Association of PTPN22 gene (rs2488457) polymorphism with ulcerative colitis and high levels of PTPN22 mRNA in ulcerative colitis

Purpose

Our aims were to evaluate protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene polymorphisms in ulcerative colitis (UC) and explore PTPN22 mRNA levels in colonic biopsies of UC patients in central China.

Methods

A total of 165 Chinese UC patients and 300 healthy controls were enrolled in this study. PTPN22 ?1123G/C, +1858C/T, and +788G/A polymorphisms were genotyped by PCR-restriction fragment length polymorphism method. PTPN22 mRNA expressions in colonic biopsies and serum C-reactive protein (CRP) levels were determined by quantitative PCR and immunonephelometry, respectively.

Results

The frequency of C carrier was higher in UC patients than in healthy controls (66.7 vs. 53.3 %, P?=?0.005, odds ratios?=?1.75, 95 % CI 1.18–2.60) and associated with extensive colitis (P?=?0.029). PTPN22 mRNA levels were elevated in UC patients than in healthy controls (P?<?0.001). Among UC patients, PTPN22 mRNA expression levels were higher in biopsies of inflamed colonic tissue compared with noninflamed tissue (P?<?0.001) and were correlated with CRP levels (r?=?0.578, P?<?0.001). PTPN22 mRNA expression levels were elevated in extensive colitis compared to proctitis (P?=?0.008) and to left-sided colitis (P?=?0.029) and were higher in moderate and severe disease than in mild disease (P?=?0.005).

Conclusions

Our study showed the potential association between PTPN22 ?1123G/C polymorphism and UC in central China. PTPN22 mRNA levels were highly expressed in UC, especially in active disease, and were correlated with CRP levels, disease location, and disease severity in UC patients.     

Polymorphisms in DNA repair genes XRCC1, XRCC3 and XPD, and colorectal cancer risk: a case–control study in an Indian population

Purpose

Genetic polymorphisms in DNA repair genes may influence variations in individual DNA repair capacity, which could be associated with the development of cancer. We detected the distributions of three single-nucleotide polymorphisms (XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln) in DNA repair genes, and assessed the associations of these genetic polymorphisms with colon and rectal cancer susceptibility as well as evaluated the interactions of gene–gene and gene–environment in a case–control study of an Indian population.

Methods

This case–control study was conducted with 302 cases (including 59 colon and 243 rectal cancer patients) and 291 cancer-free healthy controls. Genotypes were determined by PCR–RLFP assays. The effects [odds ratios (ORs) and 95% confidence intervals (95% CIs)] of genetic polymorphisms on colorectal cancer were estimated using unconditional logistic regression.

Results

The XRCC1 399Gln allele was found to be associated with a significantly increased rectal cancer risk among men (OR = 1.65, 95% CI 1.04–2.64). Whereas the XRCC3 241Met allele showed a protective tendency against rectal cancer (OR = 0.68, 95% CI 0.46–1.02) for both men and women. Furthermore, a combination of the XRCC1 399Gln allele with XRCC3 Thr/Thr genotype and the XPD 751Gln allele demonstrated the highest rectal cancer risk (OR = 3.52, 95% CI 1.43–9.44).

Conclusions

The combined effects of putative risk alleles/genotypes for different DNA repair pathways may strengthen the susceptibility to rectal cancer.     

Predictive value of ABCB1 polymorphisms G2677T/A, C3435T, and their haplotype in small cell lung cancer patients treated with chemotherapy

Purpose

Multiple drug resistance limits the efficacy of numerous cytotoxic drugs used in the treatment of small cell lung cancer (SCLC). The drug efflux protein ATP-binding cassette transporter B1 (ABCB1) has an important role in this process, and its gene variability may affect chemotherapy outcomes.

Patients and methods

This study aimed to evaluate the associations between ABCB1 polymorphisms G2677T/A, C3435T, and their haplotype with progression-free survival (PFS) and overall survival (OS) in 177 SCLC patients treated with cisplatin–etoposide or cyclophosphamide–epirubicin–vincristine chemotherapy. To determine the ABCB1 genotype, allelic specific TaqMan^? probes were used in a RT-PCR .

Results

Patients carrying the G2677T/A TT?+?TA?+?AA genotypes (24?%) or the C3435T CT?+?TT genotypes (72?%) or the 2677T/A-3435T haplotype (40?%) had a longer PFS (Cox regression, P?=?0.052, 0.037 and 0.037, respectively); these associations persisted also in multivariate analyses (Cox regression, P?=?0.028, 0.037 and 0.030, respectively). Moreover, patients with the C3435T CT?+?TT genotypes had a longer OS both in univariate and multivariate analysis (Cox regression, P?=?0.022 and 0.028, respectively). A trend toward longer OS was noted for the 2677T/A-3435T haplotype (Cox regression, P?=?0.051), but its independent value was not confirmed (Cox regression, P?=?0.071).

Conclusions

Our study reported a possible predictive value of ABCB1 polymorphisms G2677T/A, C3435T, and their haplotype for longer PFS and OS in Caucasian SCLC patients treated with chemotherapy. However, to be implemented into routine clinical practice, ABCB1 polymorphisms require further validation.     

Pharmacogenetic assessment of clinical outcome in patients with metastatic breast cancer treated with docetaxel plus capecitabine

Purpose

Docetaxel plus capecitabine, a commonly used chemotherapeutic regimen for metastatic breast cancer (MBC), is highly variable in its effectiveness. We aimed to investigate whether allelic variants of cytochrome P450 (CYP450) affected objective response, progression-free survival (PFS), and overall survival (OS) in MBC.

Patients and methods

79 SNPs in CYP450, whose minor allele frequency were ≥10%, were genotyped in 69 MBC patients who were treated with docetaxel plus capecitabine. Pearson’s χ² test or Fisher’s exact test was used to investigate the influence of SNPs on objective response as appropriate. Log-rank test was used to assess the association between SNPs and survival outcomes.

Results

There is no significant association between polymorphisms and both objective response and OS. Only one SNP, CYP1A1 rs1048943 A>G (Ile462Val), was significantly associated with PFS (P?=?0.0003). Multivariate analysis confirmed its prognostic significance for PFS (P?=?0.004).

Conclusion

CYP1A1 rs1048943 A>G (Ile462Val) polymorphism is a potential prognostic marker for survival outcome after docetaxel plus capecitabine chemotherapy in MBC patients. However, confirmatory study is needed to validate this finding.     

XPD Asp312Asn polymorphism is a risk factor for prostate cancer

Purpose

The association between Asp312Asn and Lys751Gln polymorphisms of Xeroderma pigmentosum Group D (XPD) and prostate cancer risk are still inconclusive. For better understanding of the effects of these two polymorphisms on prostate cancer risk, a meta-analysis was performed.

Methods

An extensive search was performed to identify all case–control studies investigating such association. The strength of association between these two polymorphisms and prostate cancer risk was assessed by odds ratio (OR) with the corresponding 95?% confidence interval (95?% CI).

Results

A total of seven case–control studies were identified, among which five studies (1,257 cases and 1,956 controls) were eligible for Asp312Asn polymorphism and six studies (1,451 cases and 2,375 controls) were eligible for Lys751Gln polymorphism. Asp312Asn polymorphism was associated with an increased risk of prostate cancer in additive and recessive genetic models (additive model: OR?=?1.68, 95?% CI?=?1.28–2.22, P?=?0.00; recessive model: OR?=?1.65, 95?% CI?=?1.27–2.15, P?=?0.00). In the subgroup analysis, Asp312Asn polymorphism was associated with an increased risk of prostate cancer among Asians in all three genetic models (additive model: OR?=?2.09, 95?% CI?=?1.39–3.14, P?=?0.00; dominant model: OR?=?1.49, 95?% CI?=?1.12–1.98, P?=?0.01; recessive model: OR?=?1.93, 95?% CI?=?1.31–2.83, P?=?0.00). However, no significant associations were found between Lys751Gln polymorphism and prostate cancer risk in the overall analyses or the subgroup analyses by ethnicity.

Conclusions

The results of this meta-analysis indicate that the XPD Asp312Asn polymorphism is a risk factor for prostate cancer development.     

Associations between polymorphisms in IL-12A, IL-12B, IL-12Rβ1, IL-27 gene and serum levels of IL-12p40, IL-27p28 with esophageal cancer

Purpose

The aim of this study was to investigate whether IL-12A, IL-12B, IL-12Rβ1, and IL-27 gene polymorphisms and serum levels of IL-12, IL-27 are associated with esophageal cancer.

Methods

We genotyped IL-12A gene rs568408, IL-12B gene rs3212227, IL-12Rβ1 gene 378 C/G, IL-27 gene rs153109, rs17855750, and rs181206 polymorphisms in a case–control study of 426 esophageal cancer patients and 432 health controls, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and serum IL-12p40 and IL-27p28 levels were measured by enzyme-linked immunosorbent assay.

Results

Both serum IL-12p40 and IL-27p28 levels were significantly higher in controls than those in patients (P?<?0.01). Rs568408 AG/AA, rs3212227 CC/AC, and IL-12Rβ1 378 GG/GC genotypes were associated with significantly increased risk of esophageal cancer (rs568408: χ²?=?5.704, P?=?0.017; rs3212227: χ²?=?7.689, P?=?0.006; IL-12Rβ1 378C/G: χ²?=?5.206, P?=?0.023). Moreover, rs3212227 CC/AC and 378 GG/GC genotypes were observed significantly associated with decreased serum IL-12p40 level in patients compare to other genotypes (rs3212227: t?=?2.129, P?=?0.034; IL-12Rβ1 378 C/G: t?=?2.178, P?=?0.030). Furthermore, frequency of rs3212227 CC/AC genotypes was significantly higher in patients with poor differentiation than those with AA genotype (χ²?=?4.314, P?=?0.035).

Conclusion

Our data suggest that the impaired production of IL-12p40 and IL-27p28 behaves as risk factors for esophageal cancer occurrence. IL-12B gene rs3212227 CC/AC and IL-12Rβ1 gene 378 GG/GC genotypes, which associated with decreased IL-12p40 level, may contribute to esophageal cancer susceptibility.     

Interaction between CTLA4 gene and IBD5 locus in Hungarian Crohn��s disease patients

Backgrounds and aims

The IGR2198a_1 and IGR2096a_1 variants of the IBD5 region were found to be associated with Crohn??s disease (CD) in the Hungarian population, while IGR2230a_1 does not seem to confer risk for the disease. In the present study, our aim was to investigate the statistical interaction of these three IBD5 polymorphisms with the +49 A/G substitution within the cytotoxic T lymphocyte antigen-4 (CTLA4) gene, detected previously as neutral gene variant in Hungarian IBD patients.

Methods

A total of 305 unrelated subjects with CD and 310 healthy controls were genotyped with PCR-RFLP methods.

Results

In contrast with single gene effects, after genotype stratification, the IGR2198a_1 C and IGR2096a_1 T variants were found to confer susceptibility only in subjects with CTLA4 +49 AA genotype (P?=?0.008; OR?=?1.86 and P?=?0.016; OR?=?1.74, respectively), for IGR2230a_1 no such effect on disease risk could be demonstrated.

Conclusion

Analysis of specific genotype combinations unfolded a possible association between the CTLA4 +49 A/G substitution and two of the observed IBD5 variants with respect to disease risk.     

Thiopurine methyltransferase genotyping in Palestinian childhood acute lymphoblastic leukemia patients

Background

The genetic polymorphism of thiopurine methyltransferase (TPMT) is well characterized in most populations. Four common polymorphic alleles are associated with impaired activity of the enzyme. These are TPMT*2 (238G>C), TPMT*3B (c.460G>A), TPMT*3A (c.460G>A and c.719A>G) and TPMT*3C (c.719A>G). The aim of the present study was to determine the frequency of TPMT polymorphisms and their association with the occurrence of adverse events, during 6-mercaptopurine therapy in pediatric acute lymphoblastic leukemic (ALL) patients in Gaza Strip.

Methods

A total of 56 DNA samples from all pediatric ALL patients admitted to the pediatric hematology departments of Gaza strip hospitals were analyzed. Genomic DNA from peripheral blood leukocytes was isolated and the TPMT*2, TPMT*3B TPMT*3A and TPMT*3C allelic polymorphism was determined by PCR-RFLP and allele specific PCR technique.

Results

No TPMT*2, *3B or *3C alleles were detected. Only one, out of 56 patients, was found heterozygous for the TPMT*3A allele. Thus, the frequency of TPMT*3A allele was calculated to be 0.89%. Fourteen patients of ALL were suffering from myelotoxicity during 6-MP therapy. From our results, no significant association could be established between clinical and laboratory data and/or the presence of the mutation in TPMT gene.

Conclusion

TPMT*3A was the only deficiency allele detected in our population with an allelic frequency of 0.89%. Other polymorphic alleles in TPMT gene, or factors other than TPMT polymorphisms may be responsible for the development of myelosuppression in cases that don’t carry the investigated TPMT alleles (*2, *3A, *3B and *3C). Therefore, more studies are recommended to study such factors.     

Risk factors for anastomotic leakage following anterior resection for colorectal cancer: the effect of epidural analgesia on occurrence

Purpose

The effect of thoracic epidural analgesia (TEA) on anastomotic leakage (AL) after anterior resection for colorectal cancer is controversial. The aim of this study was to evaluate the risk factors including TEA for the occurrence of AL after anterior resection for colorectal cancer.

Methods

This retrospective study included 1,312 patients with colorectal cancer who underwent anterior resection between 2000 and 2011 at the Cancer Center, Sun Yat-sen University. Univariate and multivariate logistics analyses were performed to determine the risk factors, including TEA, for AL. Additionally, we evaluated the effect of TEA on outcome parameters.

Results

AL occurred in 118 (9 %) of the 1,312 patients. In univariate analysis, the American Society of Anesthesiologists (ASA) score, history of hypertension, episodes of hypotension, anastomosis technique, tumor localization, anesthesia duration, and perioperative blood transfusion were significant risk factors for AL. Multivariate analysis showed that ASA (P?=?0.001), perioperative blood transfusion (P?<?0.001), anastomosis technique (P?=?0.019), anesthesia duration (P?=?0.033), and tumor localization (P?=?0.009) were independent factors affecting AL. TEA had no effect on the occurrence of AL (P?=?0.451) in multivariate analysis. However, the length of hospital stay was shortened by the use of TEA (P?<?0.001).

Conclusions

The results of this retrospective study suggest that TEA has no effect on the occurrence of AL. However, TEA may be recommended to shorten the length of hospital stay.     

Specialty Use Among Patients With Treated Hypertension in a Patient-Centered Medical Home

BACKGROUND

Little is known about how delivery of primary care in the patient-centered medical home (PCMH) influences outpatient specialty care use.

OBJECTIVE

To describe changes in outpatient specialty use among patients with treated hypertension during and after PCMH practice transformation.

DESIGN

One-group, 48-month interrupted time series across baseline, PCMH implementation and post-implementation periods.

PATIENTS

Adults aged 18–85 years with treated hypertension.

INTERVENTION

System-wide PCMH redesign implemented across 26 clinics in an integrated health care delivery system, beginning in January 2009.

MAIN MEASURES

Resource Utilization Band variables from the Adjusted Clinical Groups case mix software characterized overall morbidity burden (low, medium, high). Negative binomial regression models described adjusted annual differences in total specialty care visits. Poisson regression models described adjusted annual differences in any use (yes/no) of selected medical and surgical specialties.

KEY RESULTS

Compared to baseline, the study population averaged 7 % fewer adjusted specialty visits during implementation (P?<?0.001) and 4 % fewer adjusted specialty visits in the first post-implementation year (P?=?0.02). Patients were 12 % less likely to have any cardiology visits during implementation and 13 % less likely during the first post-implementation year (P?<?0.001). In interaction analysis, patients with low morbidity had at least 27 % fewer specialty visits during each of 3 years following baseline (P?<?0.001); medium morbidity patients had 9 % fewer specialty visits during implementation (P?<?0.001) and 5 % fewer specialty visits during the first post-implementation year (P?=?0.007); high morbidity patients had 3 % (P?=?0.05) and 5 % (P?=?0.009) higher specialty use during the first and second post-implementation years, respectively.

CONCLUSIONS

Results suggest that more comprehensive primary care in this PCMH redesign enabled primary care teams to deliver more hypertension care, and that many needs of low morbidity patients were within the scope of primary care practice. New approaches to care coordination between primary care teams and specialists should prioritize high morbidity, clinically complex patients.     

Associations between single-nucleotide polymorphisms (+45T>G, +276G>T, ?11377C>G, ?11391G>A) of adiponectin gene and type 2 diabetes mellitus: a systematic review and meta-analysis

Aims/hypothesis

The associations between adiponectin polymorphisms and type 2 diabetes have been studied widely; however, results are inconsistent.

Methods

We searched electronic literature databases and reference lists of relevant articles. A fixed or random effects model was used on the basis of heterogeneity. Sub-group and meta-regression analyses were conducted to explore the sources of heterogeneity.

Results

There were no statistically significant associations between +45T>G (rs2241766), +276G>T (rs1501299), ?11391G>A (rs17300539) and type 2 diabetes risk. However, for ?11377C>G (rs266729), the pooled OR (95% CI) for G vs C allele was 1.07 (1.03?C1.11, p?=?0.001). Subgroup analysis by study design revealed that ?11377C>G (rs266729) dominant model (CG+GG vs CC, p?=?0.0008) and G vs C allele (p?=?0.0004) might be associated with type 2 diabetes risk in population-based case?Ccontrol studies. After stratification by ethnicity, we found that ?11377C>G (rs266729) dominant model (CG+GG vs CC, p?=?0.004) and G vs C allele (p?=?0.001) might be associated with type 2 diabetes risk in white individuals. In individuals with a family history of diabetes, the presence of ?11391G>A (rs17300539) dominant model (GA+AA vs GG) and A vs G allele might be associated with increased risk of type 2 diabetes.

Conclusions/interpretation

The presence of +45T>G (rs2241766), +276G>T (rs1501299) and ?11391G>A (rs17300539) do not appear to influence the development of type 2 diabetes. However, G vs C allele of ?11377C>G (rs266729) might be a risk factor for type 2 diabetes.     

Prognostic impact of microRNA-related gene polymorphisms on survival of patients with colorectal cancer

Purpose

The polymorphisms in microRNA (miRNA) machinery genes and miRNA-containing genomic regions may play an important role in cancer development and prognosis. Accordingly, the present study analyzed the single nucleotide polymorphisms (SNPs) of miRNA-related genes and their impact on the prognosis for patients with colorectal cancer.

Methods

Four hundred and twenty-six consecutive patients with surgically treated colorectal adenocarcinoma were enrolled. The genomic DNA was extracted from fresh colorectal tissue and 40 polymorphisms of miRNA-related genes determined using a real-time PCR genotyping assay.

Results

In a univariate analysis, the progression-free survival of the patients with the combined mir492 C/G and G/G genotype was significantly worse than that of the patients with the mir492 C/C genotype (rs2289030) (P value = 0.0426), although there was no difference in the overall survival. However, no association was noted between the SNPs of the miRNA-related genes evaluated and survival in a multivariate analysis.

Conclusions

None of the 40 miRNA-related gene polymorphisms investigated in this study was found to be an independent prognostic marker for Korean patients with surgically resected colorectal cancer. However, further studies are warranted to clarify the role of miRNA-related gene polymorphisms as a prognostic biomarker for colorectal cancer patients.     

Management of Occluded Metal Stents in Malignant Biliary Obstruction: Similar Outcomes with Second Metal Stents Compared to Plastic Stents

Background

Covered or uncovered self expandable metallic stents (SEMS) placed in patients with malignant biliary obstruction can occlude in 19–40?%, but optimal management is unclear.

Aim

We sought to summarize current evidence regarding management of occluded SEMS in patients with malignant biliary obstruction.

Methods

Two investigators independently searched Pubmed, Embase, and Web of Science using pre-defined search criteria, and reviewed bibliographies of included studies. Data were independently abstracted by two investigators, and analyzed using RevMan. We compared strategies of second SEMS versus plastic stents with respect to the following outcomes: rate of second stent re-occlusion, duration of second stent patency, and survival.

Results

Ten retrospective studies met inclusion criteria for the systematic review. Management options described were placement of an uncovered SEMS (n?=?125), covered SEMS (n?=?106), plastic stent (n?=?135), percutaneous biliary drain (n?=?7), mechanical cleaning (n?=?18), or microwave coagulation (n?=?7). Relative risk of re-occlusion was not significantly different in patients with second SEMS compared to plastic stents (RR 1.24, 95?% CI 0.92, 1.67, I²?=?0, p 0.16). Duration of second stent patency was not significantly different between patients who received second SEMS versus plastic stents (weighted mean difference 0.46, 95?% CI ?0.30, 1.23, I²?=?83?%). Survival was not significantly different among patients who received plastic stents versus SEMS (weighted mean difference ?1.13, 95?% CI ?2.33, 0.07, I² 86?%, p = 0.07).

Conclusions

Among patients with malignant biliary obstruction and occluded SEMS, available evidence suggests a strategy of placing a plastic stent may be as effective as second SEMS. Limitations of these findings were that all studies were retrospective and heterogeneity between studies was detected for two of the outcomes.     

RIPK1 and CASP7 polymorphism as prognostic markers for survival in patients with colorectal cancer after complete resection

Background

Since apoptosis plays a key role in cancer progression, the present study analyzed the polymorphisms of apoptosis-related genes and their impact on survival after curative resection in patients with colorectal cancer.

Materials and methods

Three hundred and seventy-seven patients were enrolled in the present study. The genomic DNA was extracted from fresh colorectal mucosal tissue, and 15 SNPs of 12 apoptosis-related genes were determined using a Sequenom MassARRAY system.

Results

During the median follow-up of 41.8 (range, 1.1?C85.5) months patients alive at last follow-up, 65 relapses and 57 deaths occurred. Among the target polymorphisms, the RIPK1 rs2272990 in a dominant model and the CASP7 rs2227310 in a recessive model of the minor allele were associated with survival in a log-rank test. Moreover, the GA+AA genotype of the RIPK1 rs2272990 and the GG genotype of the CASP7 rs2227310 were significantly correlated with a worse disease-free (hazard ratio [HR]?=?2.093; P?=?0.007 and HR?=?2.641; 0.002, respectively) and disease-specific survival (HR?=?2.222; P?=?0.013 and HR?=?2.247; P?=?0.031, respectively) in a multivariate survival analysis.

Conclusion

The RIPK1 and CASP7 polymorphisms can be considered as possible prognostic markers for survival after curative resection in patients with colorectal cancer.     

An Investigation of Associations Between Clinicians’ Ethnic or Racial Bias and Hypertension Treatment,Medication Adherence and Blood Pressure Control

BACKGROUND

Few studies have directly investigated the association of clinicians’ implicit (unconscious) bias with health care disparities in clinical settings.

OBJECTIVE

To determine if clinicians’ implicit ethnic or racial bias is associated with processes and outcomes of treatment for hypertension among black and Latino patients, relative to white patients.

RESEARCH DESIGN AND PARTICIPANTS

Primary care clinicians completed Implicit Association Tests of ethnic and racial bias. Electronic medical records were queried for a stratified, random sample of the clinicians’ black, Latino and white patients to assess treatment intensification, adherence and control of hypertension. Multilevel random coefficient models assessed the associations between clinicians’ implicit biases and ethnic or racial differences in hypertension care and outcomes.

MAIN MEASURES

Standard measures of treatment intensification and medication adherence were calculated from pharmacy refills. Hypertension control was assessed by the percentage of time that patients met blood pressure goals recorded during primary care visits.

KEY RESULTS

One hundred and thirty-eight primary care clinicians and 4,794 patients with hypertension participated. Black patients received equivalent treatment intensification, but had lower medication adherence and worse hypertension control than white patients; Latino patients received equivalent treatment intensification and had similar hypertension control, but lower medication adherence than white patients. Differences in treatment intensification, medication adherence and hypertension control were unrelated to clinician implicit bias for black patients (P?=?0.85, P?=?0.06 and P?=?0.31, respectively) and for Latino patients (P?=?0.55, P?=?0.40 and P?=?0.79, respectively). An increase in clinician bias from average to strong was associated with a relative change of less than 5 % in all outcomes for black and Latino patients.

CONCLUSIONS

Implicit bias did not affect clinicians’ provision of care to their minority patients, nor did it affect the patients’ outcomes. The identification of health care contexts in which bias does not impact outcomes can assist both patients and clinicians in their efforts to build trust and partnership.     

Analysis of EGF+61A>G polymorphism and EGF serum levels in Brazilian glioma patients treated with perillyl alcohol-based therapy

Purpose

Malignant gliomas are associated with alteration in EGF/EGFR signaling. Functional EGF+61A>G polymorphism is implicated with risk, recurrence, and progression of glioma. This study aimed to establish a putative association of EGF+61A>G with risk of glioma development, production of angiogenic growth factor EGF, and the response to perillyl alcohol administered by intranasal route.

Methods

The study included 83 patients with recurrent glioma enrolled in Phase I/II trial for intranasal perillyl alcohol therapy and subjects without cancer (n?=?196) as control group. DNA was extracted from blood samples, EGF genotype performed with PCR–RFLP assay, and EGF circulating levels by enzyme immunoassay. Adequate statistical tests were performed to verify associations between polymorphism and glioma risk, and genotype correlation with EGF circulating levels. The log-rank test was also used to evaluate differences on patient survival.

Results

Patients with primary glioblastoma had high frequency of AA genotype (p?=?0.037) and A allele (p?=?0.037). Increased EGF circulating levels were observed in glioma patients with AA (p?=?0.042), AG (p?=?0.006), and AA?+?AG (p?=?0.008) genotypes compared with GG. Patients with GG genotype showed increased but not significant (p?>?0.05) survival rate, and EGF levels lower than 250?pg/mL was consistently (p?=?0.0374) associated with increased survival.

Conclusion

Presence of EGF+61A>G polymorphism in Brazilian subjects was associated with glioma risk and increased circulating EGF levels. Better response to perillyl alcohol-based therapy was observed in a group of adult Brazilian subjects with lower EGF levels.     

XRCC1 Arg399Gln, Arg194Trp, and Arg280His Polymorphisms in Esophageal Cancer Risk: A Meta-Analysis

Background

The X-ray repair cross-complementation group 1 (XRCC1) protein plays an important role in base excision repair.

Aim

To elucidate the role of XRCC1 Arg399Gln, Arg194Trp and Arg280His genotypes in esophageal cancer risk, all available studies were considered in the present meta-analysis.

Methods

Eligible studies were identified by searching several electronic databases for relevant reports published before June 2012.

Results

According to the inclusion criteria and exclusion criteria, a total of 21 eligible studies were included in the pooled analyses. Among the 21 studies, 18 focused on Arg399Gln polymorphism, 11 described the Arg194Trp, and 4 articles investigated on Arg280His. Our analysis suggested that there was no evidence of significant association between XRCC1 Arg399Gln polymorphism and esophageal cancer risk in any genetic model. In the stratified analysis by ethnicity for Arg399Gln polymorphism and esophageal cancer, the results showed that Arg399Gln polymorphism was not associated with esophageal cancer risk. Only 4 studies analyzed the relationship between XRCC1 Arg280His polymorphism and the risk of esophageal cancer. The Arg/His and His/His genotypes were not significantly associated with increased risk of EC. A similar negative association was maintained in dominant and recessive models. However, for XRCC1 Arg194Trp polymorphism, our study showed individuals carrying the variant genotype Trp/Trp had a significant increased risk of esophageal cancer (OR = 1.295, 95 % CI 1.053–1.591, P = 0.014). In addition, increased associations were found in recessive model (OR = 1.332, 95 % CI 1.093–1.624, P = 0.005).

Conclusions

Our meta-analysis suggested that Arg194Trp Trp allele might act as a risk allele in its association with esophageal cancer.     

GSTT1 and GSTM1 Gene Polymorphisms as Major Risk Factors for Asthma in a North Indian Population

Background

According to the National Family Health Survey, asthma is one of the leading diseases in India. In order to understand the complexity of asthma, the susceptibility genes need to be targeted for their association. Glutathione S-transferases play a major role in the detoxification of metabolites of oxidative stress resulting in inflammation and asthma. In the present study, the hypothesis that GSTT1 and GSTM1 gene polymorphisms are associated with asthma was examined.

Methods

This is the first study to investigate the role of GSTT1 and GSTM1 gene polymorphisms in asthma pathogenesis in a North Indian population. A total of 824 subjects were recruited, of which 410 were asthma patients, including 323 patients suffering from allergic rhinitis. The other 414 recruits were healthy controls from regions of North India. Multiplex PCR was used for genotyping the GSTT1 and GSTM1 gene polymorphisms.

Results

The GSTT1 null allele was more prevalent in asthma patients (40?%) than in the control subjects (13.3?%), which yielded a nearly fourfold risk towards asthma with odds ratio (OR) (95?% CI)?=?4.35 (3.04–6.24), χ²?=?75.34, and p?=?0.000. The GSTM1 polymorphism also revealed a greater prevalence of the GSTM1 null allele in asthma patients (46.6?%) than in controls (39.4?%). Statistical analysis yielded a marginal risk toward asthma with OR (95?% CI)?=?1.34 (1.01–1.79), χ²?=?4.37, and p?=?0.036.

Conclusions

Polymorphisms as a result of deletions in the GSTT1 and GSTM1 genes confer an increased risk towards asthma thereby suggesting the protective role of these functional genes in the development of the disease.     

TNFRSF11B gene polymorphisms increased risk of peripheral arterial occlusive disease and critical limb ischemia in patients with type 2 diabetes

Aims

Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family and plays a role in atherosclerosis. OPG has been hypothesized to modulate vascular functions; however, its role in mediating atherosclerosis is controversial. Epidemiological data in patients with cardiovascular disease (CVD) indicate that OPG serum levels are associated with several inflammatory markers, myocardial infarction events, and calcium scores, suggesting that OPG may be causative for CVD.

Methods

The present study aimed to evaluate whether the OPG gene (TNFRSF11B) polymorphisms are involved in the development of peripheral arterial occlusive disease (PAOD) and critical limb ischemia (CLI) in patients with type 2 diabetes. This genetic association study included 402 diabetic patients (139 males and 263 females) with peripheral arterial occlusive disease and 567 diabetic subjects without peripheral arterial occlusive disease (208 males and 359 females). The T245G, T950C, and G1181C polymorphisms of the OPG gene were analyzed by polymerase chain reaction and restriction fragment length polymorphism.

Results

We found that the T245G, T950C, and G1181C gene polymorphisms of the OPG gene were significantly (27.9 vs. 12.2 %, P < 0.01; 33.6 vs. 10.4 %, P < 0.01 and 24.4 vs. 12.7 %, P < 0.01, respectively) and independently (adjusted OR 4.97 (3.12–6.91), OR 7.02 (4.96–11.67), and OR 2.85 (1.95–4.02), respectively) associated with PAOD. We also found that these three polymorphisms act synergistically in patients with PAOD and are associated with different levels of risk for PAOD and CLI, depending on the number of high-risk genotypes carried concomitantly by a given individual.

Conclusion

The TNFRSF11B gene polymorphisms under study are associated with PAOD, and synergistic effects between these genotypes might be potential markers for the presence and severity of atherosclerotic disorders.     

Bleeding of New Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Meta-Analysis of Randomized Controlled Trials

Purpose

Oral direct factor Xa inhibitors and oral direct thrombin inhibitors are new oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation (AF). We systematically reviewed their risk of major bleeding and efficacy in thromboembolism reduction in AF.

Methods

Eligible randomized controlled trials evaluating NOACs for stroke prevention in AF patients were identified from a systematic search of MEDLINE, EMBASE and the Cochrane database. Risk ratios (RRs) and 95 % confidence intervals (CIs) were calculated using a Mantel-Haenzel random-effects model.

Results

A total of 13 studies (n?=?61,406) were included. Oral direct factor Xa inhibitors were more effective in reducing stroke and systemic embolism compared to controls (RR 0.71, 95 % CI 0.54–0.92, P?=?0.009) or vitamin K antagonists (VKAs) (RR 0.84, 95 % CI 0.74–0.94, P?=?0.002), with no significant difference in major and clinically relevant non-major (CRNM) bleeding (against controls: RR 0.94, 95 % CI 0.75–1.18, P?=?0.60; against VKAs: RR 0.90, 95 % 0.69–1.17, P?=?0.44). Oral direct thrombin inhibitors were associated with an improved major and CRNM bleeding profile (both comparisons: RR 0.88, 95 % CI 0.78–0.98, P?=?0.02) and a significant reduction in stroke and systemic embolism (against controls: RR 0.79, 95 % CI 0.66–0.93, P?=?0.006; against VKAs: RR 0.78, 95 % CI 0.66–0.93, P?=?0.006).

Conclusions

Oral direct factor Xa inhibitors and oral direct thrombin inhibitors are more effective in reducing stroke and systemic embolism without increasing the risk of major bleeding compared to traditional oral anticoagulants. This favorable risk-benefit balance should be further confirmed by long-term, large-scale safety studies.