Promoter polymorphisms of pri-miR-34b/c are associated with hepatocellular carcinoma

Background

Numerous studies have focused on the association between miR-34 family members, which are direct p53 targets, and carcinogenesis of many cancers, including hepatocellular carcinoma (HCC). This study aimed to assess whether polymorphisms in the single-nucleotide polymorphism miR-34b/c T>C (rs4938723) and TP53 Arg72Pro (rs1042522) increase the risk of HCC and influence outcome in patients with HCC.

Patients and methods

We enrolled 157 HCC patients and 201 cancer-free control subjects from the Korean population. MicroRNA polymorphisms were genotyped using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method.

Results

We found that the miR-34b/c TC + CC frequency was significantly higher in HCC patients than in controls (adjusted odds ratio [AOR]: 1.580; 95% confidence interval [CI]: 1.029–2.426). The miR-34b/c CC-TP53 Arg/Arg combination significantly increased the risk of HCC (AOR: 13.644; 95% CI: 1.451–128.301). The SNPs miR-34b/c T>C and TP53 Arg72Pro(G>C) had no influence on survival of HCC patients.

Conclusions

Our findings suggest that loss of the T allele in miR-34b/c T>C, and the miR-34b/c CC-TP53 Arg/Arg combination increases the risk of HCC in the Korean population.     

Association study of microRNA polymorphisms with hepatocellular carcinoma in Korean population

Background

Recent studies have suggested that common genetic polymorphisms alter the processing of microRNA (miRNA) and may be associated with the development and progression of cancer.

Patients and methods

The association of miRNA polymorphisms with HCC survival was analyzed in 159 HCC patients and 201 controls by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

Results

The risk of HCC was significantly lower for the miR-499A>G, AG + GG in HCC patients (AOR = 0.603, 95% CI = 0.370–0.984) and hepatitis B virus (HBV)-related HCC patients (AOR = 0.561, 95% CI 0.331–0.950). In addition, the risk of HCC was significantly lower for the miR-149C>T, CT and CT + CC in HCC patients (CT; AOR = 0.542, 95% CI = 0.332–0.886, CT + CC; AOR = 0.536, 95% CI = 0.335–0.858) and HBV-related HCC patients (CT: AOR = 0.510, 95% CI 0.305–0.854, CT + CC: AOR = 0.496, 95% CI 0.302–0.813). The miR-149C>T polymorphism was also associated with survival rate of HCC patients in OKUDA II stage.

Conclusions

miR-149C>T and miR-499A>G were associated with HBV-related HCC. Further studies on larger populations will need to be conducted to confirm these results.     

Association of microRNA-499 rs3746444 Polymorphism with Cancer Risk: Evidence from 7188 Cases and 8548 Controls

Background

Owing to inconsistent and inconclusive results, we performed a meta-analysis to derive a more precise estimation of the association between miR-499 rs3746444 polymorphism and cancer risk.

Methodology/Principal Findings

A systematic search of the Pubmed, Excerpta Medica Database (Embase) and Chinese Biomedical Literature Database (CBM) databases was performed with the last search updated on May 6, 2012. The odds ratio (OR) and its 95% confidence interval (95%CI) were used to assess the strength of the association. A total of 15 independent studies including 7,188 cases and 8,548 controls were used in the meta-analysis. In the present meta-analysis, we found a significant association between miR-499 rs3746444 polymorphism and cancer risk in the overall analysis (G versus A: OR = 1.10, 95%CI 1.01–1.19, P = 0.03; GG+AG versus AA: OR = 1.15, 95%CI 1.02–1.30, P = 0.02; GG versus AG+AA: OR = 1.07, 95%CI 0.89–1.28, P = 0.50; GG versus AA: OR = 1.13, 95%CI 0.98–1.31, P = 0.09; AG versus AA: OR = 1.16, 95%CI 1.02–1.33, P = 0.03). In the subgroup analysis by ethnicity, miR-499 rs3746444 polymorphism was significantly associated with cancer risk in Asian population. In the subgroup analysis by cancer types, miR-499 rs3746444 polymorphism was significantly associated with breast cancer.

Conclusions/Significance

This meta-analysis suggests a significant association between miR-499 rs3746444 polymorphism and cancer risk. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.     

A common polymorphism in pre-microRNA-146a is associated with lung cancer risk in a Korean population

Introduction

MicroRNAs (miRs) play important roles in the development and progression of human cancers. MiR-146a down-regulates epidermal growth factor receptor and the nuclear factor-κB regulatory kinase interleukin-1 receptor-associated kinase 1 genes that play important roles in lung carcinogenesis. This study was conducted to evaluate the association between rs2910164C>G, a functional polymorphism in the pre-miR-146a, and lung cancer risk.

Material and methods

The rs2910164C>G genotypes were determined in 1094 patients with lung cancer and 1100 healthy controls who were frequency matched for age and gender.

Results

The rs2910164 CG or GG genotype was associated with a significantly decreased risk for lung cancer compared to that of the CC genotype (adjusted odds ratio = 0.80, 95% confidence interval = 0.66–0.96, P = 0.02). When subjects were stratified according to smoking exposure (never, light and heavy smokers), the effect of the rs2910164C>G genotype on lung cancer risk was significant only in never smokers (adjusted odds ratio = 0.66, 95% confidence interval = 0.45–0.96, P = 0.03, under a dominant model for the C allele) and decreased as smoking exposure level increased (P_trend < 0.001). In line with this result, the level of miR-146a expression in the tumor tissues was significantly higher in the GG genotype than in the CC or CG genotype only in never-smokers (P = 0.02).

Conclusions

These findings suggest that the rs2910164C>G in pre-miR-146a may contribute to genetic susceptibility to lung cancer, and that miR-146a might be involved in lung cancer development.     

The Association between Two MicroRNA Variants (miR-499, miR-149) and Gastrointestinal Cancer Risk: A Meta-Analysis

Background

MicroRNAs (miRNAs) are small RNA molecules that regulate the expression of corresponding messenger RNAs (mRNAs). Single nucleotide polymorphisms (SNPs) in miRNAs may contribute to cancer susceptibility due to changes in the microRNA’s properties and/or maturation. The present study aimed to investigate the association between two miRNA polymorphisms (miR-499 rs3746444 and miR-149 rs2292832) and gastrointestinal (GI) cancer risk.

Methodology/Principal Findings

We conducted a search of case-control studies in PubMed, Wiley Online Library, Web of Science and the CNKI database. Eleven rs3746444 studies and six rs2292832 studies were included in our meta-analysis. The only obvious association between the miR-499 polymorphism and colorectal cancer susceptibility was found in the homozygote comparison (GG vs. AA: OR = 1.66, 95% CI: 1.02–2.70, P _h = 0.10, P = 0.04). No significant association was found in the subgroup analysis for ethnicity and risk of hepatocellular and gastric cancer. A marginally elevated GI cancer risk was discovered in the recessive model for miR-149 (TT vs. TC+CC: OR = 1.15, 95% CI: 1.03–1.30, P _h = 0.68, P = 0.02). Stratifying the results by ethnicity revealed a slight association between the recessive model and the Asian population (TT vs. TC+CC: OR = 1.14, 95% CI: 1.01–1.29, P _h = 0.79, P = 0.03).

Conclusions/Significance

The present meta-analysis indicates that miR-499 may be associated with the risk to colorectal cancer. MiR-149 may confer a marginally increased risk of susceptibility to gastrointestinal cancer, especially for Asians.     

Prenatal diagnosis of partial trisomy 3q resulting from t(3;14) in a fetus with multiple anomalies including vermian hypoplasia

Context

Myostatin (MSTN) is a member of the TGF-β superfamily of signal transduction proteins, which plays an important role in muscular growth and lipid metabolism.

Objective

To study the association of myostatin gene polymorphisms with obesity in Chinese north Han human subjects.

Design

297 healthy and 606 over-weight/obesity Chinese north Han subjects were selected as healthy control group and overweight/obesity group, respectively. The methods of DNA Sequencing, Restriction Fragment Length Polymorphism (RFLP) and TaqMan® probe were used to screen myostatin gene SNPs and clarify genotype in every individual.

Results

Total 11 SNPs in MSTN gene were identified by DNA sequencing and three SNPs including rs35781413 (G/A), rs3791783 (A/G) and rs3791782 (A/G) were selected for further study in total 903 samples. The results showed that the frequency of AA genotype of rs3791783 A/G SNP was significantly higher (56.4% vs. 50.8%) and the frequency GG genotype was significantly lower (3.2% vs. 6.7%) in overweight/obese patients than in normal weight subjects. A logistic regression analysis under a recessive inheritance model (AA + AG vs.GG) demonstrated that the Odd ratio for AA + AG vs.GG were 1.985 (95% CI 1.078-3.643; P = 0.029). Among three genotypes of rs3791783, the subjects with AA genotype have much more higher body weight, BMI, waist circumference, TC, TG and LDL-C than those with GG genotype.

Conclusions

Our data firstly suggest that genetic variant rs3791783 A/G in myostatin gene are associated with obesity. The A allele carriers in rs3791783 SNP have an increased susceptibility to obesity compared with the G allele carriers. Participants with AA genotype in rs3791783 SNP site will have higher risk suffered from overweight or obesity than those with GG genotype.     

Hsa-miR-499 polymorphism (rs3746444) and cancer risk: A meta-analysis of 17 case–control studies

Introduction

MicroRNAs (miRNAs) are a family of endogenous, small and noncoding RNAs that negatively regulate gene expression by suppressing translation or degrading mRNAs. Recently, many studies investigated the association between hsa-miR-499 rs3746444 polymorphism and cancer risk, which showed inconclusive results.

Methodology/main results

We conducted a meta-analysis of 17 studies that included 7842 cancer cases and 8989 case-free controls and assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, hsa-miR-499 rs3746444 polymorphism was associated with higher cancer risk in heterozygote model (AG vs AA, OR = 1.15, 95%CI = 1.01–1.30, P_{heterogeneity} < 0.001), dominant genetic model (GG/AG vs AA, OR = 1.18, 95% CI = 1.04–1.33, P_{heterogeneity} < 0.001) and allele contrast (G vs A, OR = 1.09, 95% CI = 1.01–1.18, P_{heterogeneity} = 0.021). In the stratified analyses, we observed that the GG/AG genotype might modulate breast cancer risk (OR = 1.13, 95% CI = 1.01–1.26, P_{heterogeneity} = 0.111) comparing with the AA genotype. Moreover, a significantly increased risk was found among Asian populations in heterozygote model (AG vs AA, OR = 1.23, 95% CI = 1.06–1.43, P_{heterogeneity} < 0.001), homozygote model (GG vs AA, OR = 1.22, 95% CI = 1.02–1.46, P_{heterogeneity} = 0.319), dominant model (GG/AG vs AA, OR = 1.25, 95% CI = 1.06–1.39, P_{heterogeneity} < 0.001) and allele contrast (G vs A, OR = 1.14, 95% CI = 1.04–1.25, P_{heterogeneity} = 0.021).

Conclusions

These findings supported that hsa-miR-499 rs3746444 polymorphism contributes to the susceptibility of cancers.     

rs4215 SNP in zinc-α2-glycoprotein gene is associated with obesity in Chinese north Han population

Objective

Zinc-α2-glycoprotein (ZAG) has been identified recently as a novel adipokine due to its close link with lipid and glucose metabolism, as well as regulation of body weight. The aim of our present study is to investigate the ZAG genetic polymorphism association with obesity in Chinese north Han population.

Design and methods

Five SNPs of ZAG gene including rs2247607 (A>T), rs4727442 (G>T), rs4215 (A>G), rs2527923 (C>T) and rs2527882 (C>T) were genotyped in 648 overweight/obese patients and 313 healthy controls by TaqMan-PCR methods. Crosstabs statistical analysis method with subjects stratifying by age (≦ 30 y, 31–45 y, ≧ 46 y) and gender was used.

Results

The results showed the constitution of three genotype frequencies in rs4215 (A>G) site significantly differs in male subgroup (aged 31–45 y) between overweight/obese and healthy control group (χ² = 6.401, P = 0.041). GG genotype frequency in overweight/obese group is 19.3% which is much higher than 6.1% in healthy control group. Further statistical analysis under a recessive inheritance model demonstrated odd ratio (OR) for GG vs. AA+AG in overweight/obese group was 3.674 (95% CI 1.049–12.866; P = 0.035). Among three genotypes of rs4215, the subjects with GG genotype have much more higher body weight, BMI, waist circumference and SBP.

Conclusion

Our data, for the first time, suggest the genotypes of rs4215 in ZAG gene are significantly associated with obesity in Chinese north Han population. GG genotype subjects in rs4215 site have an increased susceptibility to obesity when compared with the AA+AG genotype subjects.     

Gene Polymorphisms of Micrornas in Helicobacter pylori-Induced High Risk Atrophic Gastritis and Gastric Cancer

Background and aims

MicroRNAs (miRNAs) are known for their function as translational regulators of tumor suppressor or oncogenes. Single nucleotide polymorphisms (SNPs) in miRNAs related genes have been shown to affect the regulatory capacity of miRNAs and were linked with gastric cancer (GC) and premalignant gastric conditions. The purpose of this study was to evaluate potential associations between miRNA-related gene polymorphisms (miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608) and the presence of GC or high risk atrophic gastritis (HRAG) in European population.

Methods

Gene polymorphisms were analyzed in 995 subjects (controls: n = 351; GC: n = 363; HRAG: n = 281) of European descent. MiR-27a T>C (rs895819), miR-146a G>C (rs2910164), miR-196a-2 C>T (rs11614913), miR-492 G>C (rs2289030) and miR-608 C>G (rs4919510) SNPs were genotyped by RT-PCR.

Results

Overall, SNPs of miRNAs were not associated with the presence of GC or HRAG. We observed a tendency for miR-196a-2 CT genotype to be associated with higher risk of GC when compared to CC genotype, however, the difference did not reach the adjusted P-value (odds ratio (OR) - 1.46, 95% confidence interval (CI) 1.03-2.07, P = 0.032). MiR-608 GG genotype was more frequent in GC when compared to controls (OR −2.34, 95% CI 1.08–5.04), but significance remained marginal (P = 0.029). A similar tendency was observed in a recessive model for miR-608, where CC + CG vs GG genotype comparison showed a tendency for increased risk of GC with OR of 2.44 (95% CI 1.14–5.22, P = 0.021). The genotypes and alleles of miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608 SNPs had similar distribution between histological subtypes of GC and were not linked with the presence of diffuse or intestinal-type GC.

Conclusions

Gene polymorphisms of miR-27a, miR-146a, miR-196a-2, miR-492, miR-492a and miR-608 were not associated with the presence of HRAG, GC or different histological subtypes of GC in European subjects.     

Genetic Variants in MicroRNA Machinery Genes Are Associate with Idiopathic Recurrent Pregnancy Loss Risk

Objective

Key molecules involved in microRNA (miRNA) biogenesis, such as DROSHA, XPO5, and DICER, have been identified in trophoblast cells, confirming that the miRNA biogenesis pathway is active in human placenta. In addition, miRNAs regulate uterine gene expression associated with inflammatory responses during the peri-implantation period and participate in maternal-fetal immune tolerance. The purpose of this study was to demonstrate whether genetic polymorphisms in miRNA machinery genes show an association with idiopathic recurrent pregnancy loss (RPL) in Korean women.

Study design

We performed a case-control study with 238 controls and 338 women who had experienced at least two consecutive pregnancy losses between 1999 and 2010. Genotypes of miRNA machinery genes, including DICER rs3742330, DROSHA rs10719, RAN GTPase (RAN) rs14035, and exportin-5 (XPO5) rs11077 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The logistic odds ratios (ORs) of RPL were estimated with a 95% confidence interval (CI) in multivariate analysis after maternal age adjustment. Gene-gene interactions among the loci of the four gene polymorphisms were evaluated using the multifactor dimensionality reduction (MDR) method.

Results

The RAN rs14035 CC genotype and DICER rs3742330/DROSHA rs10719 GG/TC+CC, rs3742330/RAN rs14035 GG/CC, and DICER rs3742330/XPO5 rs11077 GG/AC+CC combinations were significantly associated with increased RPL risk, whereas the RAN rs14035 CT, DICER rs3742330/RAN rs14035 AA+AG/CT+TT, DROSHA rs10719/RAN rs14035 TC+CC/CT+TT, and RAN rs14035/XPO5 rs11077 CT+TT/AA combinations reduced RPL risk. The A-T-T-C and G-C-T-A allele combinations (DICER/DROSHA/RAN/XPO5) were 20 times more frequent in the RPL group than in the control group.

Conclusion

Our study demonstrates the relationship between RPL development and the polymorphism of the miRNA machinery gene RAN and combined genotype of DROSHA/DICER.     

Polymorphisms of folate metabolism-related genes and survival of patients with colorectal cancer in the Korean population

Background

5-Fluorouracil (5-FU) is a cornerstone of chemotherapy for colorectal cancer (CRC), and the major targets of 5-FU are thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and reduced folate carrier 1 (RFC1). We hypothesized that polymorphisms in the genes encoding these proteins would be associated with CRC patient survival.

Patients and methods

We genotyped the following polymorphisms in 372 CRC patients: TS enhancer region (TSER), TS 1494del6, MTHFR 677C > T and 1298A > C, and RFC1 − 43T > C, 80G > A, and 696C > T. Using Kaplan–Meier curves, log-rank tests, and Cox proportional hazard models, we evaluated associations between these polymorphisms and overall survival (OS).

Results

The combined TS 1494 0bp6bp + 6bp6bp genotype was associated with reduced OS compared to the TS 1494 0bp0bp genotype. Among rectal cancer patients, the RFC1 − 43CC and 80AA genotypes were associated with favorable OS.

Conclusions

Our data suggest that TS and RFC1 polymorphisms are associated with CRC prognosis in Korean patients. Further studies are needed to verify these findings.     

Association of eNOS polymorphisms (-786T>C, 4a4b, 894G>T) with colorectal cancer susceptibility in the Korean population

Background

Polymorphisms of endothelial nitric oxide synthases (eNOS) have been shown to be associated with cancer susceptibility. However, the results of such studies are conflicting to date. We investigated whether polymorphisms of the eNOS gene correlated with patients with colorectal cancer (CRC), relative to healthy individuals.

Patients and methods

In the present study, we analyzed three polymorphisms of eNOS (-786T>C, 4a4b, and 894G>T) in 509 healthy controls and 528 patients with CRC. The genotyping of eNOS polymorphisms was performed using polymerase chain reaction or polymerase chain reaction–restriction fragment length polymorphism assays.

Results

We found that the TC+CC genotype of the -786T>C polymorphism was significantly associated with an increased risk of CRC compared with the TT genotype. Similarly, the GT+TT genotype of the 894G>T polymorphism was associated with an increased susceptibility to CRC. However, no evidence was found for any association between the 4a4b polymorphism and CRC risk. In addition, the C/4b/G (-786T>C/4a4b/894G>T) haplotype was significantly associated with increased risk of CRC and C/4b/T (-786T>C/4a4b/894G>T) haplotype was only detected in CRC patients.

Conclusions

Our study suggests that the eNOS -786T>C and 894G>T polymorphisms may be associated with the development of CRC in the Korean population.     

Cyclooxygenase-2 169C > G and 8473T > C gene polymorphisms and prostaglandin E2 level in breast cancer: A case–control study

Aims

Cyclooxygenase 2 (COX-2) with the resulting prostaglandin E2 (PGE2) is linked to increased risk of human breast cancer (BC). The aim of this study was to determine COX-2 169C > G and 8473T > C gene polymorphisms and PGE2 level at various stages of BC clarifying the role of COX-2 gene polymorphism and PGE2 in relation to BC.

Methods

The study population comprised 160 women at different stages of BC and 150 gender- and age-matched healthy control subjects. Plasma PGE2 was measured by ELISA, the COX-2 gene polymorphisms were determined using PCR-RFLP.

Results

The variant alleles COX-2 169G and 8473C were significantly associated with BC susceptibility [OR = 3.1, 95% CI (2.2–4.4), P < 0.001 for 169C>G and OR = 1.74, 95%CI (1.3–2.4), P = 0.005 for 8473C]. However, both COX-2 gene polymorphisms were not associated with breast cancer stage. Plasma PGE2 levels were significantly increased in patients compared to the controls. In early and late stages of BC, there was a significant increase in the plasma PGE2 levels towards the presence of homozygous GG compared with homozygous CC (P < 0.001) for 169 C>G, also towards the presence of CC than TT (P < 0.001) for 8473T>C SNP.

Conclusion

The 169C>G and 8473T>C polymorphisms of the COX-2 gene were associated with the BC in Egyptian women. Furthermore, individuals with COX-2 169GG and 8473CC genotypes showed significant increase in plasma PGE2 levels. PGE2 levels may serve as a predictor of poor prognosis in patients with BC.     

Identification of microRNAs associated with allergic airway disease using a genetically diverse mouse population

Background

Allergic airway diseases (AADs) such as asthma are characterized in part by granulocytic airway inflammation. The gene regulatory networks that govern granulocyte recruitment are poorly understood, but evidence is accruing that microRNAs (miRNAs) play an important role. To identify miRNAs that may underlie AADs, we used two complementary approaches that leveraged the genotypic and phenotypic diversity of the Collaborative Cross (CC) mouse population. In the first approach, we sought to identify miRNA expression quantitative trait loci (eQTL) that overlap QTL for AAD-related phenotypes. Specifically, CC founder strains and incipient lines of the CC were sensitized and challenged with house dust mite allergen followed by measurement of granulocyte recruitment to the lung. Total lung RNA was isolated and miRNA was measured using arrays for CC founders and qRT-PCR for incipient CC lines.

Results

Among CC founders, 92 miRNAs were differentially expressed. We measured the expression of 40 of the most highly expressed of these 92 miRNAs in the incipient lines of the CC and identified 18 eQTL corresponding to 14 different miRNAs. Surprisingly, half of these eQTL were distal to the corresponding miRNAs, and even on different chromosomes. One of the largest-effect local miRNA eQTL was for miR-342-3p, for which we identified putative causal variants by bioinformatic analysis of the effects of single nucleotide polymorphisms on RNA structure. None of the miRNA eQTL co-localized with QTL for eosinophil or neutrophil recruitment. In the second approach, we constructed putative miRNA/mRNA regulatory networks and identified three miRNAs (miR-497, miR-351 and miR-31) as candidate master regulators of genes associated with neutrophil recruitment. Analysis of a dataset from human keratinocytes transfected with a miR-31 inhibitor revealed two target genes in common with miR-31 targets correlated with neutrophils, namely Oxsr1 and Nsf.

Conclusions

miRNA expression in the allergically inflamed murine lung is regulated by genetic loci that are smaller in effect size compared to mRNA eQTL and often act in trans. Thus our results indicate that the genetic architecture of miRNA expression is different from mRNA expression. We identified three miRNAs, miR-497, miR-351 and miR-31, that are candidate master regulators of genes associated with neutrophil recruitment. Because miR-31 is expressed in airway epithelia and is predicted to target genes with known links to neutrophilic inflammation, we suggest that miR-31 is a potentially novel regulator of airway inflammation.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1732-9) contains supplementary material, which is available to authorized users.     

Genetic polymorphism c.1562C>T of the MMP-9 is associated with macroangiopathy in type 2 diabetes mellitus

Objective

To determine whether the matrix metalloproteinase-9 (MMP-9) c.1562C>T polymorphism has an effect on the plasma MMP-9 levels and the macroangiopathic complications in type 2 diabetes mellitus (T2DM).

Methods

The genotypes and allelic frequencies of the MMP-9 c.1562C>T were examined with polymerase chain reaction and restriction fragment length polymorphism in 320 patients with T2DM and 160 unrelated healthy subjects. The plasma concentrations of MMP-9 were determined in all subjects.

Results

The mean plasma concentrations of MMP-9 of patients with T2DM were significantly higher than that of controls and the plasma levels of MMP-9 were higher in diabetic patients with macroangiopathy than in patients without macroangiopathy (P < 0.05). The genotype (CC, CT, and TT) distribution of c.1562C>T polymorphism of the MMP-9 gene was 60.0%, 31.3%, and 8.8% in diabetic patients with macroangiopathy, 76.3%, 21.3%, and 2.5% in patients without macroangiopathy, and 77.5%, 21.3%, 1.3% in controls, respectively, a significant difference was found between diabetic patients with and without macroangiopathy (P < 0.05). The frequency of the allele T was higher in patients with macroangiopathy than in patients without macroangiopathy (24.4% vs 13.1%; P < 0.05). Moreover, the plasma MMP-9 levels were markedly higher in patients with TT genotype than those with CC or CT genotype in patients with macroangiopathy (P < 0.05).

Conclusion

The MMP-9 c.1562C>T gene polymorphism associated with a predisposition to increased plasma MMP-9 levels could constitute a useful predictive marker for diabetic macroangiopathy.     

A genetic variant in the promoter region of miR-106b-25 cluster and risk of HBV infection and hepatocellular carcinoma

Background

MiR-106b-25 cluster, hosted in intron 13 of MCM7, may play integral roles in diverse processes including immune response and tumorigenesis. A single nucleotide polymorphism (SNP), rs999885, is located in the promoter region of MCM7.

Methods

We performed a case-control study including 1300 HBV-positive hepatocellular carcinoma (HCC) cases, 1344 HBV persistent carriers and 1344 subjects with HBV natural clearance to test the association between rs999885 and the risk of HBV persistent infection and HCC. We also investigated the genotype-expression correlation between rs999885 and miR-106b-25 cluster in 25 pairs of HCC and adjacent non-tumor liver tissues.

Results

Compared with the HBV natural clearance subjects carrying rs999885 AA genotype, those with AG/GG genotypes had a decreased risk of chronic HBV infection with an adjusted odds ratio (OR) of 0.79 [95% confidence intervals (CIs) = 0.67–0.93]. However, the AG/GG genotypes were significantly associated with an increased HCC risk in HBV persistent carriers (adjusted OR = 1.25, 95% CIs = 1.06–1.47). Expression analysis revealed that the expression level of miR-106b-25 cluster was significantly higher in AG/GG carriers than those in AA carriers in non-tumor liver tissues.

Conclusions

These findings indicate that the A to G base change of rs999885 may provide a protective effect against chronic HBV infection but an increased risk for HCC in HBV persistent carriers by altering the expression of the miR-106b-25 cluster.     

Meta-Analysis of MicroRNA-146a rs2910164 G>C Polymorphism Association with Autoimmune Diseases Susceptibility,an Update Based on 24 Studies

Background

Published data showed that the susceptibility of autoimmune diseases (ADs) was associated with the polymorphism rs2910164 in microRNA-146a (miR-146a). However, the results remain controversial so far. Two meta-analyses published in 2013 and 2014 came to opposite conclusions. In order to derive a more precise estimation of the relationship, we performed this meta-analysis.

Methods

We searched the PubMed, OvidSP and CNKI databases (published prior to September 8th, 2014) and extracted data from eligible studies. The procedure of meta-analysis was performed by using the Stata 12.0 software. Random effect model or fixed effect model were chosen respectively, according to the between study heterogeneities.

Results

A total of 24 case-control studies, 11 more than previous meta-analysis on this topic, were involved. We took stratified analyses by different ethnicities and different types of diseases in different genetic models. In Caucasian subgroup, significant increased risks of GC genotype and GC+CC genotype with ADs susceptibility were found in heterozygote model (GC vs GG, OR = 1.38, 95% CI 1.04–1.83, p = 0.024) and dominant model (GC+CC vs GG, OR = 1.37, 95% CI 1.01–1.85, p = 0.041), respectively. Meanwhile, in other disease subgroup, significant increased risks of C allele, CC genotype and GC+CC genotype were found in allele model (C vs G, OR = 1.16, 95% CI 1.04–1.31, p = 0.010), homozygote model (CC vs GG, OR = 1.42, 95% CI 1.10–1.84, p = 0.006) and dominant model (GC+CC vs GG, OR = 1.25, 95% CI 1.04–1.51, p = 0.020), respectively.

Conclusions

MiR-146a rs2910164 G>C polymorphism was associated with the susceptibility of ADs.     

Relation between 3435C>T multidrug resistance 1 gene polymorphism with high dose methylprednisolone treatment of childhood acute idiopathic thrombocytopenic purpura

The current study was conducted to assess 3435C>T multidrug resistance 1 gene polymorphism and the efficacy of high dose methylprednisolone (HDMP) in childhood acute idiopathic thrombocytopenic purpura patients.

Methods

A total of 31 childhood acute Idiopathic thrombocytopenic purpura patients (17 females, 14 males) between the ages of 2 and 16 years of age were included in the study. High-dose methylprednisolone was given at a dose of 30 mg/kg/day for 3 days and 20 mg/kg/day for 4 days, consecutively and intravenously. Polymerase chain reaction-restriction fragment length polymorphism was used for the detection of C3435T single nucleotide polymorphism. Fragments obtained were 238 bp to T/T genotype, 172 bp and 60 bp fragments to the C/C genotype, and 238 bp, 172 bp and 60 bp to the C/T genotype.

Results

The distribution of CC, CT, and TT genotypes were 19.0%, 61.3%, and 19.4%, respectively. Both allele frequencies of C and T were the same — 50%. There was no significant difference in genotype and allele distribution between the patients with ITP and the control group (χ² = 0.84 p = 0.65, χ² = 0.2 p = 0.63, respectively). There were no significant differences in age, gender, and pre- and post-treatment platelet counts between CC, CT, and TT genotypes of the MDR gene. Response to treatment shows no significant difference between genotype and allele groups.

Conclusion

In our study, there was no difference in the HDMP treatment response between MDR1 gene genotypes. However, it should be noted that this study includes a small group of patients. Our data should therefore be considered preliminary, awaiting further confirmatory studies on an expanded patient base.     

Haplotype study of the CYP4A11 gene and coronary artery disease in Han and Uygur populations in China

Background

CYP4A11 converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), which has a crucial role in the modulation of cardiovascular homeostasis. We assessed the association between the human CYP4A11 gene and coronary artery disease (CAD) in Han and Uygur populations in China.

Methods and Results

In the Han population, 361 CAD patients and 315 controls were genotyped for four single-nucleotide polymorphisms (SNPs) of the human CYP4A11 gene (rs9332978, rs4660980, rs3890011, rs1126742). In the Uygur population, 331 CAD patients and 182 controls were genotyped for the same four SNPs. Data were assessed via haplotype-based case–control studies. For the Han population, the significance of the recessive model of SNP3 (GG vs. CC+GC) between CAD patients and control subjects was retained after adjustment for EH, DM and smoking (for men, 95% CI: 1.173–3.013, P = 0.009). The G-G-T haplotype in CAD was significantly higher than that in the control group (P = 0.037). In the Uygur population, neither the distribution of genotypes and alleles for the four SNPs nor the distribution of haplotypes constructed with the same three SNPs showed a significant difference between CAD and control subjects.

Conclusions

The GG genotype of rs3890011 and the G-G-T haplotype in the CYP4A11 gene could be a useful genetic marker of CAD in Han populations in China.     

The impact of GGH -401C > T polymorphism on cisplatin-based chemoradiotherapy response and survival in cervical cancer

Aims

Cervical cancer is the third most frequent cancer in women worldwide, mostly treated with cisplatin-based chemoradiotherapy. Since it is known that folate metabolism might interfere with cisplatin effectiveness, we intended to study the influence of the Gamma Glutamyl Hydrolase -401C > T polymorphism in treatment response in cervical cancer.

Methods

We retrospectively reviewed the clinical data of 167 patients with bulky cervical cancer submitted to cisplatin-based chemoradiotherapy. The genotypes of GGH -401C > T SNP were determined by real-time PCR and statistical analysis was performed by χ² test and survival analysis.

Results

The genotypes of GGH-401C > T were significantly associated with the response to platinum-based chemoradiotherapy. Treatment response was higher in patients carrying the CC genotype, who presented a significant increased chance of treatment response (survival time in months/genotype: 91 for CC Vs 72 for CT/TT; p = 0.035, log rank test). A Cox regression analysis accordingly showed that the presence of the T allele was significantly linked to a worse treatment response (HR = 3.036; CI 95% 1.032-8.934, p = 0.044).

Conclusions

The results of our study suggested the potential interest of GGH -401C > T as a predictive factor of the outcome of cervical carcinoma treated with cisplatin-based chemoradiotherapy.