patients with rs4646437 genotype non-CC (allele T) had grade ≥2 ALT elevation. SNP genotyping prior to treatment might be useful for carefully monitoring patients to complete treatment safely.

Influence of polymorphisms of VEGFR2 on clinical outcomes and safety of advanced non-small-cell lung cancer treated by first line Bevacizumab plus chemotherapy regimens

Objective: To investigate the influence of polymorphisms of vascular endothelial growth factor receptor-2(VEGFR2) on clinical outcomes and safety of advanced non-small-cell lung cancer (NSCLC) treated by first line Bevacizumab plus chemotherapy regimens. Methods: A total of 148 patients with advanced NSCLC who were treated by bevacizumab based first line regimens from January 2013 to January 2017 in the Department of Oncology of the First Affiliated Hospital of Zhengzhou University were included in this study. Peripheral blood and the biopsy tissue specimens of the NSCLC patients were collected for the genotyping of genetic variation and VEGFR2 mRNA expression, respectively. The association between genotype and other characteristics and VEGFR2 mRNA expression were analyzed. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, and multivariate analysis were adjusted by Cox regression analysis. Results: Of the polymorphisms analyzed, only 889C>T was of clinical significance. Located in the coding region, the prevalence of 889C>T in VEGFR2 among the study population were as follows: CC genotype 108 cases (72.97%), CT genotype 36 cases (24.32%), TT genotype 4 cases (2.71%), minor allele frequency of 889C>T was 0.15. The distribution of three genotypes was in accordance with Hardy-Weinberg Equilibrium (P=0.636). TT and CT genotype patients were merged in the comparison of clinical outcomes. The analysis of patients with different genotypes found that the objective response rates (ORR) of CT/TT genotypes and CC genotypes were 40.00% and 48.15% (P=0.377), respectively. And the median progression free survival (mPFS) of patients with CT/TT genotype and CC genotype were 6.1 and 8.7 months, respectively, which was statistically significant (P=0.002). In terms of overall survival (OS), the median overall survival (mOS) of the two genotypes were 18.7 and 21.4 months (P=0.012), respectively. Adjusted in multivariate analysis, 889C>T were an independent factor for progression free survival (OR=1.96, P=0.014). No association between the 889C>T and adverse reactions was found in the safety analysis. Of the 69 biopsy tissue specimens, gene expression analysis showed that the mRNA expression of VEGFR2 in cancer tissues of the patients with CT/TT genotypes were significantly higher than those of the CC genotype patients (P<0.001). Conclusion: The polymorphism 889C>T of VEGFR2 may have worse influence on clinical outcomes of advanced NSCLC treated by first line bevacizumab plus chemotherapy regimens, while no significant impact on safety.

Influence of apatinib and VEGFR2-906T>C polymorphism on clinical outcomes of advanced non-small cell lung cancer patients

Objective: To investigate the clinical outcomes of advanced non-small cell lung cancer (NSCLC) treated by apatinib regimens and the influence of VEGFR2-906T>C polymorphism. Methods: A total of 109 patients with advanced NSCLC who were treated by apatinib after three and more lines from March 2015 to December 2017 in the Department of Oncology of the First Affiliated Hospital of Zhengzhou University were included in this study. Overall response rates were evaluated after 2 cycles, then progression free survival (PFS) and overall survival (OS) were investigated, and safety data were recorded. Additionally, peripheral blood and the biopsy tissue specimens of some NSCLC patients were collected for the genotyping of genetic variation and VEGFR2 gene mRNA expression, respectively. The association between genotype and other characteristics and VEGFR2 gene mRNA expression were analyzed. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, and multivariate analysis were adjusted by Cox regression analysis. Results: The treatment effect could be evaluated in all the 109 patients, among them, complete remission (CR) 0 case, partial remission (PR) 19 case, stable disease (SD) 58 case, progression disease (PD) 32 case. Overall response rate (ORR) was 17.43%, disease control rate (DCR) was 70.64%, median PFS was 4.35 months, median OS was 8.35 months. Of the polymorphisms analyzed, only -906T>C was of clinical significance. The prevalence of -906T>C in VEGFR2 among the study population were as follows: TT genotype 64 cases (58.72%), TC genotype 37 cases (33.94%), CC genotype 8 cases (7.34%), minor allele frequency of -906T>C was 0.24. The distribution of three genotypes was in accordance with Hardy-Weinberg Equilibrium (P=0.418). CC and TC genotype patients were merged in the comparison of clinical outcomes. The analysis of patients with different genotypes found that the ORR of CC/TC genotypes and TT genotypes were 13.33% and 20.31% (P=0.377), respectively. And the median PFS of patients with CC/TC genotype and TT genotype were 3.25 and 5.35 months, respectively, which was statistically significant (P=0.007). In terms of OS, the median OS of the two genotypes were 7.35 and 9.15 (P=0.014), respectively. Adjusted in multivariate Cox regression analysis of PFS, TC/CC genotypes were an independent factor for PFS (OR=1.83, P=0.015). The correlation between -906T>C and adverse reactions was not found in the safety analysis. Additionally, of the 69 biopsy tissue specimens, gene expression analysis was conducted. And the results show that the mRNA expression of VEGFR2 in cancer tissues of the patients with CC/TC genotypes were significantly higher than those of the TT genotype patients (P<0.001). Conclusions: Apatinib is safe and effective for patients with advanced non-small cell in multiline therapy. VEGFR2 -906T>C CC/TC genotype has a worse effect on apatinib multiline treatment in patients with advanced NSCLC.

Enhancement of Eligibility Guidelines for Gemtuzumab Ozogamicin Therapy for Childhood Acute Myeloid Leukemia: A Report from Children's Oncology Group Protocol AAML0531

Background: CD33 is variably expressed on leukemia blasts in most patients with acute myeloid leukemia (AML). Efforts to target CD33 therapeutically have focused on gemtuzumab ozogamicin (GO), an antibody-drug conjugate delivering a DNA-damaging calicheamicin derivative. Qualification for GO therapy has been determined by expression of CD33 by multidimensional flow cytometry (MDF); patients with positive CD33 expression receive GO. Previous studies from the AAML0531 protocol demonstrated that the cell surface intensity expression of CD33, determined by MDF, predicts the response to treatment with GO, and that in part this expression is regulated by a pair of CD33 single nucleotide polymorphisms (SNPs) in linkage disequilibrium that also, independently, predict response to therapy. Patients with CC genotype for rs12459419 have lower relapse risk and improved disease-free survival, compared to CT and TT genotypes. Because GO therapy is associated with treatment-related toxicity, it is important to identify biologic variables associated with benefits and risks. To date, there has been no report associating SNP status among CD33 positive versus CD33 negative patients that could assess how the combination of these biomarkers for determining administration of GO therapy could improve patient outcomes.Objective: In an effort to determine which children would benefit most from GO treatment in future prospective pediatric AML protocols, we aimed to elucidate if CD33 SNP genotype status should be combined with quantitative CD33 cell surface antigen expression on the diagnostic leukemia cells (CD33+ versus CD33-) to determine GO eligibility, with a retrospective analysis of children enrolled in Children's Oncology Group AAML0531.Methods: Of 1022 newly diagnosed pediatric patients with de novo AML enrolled on protocol AAML0531, 666 satisfied two criteria for this study: (1) submission of a blood or bone marrow sample for MDF at diagnosis with corresponding CD33 SNP genotype data available, and (2) proper consent for specimen testing.CD33 Expression Levels on Leukemic BlastsThe diagnostic AML leukemia population was identified by gating on CD45 versus log-side scatter and CD33 expression levels were determined by measuring the mean fluorescence intensity (MFI) by flow cytometry. For a patient to be considered CD33+ two criteria were required: intensity of CD33 on blasts was at minimum four times the MFI of its correspondent autofluorescent control, and at least 80% of the total blasts were greater than this minimum.Genotyping CD33 SNPsCD33-coding SNP rs12459419-Ala14Val and linked promoter SNP rs3865444 were genotyped using the Sequenome (San Diego, CA) platform at the Biomedical Genomics Center, University of Minnesota. Both SNPs had a call rate of 0.98 and were in Hardy-Weinberg equilibrium (P=0.05).Results:Association of Genotype and cell surface expression of CD33 for AAML0531 patients Of 666 patients, 84% (560/666) were CD33+. CC genotype was observed in 54.5% (305/560) of CD33+ cases, 37.5% (210/560) had CT genotype and 8% (45/560) TT genotype. Of the 16% (106/666) of patients who were CD33 negative, 33% (35/106) had CC genotype, 47% (50/106) CT genotype, and 20% (21/106) had TT genotype. Comprehensively, 340/666 (51%) had CC genotype (51%) and 10% were CD33 negative (35/340). Conversely, out of a total of 66 patients with TT genotype, 45 (68%) were CD33+ and 32% (21/66) were CD33 negative.Conclusions: These results clarify the relationship between the amount of CD33 expressed on AML at diagnosis as measured by MDF and CD33 SNP genotype status. While correlation with clinical outcome analysis is ongoing, these data support inclusion of CD33 SNP genotyping for eligibility of GO therapy. Therefore, the current recommendation for future COG AML clinical protocols is that GO will be administered to patients with CD33 expression as determined by MDF and CC genotype patients regardless of CD33 expression. DisclosuresPardo:Hematologics, Inc: Employment. Eidenschink Brodersen:Hematologics, Inc: Employment. Paine:Hematologics, Inc: Employment. Loken:Hematologics, Inc: Employment, Equity Ownership.

Clinical outcomes of gastric cancer patients received capecitabine based adjuvant chemotherapy and the corresponding pharmacogenomics analysis

Objective: To investigate the association between Thymidine phosphorylase(TYMP)genetic variation and clinical outcomes of postoperative gastric cancer (GC) patients received capecitabine based regimens. Methods: A total of 198 GC patients underwent surgical treatment and received capecitabine based adjuvant chemotherapy were included in this retrospective study. Peripheral blood and the postoperative tissue specimen of the GC patients were collected for the genotyping of polymorphism and TYMP mRNA expression, respectively. The correlation between polymorphism and clinical outcomes and safety of postoperative GC patients were analysed. Results: Located in the upstream, rs11479 was of clinical significance. The prevalence of rs11479 in TYMP among the GC patients were as follows: CC genotype 125 cases (63.13%), CT genotype 65 cases (32.83%), TT genotype 8 cases (4.04%), minor allele frequency of rs11479 is 0.20. The distribution of three genotypes were in accordance with Hardy-Weinberg Equilibrium (P=0.901). The analysis results of patients with different genotypes found that the 3-year disease free survival rate of the patients with CT/TT genotype and CC genotype were 73.97% and 65.60%, respectively, which was statistically significant (P=0.003). In terms of overall survival, the 3-year overall survival rate of the two genotypes were 83.56% and 72.80% (P=0.012), respectively. Adjusted in multivariate Cox regression analysis, CT/TT genotype was an independent favorable factor for disease free survival (OR=0.55, P=0.011). Safety analysis indicated that there was no significant association between genotypes and grade 2 adverse reaction. Additionally, of the 79 postoperative tissue specimens, the results showed that the expression of TYMP in cancer tissues of the patients with CT/TT genotypes were significantly higher than those of the wild type CC genotype patients (P<0.001). Conclusion: The polymorphism rs11479 of TYMP have favorable influence on the clinical outcomes of gastric cancer patients received capecitabine based adjuvant chemotherapy treatment through changing the mRNA expression of TYMP.

ENHO, RXRA, and LXRA polymorphisms and dyslipidaemia, related comorbidities and survival in haemodialysis patients

BackgroundThe energy homeostasis-associated gene (ENHO), retinoid X receptor alpha gene (RXRA), and liver X receptor alpha gene (LXRA) are involved in adipogenic/lipogenic regulation. We investigated whether single-nucleotide polymorphisms in these genes (ENHO rs2281997, rs72735260; RXRA rs749759, rs10776909, rs10881578; LXRA rs2279238, rs7120118, rs11039155) are associated with dyslipidaemia, related comorbidities and survival of haemodialysis (HD) patients also tested for T-helper (Th) cell interleukin genes (IL).MethodsThe study was carried out in 873 HD patients. Dyslipidaemia was diagnosed by the recommendations of the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines (2003); atherogenic dyslipidaemia was referred to if the TG/HDL cholesterol ratio was equal to or higher than 3.8. Genotyping of ENHO SNPs, LXRA SNPs, and IL12A rs568408 was carried out using HRM analysis. RXRA SNPs, IL12B rs3212227, and IL18 rs360719 were genotyped using PCR-RFLP analysis. The circulating adropin concentration was determined in 126 patients by enzyme-linked immunosorbent assay. Survival probability was analysed using the Kaplan-Meier method in 440 patients followed through 7.5 years.ResultsDyslipidaemia by K/DOQI was diagnosed in 459 patients (91% revealed hyper-LDL- cholesterolaemia), atherogenic dyslipidaemia was diagnosed in 454 patients, and 231 patients were free of dyslipidaemia by both criteria. The variant allele (T) of ENHO rs2281997 was associated with the hyper-LDL cholesterolaemic pattern of dyslipidaemia by K/DOQI. The frequency of atherogenic dyslipidaemia was lower in T-allele bearers than in CC-genotype patients. The rs2281997 T allele was associated with lower cardiovascular mortality in HD patients showing atherogenic dyslipidaemia. ENHO, RXRA, and LXRA showed epistatic interactions in dyslipidaemia. Circulating adropin was lower in atherogenic dyslipidaemia than in non-atherogenic conditions. RXRA rs10776909 was associated with myocardial infarction. Bearers of LXRA rs2279238, rs7120118 or rs11039155 minor alleles showed higher mortality. ENHO SNP positions fell within the same DNase 1 hypersensitivity site expressed in the Th1 cell line. Epistatic interactions occurred between rs2281997 and Th1 IL SNPs (rs360719, rs568408).ConclusionsAtherogenic dyslipidaemia occurs in HD patients in whom ENHO encodes less adropin. ENHO, RXRA, and LXRA SNPs, separately or jointly, are associated with dyslipidaemia, myocardial infarction, and survival in HD patients. Differences in the availability of transcription binding sites may contribute to these associations.

The impact of genetic variation of KDR on clinical outcomes of advanced colorectal cancer patients treated by first line bevacizumab based regimens

Objective: To investigate the association between kinase insertion region receptor (KDR) gene genetic variation and the efficacy of bevacizumab in patients with advanced colorectal cancer(CRC) were investigated in this study. Methods: 118 patients with advanced colorectal cancer who were treated by bevacizumab based first line regimens were included in this study. Peripheral blood and the biopsy tissue specimens of the CRC patients were collected for the genotyping of genetic variation and KDR gene expression, respectively. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, and multivariate were adjusted by Cox regression analysis. Results: Located in the coding region, the prevalence of 889 C>T in KDR among the study population were as follows: CC genotype 86 cases (72.88%), CT genotype 30 cases (25.42%), TT genotype 2 cases (1.70%), minor allele frequency of 889 C>T is 0.14. The distribution of three genotypes in accordance with Hardy-Weinberg Equilibrium (P=0.737). There were no statistical differences in the distribution of the genotypes in baseline clinical data. TT and CT genotype patients were merged in the comparison of clinical outcomes. The clinical outcomes analysis of patients with different genotypes found that the objective response rates (ORR) of CT/TT genotypes were 34.38% and 43.02% (P=0.395), respectively. And the median progression free survival (PFS) of patients with CT/TT genotype and CC genotype were 7.5 and 9.7 months respectively, which was statistically significant (P=0.009). In terms of overall survival (OS), the median OS of the two genotypes were 19.3 and 20.1 (P=0.025), respectively. Adjusted in multivariate Cox regression analysis of PFS, CT/TT genotypes were an independent factor for PFS (OR=1.88, P=0.023). Additionally, of the 57 biopsy tissue specimens, gene expression analysis was conducted. And the results showed that the expression of KDR in cancer tissues of the patients with CT/TT genotypes were significantly higher than those of the CC genotype patients (P<0.001). Conclusion: Among advanced colorectal cancer patients treated by bevacizumab, the polymorphism 889 C>T of KDR may impact the clinical outcomes of bevacizumab first line treatment by influencing the mRNA expression of KDR.

The influence of Thymidine Phosphorylase genetic variation on clinical outcomes and safety of colorectal cancer patients received adjuvant chemotherapy after R0 resection

Objective: To study the association between Thymidine Phosphorylase (TYMP) genetic variation and clinical outcomes and safety of postoperative colorectal cancer (CRC) patients. Methods: A total of 235 patients with colorectal cancer underwent surgical treatment were included in this retrospective analysis. Peripheral blood and the postoperative tissue specimen of the CRC patients were collected for the genotyping of polymorphism and TYMP mRNA expression, respectively. The correlation between polymorphism and clinical outcomes and safety of postoperative CRC patients were analysed. Results: Located in the upstream, 5633C>T was of clinical significance. The prevalence of 5633C>T in TYMP among the CRC patients were as follows: CC genotype 149 cases (63.40%), CT genotype 73 cases (31.06%), TT genotype 13 cases (5.54%), minor allele frequency of 5633C>T is 0.21. The distribution of three genotypes was in accordance with Hardy-Weinberg Equilibrium (P=0.313). CT genotype and TT genotype patients were merged in the comparison of prognosis. The survival analysis of patients with different genotypes found that the median Overall Survival (OS) of CT/TT genotype and CC genotype were 5.8 and 4.5 year, which was statistically significant (P=0.009). Adjusted in multivariate Cox regression analysis, CT/TT genotype was an independent favorable factor for OS (HR=0.67, P=0.015). Additionally, of the 87 postoperative tissue specimens, the results showed that the expression of TYMP in cancer tissues of the patients with CT or TT genotypes were significantly higher than those of the wild type CC genotype patients (P=0.019). And the safety analysis showed that the incidence of grade 3 hand-foot syndrome among CT/TT genotype patients were higher than that of CC genotype patients (33.72% vs 20.13%, OR=1.68, P=0.021). Conclusion: The polymorphism 5633C>T of TYMP may impact the prognosis of CRC patients received adjuvant chemotherapy by influencing the mRNA expression of TYMP.

Preliminary report: one of the PD-1 gene variants may be a valuable marker for colorectal cancer

IntroductionIntroduction: Programmed death-1 (PD-1), an important immunosuppressive molecule, plays a key role in tumor-cell-mediated immune escape. The present study aimed to investigate the role of PD-1.5 (C/T) gene polymorphisms on the susceptibility and progression of colorectal cancer (CRC).Material and methodsIn this study, the PD-1.5 C/T polymorphism was investigated in 99 CRC patients and 150 healthy individuals as controls by nested polymerase chain reaction-restriction fragment length polymorphism methodResultsThe distributions of PD-1.5 (C/T) genotypes and alleles were in agreement with Hardy–Weinberg equilibrium in controls (p&gt;0.05) but not in CRC patients (p=0.02). We found a statistical significance difference between CRC patients and controls for the genotypic distribution of PD-1.5(C/T) genotypes (p=0.003) and also for alleles (p=0.004). The patients who have T allele have increased according to the controls (p=0.001). The patients who have C allele with distance metastasis have increased heterozygous CT genotype of PD-1.5 (C/T) polymorphism than those with no metastasis (p&lt;0.001). We also detected the increased CC genotype in patients who have angiolymphatic invasion (p=0.043). The patients who have mucineous component have increased frequency of T allele than those with the absence of mucineous component (p=0.023).ConclusionsOur results have shown significant associations between PD-1.5 genotypes and CRC susceptibility and progression of the disease.

PREVALENCE OF POLYMORPHISM OF THE TLR-9 TYPE GENE IN PATIENTS WITH CHRONIC EPSTEIN-BARR VIRUS INFECTION

The prevalence of polymorphism -1486T/C of the TLR-9 gene was studied in 44 patients with chronic Epstein-Barr virus infection (CEBV). The control group for the study of the polymorphisms prevalence of -1486T/C of the TLR-9 gene was 40 healthy donors. Three main genotypes of -1486T/C of the TLR-9 gene were identified based on the obtained results – TT, TC, CC. Investigation of the occurrence frequency of individual genotypes revealed the dominance of the TC genotype, compared with the homozygous TT and CC genotypes. The study of -1486T/C of the TLR-9 gene polymorphism frequency distribution for different genotypes demonstrated the specificity of changes in the TC genotype in patients with CEBV and the absence of such for the TT and CC genotypes. These results confirm the important role of the TLR-mediated signaling in the pathogenesis of the disease, which is necessary to determine the genetic background associated with the course of the disease and its possible consequences. These are the aspects that will further enable the identification of risk groups among such patients and provide timely therapy. The analysis of the results of the -1486T/C polymorphism of the TLR-9 gene revealed three main genotypes –TT, TC, CC. Investigation of the occurrence frequency of individual genotypes revealed the dominance of the genotype TC, compared with the homozygous genotypes of TT and CC. The study of frequency distribution of the polymorphism -1486T/C of TLR-9 for different genotypes demonstrated the specificity of changes in the TC genotype and the absence of suchin the TT and CC genotypes in patients with CEBV.Our study for the purpose of determining the 1486T/C polymorphism of the TLR-9, that is associated with chronic forms of CEBV infection, confirms the important role of TLR-mediated signaling in the pathogenesis of this disease, which is necessary to determine the genetic background associated with the course of the disease and possible consequences of CEBV. These aspects will further enable the identification of risk groups among such patients and provide timely therapy.Analysis of the results allowed establishing the following:1. The 1486T/C polymorphism of the TLR-9 gene is significantly more frequent in patients with CEBV than in the control.2. The frequency distribution of the -1486T/C polymorphism ofthe TLR-9 gene allowed the establishment of the association of the genotype TC with chronic forms of the EBV infection, which is very specific for this group of patients.

Meta-Analysis of Grazoprevir plus Elbasvir for Treatment of Hepatitis C Virus Genotype 1 Infection

Background and aim. Grazoprevir is an NS3/4A protease inhibitor (PI), while elbasvir is an NS5A inhibitor. We performed this meta-analysis to directly compare grazoprevir plus elbasvir and ribavirin regimen vs. grazoprevir and elbasvir without ribavirin in the treatment of hepatitis C virus genotype 1 infection and to precisely evaluate the efficacy of the latter regimen in cirrhotic, IL28 CC genotype patients and those coinfected with human immunodeficiency virus.Material and methods. A computer literature search of PubMed, Scopus, EBSCO, Embase, and Cochrane central was conducted. Studies were screened for eligibility. Sustained virologic response (SVR) rates were pooled using OpenMeta [Analyst] software for windows. A subgroup analysis was performed to stratify the treatment efficacy according to the different baseline characteristics of HCV patients.Results. Eight randomized controlled trials (n = 1,297 patients) were pooled in the final analysis. The overall SVR rate was 96.6% with 95% CI [95.5% to 98%]. For cirrhotic patients, the SVR rate was 95.7% with 95% CI [93.9% to 97.5%] and for non-cirrhotic patients, the SVR rate was 97% with 95% CI [95.9% to 98.4%]. Furthermore, the addition of ribavirin (RBV) to the treatment regimen did not significantly improve the SVR (RR 1.003, 95% CI [0.944 to 1.065]).The dual regimen was effective in patient populations with NS3 resistance-associated substitution (RAS). However, this regimen achieved lower SVR rates (< 90%) in patients with NS5A RAS.Conclusions. We conclude that the 12-week treatment regimen of the fixed dose combination of grazoprevir plus elbasvir achieved high SVR rates in patients with HCV genotype 1 infection. The addition of ribavirin to this regimen did not add a significant benefit.

The Endothelial Nitric Oxide Synthase (NOS3-786T>C) Genetic Polymorphism in Chronic Heart Failure: Effects of Mutant -786C allele on Long-term Mortality.

Nitric oxide plays an important role in the regulation of basal vascular tone and cardiac myocyte function. We investigated the NOS3-786T>C polymorphism in chronic heart failure (CHF) and its effects on long-term mortality. Ninety-one patients with CHF who were referred to the Department of Cardiology of Siyami Ersek Cardiovascular and Thoracic Surgery Center for cardiopulmonary exercise testing between April 2001 and January 2004 and 30 controls were enrolled in this study. Patient were followed prospectively for a period of 1 to 12 years. Patients and controls were divided into three groups: TT, TC and CC, according to their NOS3-786T>C polymorphism. We noted that there was no significant difference in the genotype distribution between patients and controls. There was also no significant difference in endothelial nitric oxide synthase (eNOS) gene polymorphism between ischemic HF and nonischemic HF. During the follow-up period, 61 (67%) deaths occurred. The nonsurvivor group had lower left ventricular ejection fraction (LVEF) (p = 0.01), reduced peak oxygen consumption (p = 0.04) and were of older age (p = 0.001). Age, LVEF, peak oxygen consumption and genotype were found to be predictors of mortality (p < 0.05). Additionally, mortality was significantly increased in -786CC genotype patients compared to TT genotype patients (hazard ratio = 2.2; p = 0.03). By multivariate analysis, age and eNOS genotype were determined to be significant independent predictors of death. Additionally, Kaplan-Meier analysis confirmed that homozygote -786C genotype was associated with an increased risk of death (χ2 = 4.6, p = 0.03). Our findings showed that the NOS3-786T>C polymorphism was associated with an increased risk of mortality in patients with CHF.

Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis.

Background.Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM.Methods.We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations.Results. LTA4H genotype predicted survival of human immunodeficiency virus (HIV)–uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79–5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype.Conclusions. LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.

Association of MMP-9 gene polymorphisms with nephrolithiasis patients.

Nephrolithiasis is one of the causes which lead to chronic kidney disease (CKD). Matrix metalloproteinases (MMPs) are endopeptidases degrading extracellular matrix which correlate with the pathogenesis of atherosclerosis. The current study was designed to analyze the association of (R279Q, C1562T) polymorphism of MMP-9 with nephrolithiasis patients. Genotyping of MMP-9/R279Q and of MMP-9/C1562T polymorphism were carried out by PCR-based restriction digestion method. Serum level of MMP-9, oxidative stress marker, MDA, and uric acid were measured in patients and control. Allele frequencies of the MMP-9/C1562T polymorphism for C and T allele were 71.25% and 28.75% in patients, 87.08% and 12.92% in control respectively. The homozygote TT was more frequent in the nephrolithiasis patients group, while T allele frequency was significantly higher in the nephrolithiasis patients group than in the control group. The patients with CT and TT genotype showed a significant increase in serum MMP-9, Total Oxidant Status (TOS), Oxidative Stress Index (OSI), Malondialdehyde (MDA), and uric acid when compared to CC genotype in patients with nephrolithiasis. The R279Q polymorphism site with regard to the relationship with nephrolithiasis was not significant. The result indicates that patients with TT genotype had an increased risk of stones. Also, the results demonstrate that TT allele of the C1562T polymorphism in the MMP-9gene is related with an increase of oxidative stress in nephrolithiasis patients and may possibly impose a risk for cardiovascular diseases in patients with TT genotype of MMP-9.