Association between 1603C>T polymorphism of DBH gene and bipolar disorder in a Turkish population

Objectives

Dopamine-β-hydroxylase (DBH) is the enzyme responsible for the conversion of dopamine (DA) to norepinephrine (NE, noradrenaline) which is a key neurotransmitter in the central and peripheral nervous systems. Bipolar disorder is a major psychiatric disorder. The present study was designed to explore the associations of polymorphisms of DBH gene in Turkish patients with bipolar disorder.

Methods

− 1021C>T (rs1611115) polymorphism in promoter region, 444G>A (rs1108580) polymorphism in exon 2 and 1603C>T (rs6271; C535R) polymorphism in exon11 of DBH gene were analyzed in 106 patients with bipolar disorder and 106 healthy subjects by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.

Results

The results showed statistically significant associations for genotypic and allelic distribution between the 1603C>T polymorphism and bipolar disease (p = 0.0012 and p = 0.034, respectively). There was no association observed between the genotype and allelic frequencies for − 1021C>T and 444G>A polymorphisms and bipolar disorder.

Conclusions

Our data suggests that the 1603C>T polymorphism of the DBH gene is associated with susceptibility to bipolar disorder in a Turkish population.     

Synergistic effect of anti and pro-inflammatory cytokine genes and their promoter polymorphism with ST-elevation of myocardial infarction

Background

The single-gene approach in association studies of polygenic diseases such as acute myocardial infarction (AMI) is likely to provide limited value. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) plasma levels may be genetically influenced.

Aim

We evaluate the impact of single nucleotide polymorphism of the promoter region of these genes, as well as reciprocal interaction of these genes with ST-elevation of myocardial infarction (STEMI).

Methods

In a case–control study 500 STEMI patients and 500 age- and sex-matched controls were studied. Three single-nucleotide polymorphism genotypes were evaluated by polymerase chain reaction and restriction enzyme analysis and assessed their association with STEMI. The synergistic effects of IL-6, TNF-α and IL-10 gene polymorphisms were evaluated by using logistic regression analysis.

Results

We found that IL-6 and TNF-α concentrations of studied population were significantly different (p < 0.0001) in each genotype of IL-6 − 174G>C and TNF-α − 308G>A gene polymorphisms respectively. A significant association was found in multivariate analysis for the IL-6 − 174G>C [odds ratio (OR): 0.390; 95% confidence interval (CI): 0.176–0.865, p = 0.020] and TNF-α − 308G>A [OR: 0.372; 95% CI: 0.171–808, p = 0.012] gene polymorphisms with STEMI. In contrast, IL-10 − 592C>A gene polymorphism was no longer significant in the multivariate model (OR: 0.678; 95% CI: 0.288 to 1.594, p = 0.373) whereas significant in univariate analysis (OR: 0.697; 95% CI: 0.523–0.929, p = 0.014).

Conclusions

Our findings suggest that IL-6, TNF-α and IL-10 gene polymorphisms all contribute in the association with STEMI whereas the association persisted only for IL-6 and TNF-α but not for IL-10 gene polymorphism with this disease in the multivariate analysis.     

Tumor necrosis factor alpha − 308G>A, − 863C>A, − 857C>T gene polymorphisms and tuberculosis susceptibility: A meta-analysis

Background/aims

A large number of studies have shown that polymorphisms in the tumor necrosis factor-α (TNF-α, TNFA) gene are implicated in susceptibility to tuberculosis (TB). However, the results are inconsistent. We performed this meta-analysis to estimate the association between polymorphisms in the TNFA gene and TB susceptibility.

Methods

Relevant studies published before March 2012 were identified by searching PubMed, ISI web of knowledge, EBSCO and CNKI. The strength of relationship between the TNFA gene and TB susceptibility was assessed using odds ratios (ORs).

Results

A total number of twenty-three case–control studies including 3630 cases and 4055 controls were identified referring to three previously chosen single-nucleotide polymorphisms (SNPs): − 308G>A, − 863C>A and − 857C>T. No association was found between − 308G>A, − 863C>A and TB susceptibility: − 308G>A (GG + GA vs. AA): OR 0.85, 95%CI: 0.55–1.30, P = 0.44; − 863C>A (CC + CA vs. AA): OR 0.93, 95%CI: 0.84–1.81, P = 0.83. Increased risk of TB was associated with − 857C>T in the dominant genetic model (CC + CT vs. TT: OR 2.13, 95%CI: 1.25–3.63, P = 0.01), the heterozygote comparison (CT vs. TT: OR 2.69, 95%CI: 1.44–5.02, P = 0.00) and the homozygote comparison (CC vs. TT: OR 2.08, 95%CI: 1.22–3.53, P = 0.01) in Asian subjects.

Conclusion

There is an increased association between TNFA − 857C>T polymorphism and TB risk among Asian subjects. No association was found between − 308G>A and − 863C>A with TB risk. Due to several limitations in the present study, well-designed epidemiological studies with large sample size among different ethnicities should be performed in the future.     

The polymorphism − 1131T > C in apolipoprotein A5 gene is associated with dyslipidemia in Brazilian subjects

Background

Polymorphisms in apolipoprotein A5 gene (APOA5) have been associated with higher triglyceride levels in many populations. The aim of the study was to determine the allelic and genotypic distribution of the APOA5 − 1131T > C polymorphism and to identify the association of the genetic variant and the risk for dyslipidemia.

Methods

We genotyped 109 dyslipidemic subjects and 107 controls. The total cholesterol, triglycerides and HDL-c were determined enzymatically. Comparison of means among groups was calculated by ANOVA. Significant differences among groups were evaluated by Student–Newman–Keuls test.

Results

The minor allele C was more frequent in dyslipidemic subjects than controls (p = 0.019) and confers an increased individual risk for dyslipidemia (OR = 1.726, CI 95% = 1.095–2.721). The genotype analysis by gender showed that this allele was more frequent in dyslipidemic males (p = 0.037; OR = 2.050, CI 95% = 1.042–4.023). When participants were analyzed according to genotypes TT and TC/CC, C-carriers presented higher cholesterol and triglycerides levels than TT homozygous (p = 0.046 and 0.049, respectively).

Conclusions

The allele C confers higher total cholesterol and triglycerides levels in dyslipidemic adults. The APOA5 − 1131T > C polymorphism is associated with dyslipidemia in male subjects.     

Association of IL-6 − 174G > C and − 572C > G polymorphisms with risk of young ischemic stroke patients

Aim

To investigate the association between interleukin-6 (IL-6) − 174G > C and − 572C > G polymorphisms and risk for ischemic stroke (IS) in young patients.

Methods

We genotyped IL-6  − 174G > C and − 572C > G in a case–control study of 430 young IS patients and 461 control subjects. An unconditional multiple logistical regression model was used to calculate the effects of IL-6 − 174G > C and − 572C > G polymorphisms on IS risk.

Results

Higher body mass index, diabetes, hypertension, obesity, and smoking were associated with risk of ischemic stroke. Multivariate regression analyses showed that subjects carrying the − 174CC genotype (OR = 1.69, 95% CI = 1.16–2.57) and C allele (OR = 1.37, 95% CI = 1.09–1.67) had a small but significant increased risk of IS. Similarly, those carrying the − 572GG genotype (OR = 2.12, 95% CI = 1.18–3.82) and G allele (OR = 1.43, 95% CI = 1.14–1.83) had a moderate increased risk of IS. We found the − 174G > C and − 572C > G polymorphisms interact with hypertension and obesity.

Conclusion

Our results suggest that polymorphisms in IL-6 − 174G > C and − 572C > G are associated with IS risk in young patients, and that these polymorphisms interact with hypertension, obesity and etiologic subtypes. These findings could be helpful in identifying individuals at increased risk for developing IS.     

A genetic variant in the promoter of APE1 gene (− 656 T > G) is associated with breast cancer risk and progression in a Chinese population

Background/aims

APE1 is an important DNA repair protein in the base excision repair pathway. Genetic variations in APE1 have been suggested to influence individuals' susceptibility to human malignancies. The present study was aimed to investigate the associations between two functional polymorphisms in APE1 (− 656 T > G and 1349 T>G) and breast cancer risk.

Methods

We genotyped the two polymorphisms in a case-control study of 500 breast cancer patients and 799 age-matched cancer-free controls using the TaqMan method. Unconditional logistic regression adjusted for potential confounding factors was used to assess the associations.

Results

We found that the variant genotypes of the − 656 T>G were significantly associated with decreased breast cancer risk, compared with the wild genotype [TG/GG vs. TT: adjusted odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.56–0.91], and the protective effect of this polymorphism was more predominant among the subgroups of younger subjects (< 52 years) (OR = 0.65, 95% CI = 0.46–0.92). Besides, we found that the variant genotypes were associated with less frequent lymph node metastasis (P = 0.020, OR = 0.64, 95% CI = 0.44–0.94). We did not observe any significant association between the 1349 T>G polymorphism and breast cancer risk.

Conclusion

Our results suggest that the APE1 − 656 T>G but not the 1349 T>G polymorphism may influence the susceptibility and progression of breast cancer in the Chinese population. Large population-based prospective studies are required to validate these findings.     

Association of functional FEN1 genetic variants and haplotypes and breast cancer risk

Aim

As a tumor suppressor, FEN1 plays an essential role in preventing tumorigenesis. Two functional germline variants (-69G > A and 4150G > T) in the FEN1 gene have been associated with DNA damage levels in coke-oven workers and multiple cancer risk in general populations. However, it is still unknown how these genetic variants are involved in breast cancer susceptibility.

Methods

We investigated the association between these polymorphisms and breast cancer risk in two independent case–control sets consisted of a total of 1100 breast cancer cases and 1400 controls. The influence of these variations on FEN1 expression was also examined using breast normal tissues.

Results

It was found that the FEN1-69GG genotypes were significantly correlated to increased risk for developing breast cancer compared with the -69AA genotype in both sets [Jinan set: odds ratios (OR) = 1.41, 95% confidence interval (CI) = 1.20–1.65, P = 1.9×10^− 5; Huaian set: OR = 1.51, 95% CI = 1.22–1.86, P = 1.7×10^− 4]. Similar results were observed for 4150G > T polymorphism. The genotype–phenotype correlation analyses demonstrated that the -69G or 4150G allele carriers had more than 2-fold decreased FEN1 expression in breast tissues compared with -69A or 4150T carriers, suggesting that lower FEN1 expression may lead to higher risk for malignant transformation of breast cells.

Conclusion

Our findings highlight FEN1 as an important gene in human breast carcinogenesis and genetic variants in FEN1 confer susceptibility to breast cancer.     

CHK2 1100delC,IVS2 + 1G>A and I157T mutations are not present in hepatocellular cancer cases from a Turkish population

Aim

The cell cycle checkpoint kinase 2 (CHK2) protein participates in the DNA damage response in many cell types. Germline mutations in CHK2 (1100delC, IVS2 + 1G>A and I157T) have been associated with a range of cancer types. This study aimed to investigate whether CHK2 1100delC, IVS2 + 1G>A and I157T mutations play an important role in the development of hepatocellular carcinoma (HCC) in a Turkish population.

Methods

A total of 165 hepatocellular cancer cases and 446 cancer-free controls were genotyped for CHK2 mutations by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific-polymerase chain reaction (AS-PCR) methods.

Results

We did not find CHK2 1100delC, IVS2 + 1G>A and I157T mutations in any of 611 Turkish subjects.

Conclusion

Our results demonstrate for the first time that CHK2 1100delC, IVS2 + 1G>A and I157T mutations have not been a genetic susceptibility factor for HCC in the Turkish population. Overall, our data suggests that genotyping of CHK2 mutations in clinical settings in the Turkish population should not be recommended. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins.     

Association between the − 786T>C 1polymorphism in the promoter region of endothelial nitric oxide synthase (eNOS) and risk of coronary artery disease: A systematic review and meta-analysis

Background

A variety of studies have evaluated the association between the − 786T>C polymorphism in the promoter region of endothelial nitric oxide synthase (eNOS) and risk of coronary artery disease (CAD). However, the results remain conflicting. To better understand the role of eNOS − 786T>C polymorphism in CAD risk, we conducted a comprehensive systematic review and meta-analysis.

Methods

Case–control, cohort or cross-sectional studies evaluating the association between eNOS − 786T>C polymorphism and CAD risk were searched in electronic databases of PubMed, ISI Web of Knowledge, Medline, Embase and Google Scholar Search (up to January 2013). Overall and subgroup analyses were performed. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the association between eNOS − 786T>C polymorphism and CAD risk. Statistical analysis was performed with Review Manager 5.0 and STATA12.0.

Results

Twenty-four studies were analyzed between 6192 CAD cases and 9281 healthy controls. The combined results of overall analysis showed significant positive associations between CAD risk and eNOS − 786T>C polymorphism in dominant model (OR = 1.45, 95% CI = 1.27–1.65), recessive model (OR = 1.37, 95% CI = 1.20–1.56), homozygote comparison (OR = 1.64, 95% CI = 1.31–2.04), heterozygote comparison (TC vs. TT, OR = 1.39, 95% CI = 1.23–1.57; CC vs. TC, OR = 1.20, 95% CI = 1.04–1.37) and allele comparison (OR = 1.35, 95% CI = 1.21–1.50). On subgroup analysis based on the ethnicity of population (Caucasians, Asians and others), significant differences were found in all genetic models for Caucasians, similar associations existed in Asians except heterozygote comparison (CC vs. TC). However, the associations were only found in dominant model, heterozygote comparison (TC vs. TT) and allele comparison for the populations named others.

Conclusions

Our investigations demonstrate the significant associations between eNOS − 786C>T polymorphism and CAD risk, and this polymorphism might become an early marker for the risk evaluation of CAD.     

Update meta-analysis on MMP-7 − 181A>G polymorphism and cancer risk: Evidence from 25 studies

Background

The matrix metalloproteinase (MMP) can degrade various components of the extracellular matrix and its functional genetic polymorphism may be associated with cancer development. The common MMP-7 (− 181A>G) genetic polymorphism has been reported to be functional and may contribute to genetic susceptibility to cancers. However, the association between MMP-7 (− 181A>G) and cancer risk remains inconclusive.

Methods

To better understand the role of MMP-7 (− 181A>G) polymorphism in global cancer, we conducted this comprehensive meta-analysis encompassing 6392 cases and 7665 controls.

Results

Overall, the MMP-7 (− 181A>G) polymorphism was associated with higher cancer risk. In the stratified analyses, significant associations were found between the MMP-7 (− 181A>G) polymorphism and gastric cancer, ESCC and gynecologic cancer. We also observed that the GG genotype might modulate colorectal cancer risk comparing with the AA genotype (OR = 1.31[1.02–1.69]). Moreover, a significantly increased cancer risk was found among Asian populations. When stratified by study design, significantly elevated susceptibility to cancer was found among population-based studies.

Conclusions

These findings suggested that the MMP-7 (− 181A>G) genetic polymorphism may contribute to the susceptibility of cancers, especially among Asian population.     

Population-based and family-based studies on the protein tyrosine phosphatase non-receptor 22 gene polymorphism and type 1 diabetes: A meta-analysis

Purpose

Studies investigating the association between PTPN22 gene C1858T polymorphism and type 1 diabetes (T1D) susceptibility among Caucasian population have reported conflicting results. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the relationship between the PTPN22 C1858T polymorphism and T1D.

Methods

Databases including PubMed, Web of Science, and EMBASE were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association.

Results

In total, 33 population-based studies with 22, 485 cases and 35, 292 controls, 9 family-based studies involving 7276 families were included. Under the random-effects model, the per-allele overall OR of the C1858T polymorphism for T1D was 1.89 (95% CI: 1.76–2.02, P < 10^− 5) by pooling all available case–control studies. In addition, we found significant evidence for overtransmission of the risk T allele in family-based studies (overall OR _TDT = 1.58, 95% CI: 1.43–1.74; P < 10^− 5). The summary OR from case–control and family-based association studies was 1.81 (95% CI: 1.70–1.93, P < 10^− 5).

Conclusions

In conclusion, this meta-analysis suggests that C1858T polymorphism in PTPN22 is associated with elevated T1D risk among Caucasian population.     

Association study of polymorphisms in the receptor for advanced glycation end-products (RAGE) gene with susceptibility and prognosis of heart failure

Background

Functional polymorphisms in the receptor for advanced glycation end-products (RAGE) gene have been implicated in several vascular diseases. However, to date, no study investigated the association of RAGE polymorphisms with heart failure (HF).

Objective

In this study we tested the hypothesis that the 63-bp insertion/deletion, the − 374T > A (rs1800624) and the − 429T > C (rs1800625) polymorphisms in the RAGE gene might be associated with susceptibility to HF and could predict all-cause mortality in Brazilian outpatients with left ventricular systolic dysfunction.

Methods

A total of 273 consecutive HF patients (196 Caucasian- and 77 African-Brazilians) and 334 healthy blood donors (260 Caucasian- and 74 African-Brazilians) were enrolled in a tertiary care university hospital. Genotyping of RAGE polymorphisms was done by polymerase chain reaction (PCR) or PCR followed by enzyme restriction analysis.

Results

The allele, genotype and haplotype frequencies of − 374T > A and − 429T > C polymorphisms were not significantly different between HF patients and healthy blood donors in both ethnic groups. However, among African-Brazilians, the frequency of carriership of the del allele was lower in HF patients than in blood donors (2.6% vs 12.2%, respectively, p = 0.008). Patients were followed-up for a median of 38 months and the survival analysis did not reveal a consistent association between RAGE polymorphisms and all-cause death in both ethnic groups.

Conclusion

The − 374T > A and − 429T > C polymorphisms in the RAGE gene were not associated with the susceptibility and prognosis of HF. Notwithstanding, the 63-bp ins/del polymorphism might be involved in the susceptibility to HF in African-Brazilians.     

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.     

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.     

The interleukin-4 − 589C/T polymorphism and the risk of asthma: A meta-analysis including 7345 cases and 7819 controls

Background

A number of studies assessed the association of − 589C/T polymorphism in the promoter region of interleukin-4 (IL-4) with asthma in different populations. However, the results were contradictory. A meta-analysis was conducted to investigate the association between polymorphism in the IL-4 and asthma susceptibility.

Methods

Databases including Pubmed, EMBASE, Wanfang Database, China National Knowledge Infrastructure (CNKI) and Weipu Database were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations.

Results

Thirty-four studies involving 7345 cases and 7819 controls were included. Overall, significant association between − 589C/T polymorphism and asthma was observed for TT + CT vs. CC (OR = 1.26; 95% CI 1.12–1.42; P = 0.0001; I² = 26%). In the subgroup analysis by ethnicity, significant associations were found among Asians (OR = 1.36; 95% CI 1.07–1.73; P = 0.01; I² = 0%) and Caucasians (OR = 1.30; 95% CI 1.09–1.54; P = 0.004; I² = 53%) but not among African Americans (OR = 1.20; 95% CI 0.72–2.00; P = 0.48; I² = 48%). In the subgroup analysis by atopic status, no significant association was found among atopic asthma patients (OR = 1.20; 95% CI 0.92–1.34; P = 0.27; I² = 6%) and non-atopic asthma patients (OR = 0.97; 95% CI 0.73–1.28; P = 0.81; I² = 0%).

Conclusions

This meta-analysis suggested that the IL-4 − 589C/T polymorphism was a risk factor of asthma.     

Association between -251A>T polymorphism in the interleukin-8 gene and oral cancer risk: A meta-analysis

Background

Emerging evidence showed that the most common functional polymorphism (-251A>T, rs4073) in the promoter region of the interleukin-8 (IL-8) gene is involved in the regulation of the activities of interleukin-8, thus increasing an individual's susceptibility to oral cancer; but individually published results are inconclusive. The aim of this meta-analysis was to investigate the associations between IL-8 -251A>T polymorphism and oral cancer risk.

Methods

The PubMed, Embase, Web of Science and CBM databases were searched for all articles published up to October 1st, 2012 that addressed IL-8 -251A>T polymorphism and oral cancer risk. Statistical analyses were performed using STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations.

Results

Six case–control studies were included with a total of 1324 oral cancer cases and 1879 healthy controls. When all available studies were pooled into the meta-analysis, the results showed that the AA and AT genotypes of IL-8 -251A>T polymorphism were associated with increased risk of oral cancer (OR = 1.23, 95% CI: 1.03–1.46, P = 0.025; OR = 1.25, 95% CI: 1.07–1.47, P = 0.006; respectively). In the subgroup analysis by ethnicity, significant associations were observed between the AA and AT genotypes of IL-8 -251A>T polymorphism and increased risk of oral cancer among Caucasian populations (OR = 1.40, 95% CI: 1.14–1.72, P = 0.001; OR = 1.29, 95% CI: 1.06–1.57, P = 0.011; respectively). However, no statistically significant associations were found between IL-8 -251A>T polymorphism and oral cancer risk among Asian populations.

Conclusions

Results from the current meta-analysis indicate that the AA and AT genotypes of IL-8 -251A>T polymorphism might increase the risk of oral cancer, especially among Caucasian populations.     

14-3-3ε Gene variants in a Japanese patient with left ventricular noncompaction and hypoplasia of the corpus callosum

Background

Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by a prominent trabecular meshwork and deep intertrabecular recesses, and is thought to be due to an arrest of normal endomyocardial morphogenesis. However, the genes contributing to this process remain poorly understood. 14-3-3ε, encoded by YWHAE, is an adapter protein belonging to the 14-3-3 protein family which plays important roles in neuronal development and is involved in Miller–Dieker syndrome. We recently showed that mice lacking this gene develop LVNC. Therefore, we hypothesized that variants in YWHAE may contribute to the pathophysiology of LVNC in humans.

Methods and results

In 77 Japanese patients with LVNC, including the probands of 29 families, mutation analysis of YWHAE by direct DNA sequencing identified 7 novel variants. One of them, c.− 458G > T, in the YWHAE promoter, was identified in a familial patient with LVNC and hypoplasia of the corpus callosum. The − 458G > T variant is located within a regulatory CCAAT/enhancer binding protein (C/EBP) response element of the YWHAE promoter, and it reduced promoter activity by approximately 50%. Increased binding of an inhibitory C/EBPβ isoform was implicated in decreasing YWHAE promoter activity. Interestingly, we had previously shown that C/EBPβ is a key regulator of YWHAE.

Conclusions

These data suggest that the − 458G > T YWHAE variant contributes to the abnormal myocardial morphogenesis characteristic of LVNC as well as abnormal brain development, and implicate YWHAE as a novel candidate gene in pediatric cardiomyopathies.     

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.     

Associations of the PTEN − 9C>G polymorphism with insulin sensitivity and central obesity in Chinese

Background

Phosphatase and tensin homolog on chromosome 10 gene (PTEN) is known as a tumor-suppressor gene. Previous studies demonstrated that PTEN dysfunction affects the function of insulin. However, investigations of PTEN single nucleotide polymorphisms (SNPs) and IR-related disease associations are limited. The aim of the present study was to investigate whether its polymorphism could be involved in the risk of metabolic syndrome (MetS).

Methods

The genotype frequency of PTEN − 9C>G polymorphism was determined by using a Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) method in 530 subjects with MetS and 202 healthy control subjects of the Han Ethnic Chinese population in a case–control analysis.

Results

The PTEN − 9C>G polymorphism was not associated with MetS or its hyperglycemia, hypertension and hypertriglyceridemia components. In the control individuals aged < 60 years or ≥ 60 years, the CG genotype individuals had lower insulin sensitivity than CC individuals (P < 0.05). In the < 60-year-old MetS group and normal glucose tolerance (NGT) subgroup, the CG individuals had lower insulin sensitivity and higher waist circumference (WC) and waist-height-ratio (WHtR) than CC individuals (P < 0.05). Multiple linear regression analysis showed that the PTEN polymorphism (P = 0.001) contributed independently to 4.2% (adjusted R²) of insulin sensitivity variance (estimated by Matsuda ISI), while age (P = 0.004), gender (P = 0.000) and the PTEN polymorphism (P = 0.032) contributed independently to 5.6% (adjusted R²) of WHtR variance.

Conclusions

The CG genotype of PTEN − 9C>G polymorphism was not associated with MetS and some of its components as well. However, it may not only decrease insulin sensitivity in the healthy control and MetS in pre-elderly or NGT subjects, but may also increase the risk of central obesity among these MetS individuals.     

Mutational screening of SF1 and WNT4 in Tunisian women with premature ovarian failure

Background

WNT4 and SF1 genes play an important role in ovarian development. They constitute coherent candidate genes associated with premature ovarian failure (POF) pathogenesis.

Methods

We sequenced the coding region of WNT4 and SF1 in 55 Tunisian women with POF and 100 healthy controls.

Results

We identified a synonymous variation in WNT4 (c.99G>A, p.Ser33Ser) and a substitution (c.G437C) in SF1 gene inducing G146 to Ala (GGG–GCG) missense mutation. WNT4 (c.99G>A, p.Ser33Ser) was not associated with POF pathology. However, a positive association of SF1 Gly146Ala polymorphism was noted. Gly146Ala minor allele frequency was significantly higher (p = 0.029) in POF patients versus controls and Ala allele containing genotypes (p = 0.005) were positively associated with POF pathology. The carriage of 146Ala allele was also associated with a significant reduction in estradiol plasma levels.

Conclusions

SF1 Gly146Ala polymorphism seems to be associated with POF pathology in the Tunisian population likely by reducing estradiol levels.