The β-fibrinogen –455G/A gene polymorphism and the risk of ischaemic stroke in a Polish population

Background and purposeIschaemic stroke is considered to be multifactorial and interactions between environmental and genetic factors play an important role. Although vascular risk factors are well known, the genetic ones are still undiscovered. In the present study, we assessed the significance of the β-fibrinogen –455G/A gene polymorphism and the risk of ischaemic stroke in a Polish population.Material and methods426 ischaemic stroke patients classified according to stroke aetiologies (small vessel disease, large vessel disease or cardioembolic stroke) and 234 controls were included in the study. The association of the β-fibrinogen genotypes with ischaemic stroke was tested using logistic regression analysis under dominant, recessive or additive models of inheritance.ResultsThe allele and genotype distributions of the β-fibrinogen –455G/A gene polymorphism did not differ significantly between patients and controls (patients: G – 75%, GG – 56.6%, GA – 36.8%, AA – 6.6%; controls: G – 73.7%, GG – 57.3%, GA – 32.9%, AA – 9.8%; p > 0.05, χ²). In addition, logistic regression analysis adjusted for the known risk factors, i.e. hypertension, ischaemic heart disease, myocardial infarction, hypercholesterolaemia, diabetes mellitus and smoking, did not show a role of the studied polymorphism in ischaemic stroke.ConclusionsThe β-fibrinogen –455G/A gene polymorphism is not a risk factor for ischaemic stroke in a Polish population.     

Genetic polymorphism of β-fibrinogen gene-455G/A can contribute to the risk of ischemic stroke

Many studies have investigated the association between the β-fibrinogen gene-455G/A (FGβ-455G/A) polymorphism and the risk of ischemic stroke. However, these evidences were inadequate to provide stronger conclusions because most studies were generally small. To shed light on these inconclusive findings, we conducted a large sample size meta-analysis of studies relating to the FGβ-455G/A polymorphism and the risk of ischemic stroke. Odds ratios with a 95 % confidence interval were used to investigate the association between FGβ-455G/A polymorphism and ischemic stroke. Publication bias was tested by Egger’s test and funnel plot. Inconsistency index and Cochran’s Q statistic were used to check heterogeneity. Cumulative and recursive cumulative meta-analyses were performed to provide a framework for updating a genetic effect from all of the included studies. Twenty-six independent publications with 4,070 cases and 4,649 controls were included in this meta-analysis. Results showed that the β-fibrinogen-455G/A polymorphism was significantly associated with the risk of ischemic stroke. The FGβ-455G/A polymorphism was found to be a risk factor for ischemic stroke in Asians and adults, while association was not observed for Caucasians and juveniles based on the small size and it may be necessary to conduct larger studies on them to investigate the association in the future. The cumulative meta-analysis indicated a decline from 1998 to 2003, and the results remained stable during the period 2004–2012. The results indicate that FGβ-455G/A polymorphism may be a susceptible predictor of ischemic stroke. More studies are needed to elucidate the relationship further.     

TNFα gene G-308A polymorphism and the risk of ischemic stroke

TNFα, a significant immune mediator, may contribute to the initiation and progression of the ischemic stroke. Genetics of TNFα molecule may have an important role in the risk of ischemic stroke. The most interesting aspects of the G-308A polymorphism remain unexplained; there are many discrepancies between the results. Differences in the ethnicity of the studied cohorts may be taken as one of the possibility. Our study material consisted of 101 patients with ischemic stroke, including 30% classified as lacunar stroke. The diagnosis was based on the presence of rapidly developing neurological signs lasting longer then 24 h and confirmed by neuroimaging matter. All patients were of Polish Caucasian origin. Randomly selected 100 individuals without any sign of the vascular disease of central nervous system were taken as the control material. The frequency of polymorphism G-308A in TNFα gene was determined as described by Rubattu et al. [11]. The genotype distribution in our material was similar and statistically insignificant between patients and controls. The heterozygotic G/A genotype was detected in 9% of patients and in 15% of control materials, homozygotic A/A was found in 5% of patients and only in one of control and G/G in 87% of patients and in 84% of control individuals. Our results are negative with respect to the impact of 308 TNFα polymorphism on the risk of ischemic stroke in Caucasians living in Poland.     

Influence of the β-fibrinogen-455G/A polymorphism on development of ischemic stroke and coronary heart disease

Background

Ischemic stroke (IS) and coronary heart disease (CHD) are two vascular disorders that are a common cause of death worldwide. Several studies have assessed the association of the β-fibrinogen-455G/A (FGB-455G/A) polymorphism and risk of IS and CHD, but the results are still inconsistent. Our study aimed to investigate whether the FGB-455G/A polymorphism was associated with susceptibility to IS and CHD by using meta-analysis.

Methods

Relevant studies were identified from PubMed, Embase and four Chinese database up to July 2013.Data were analyzed and processed by Stata 11.2. A pooled OR with 95% CI was calculated to estimate the strength of the genetic association. Cumulative meta-analysis was performed to assess the tendency of pooled OR over time.

Results

45 studies based on a total of 7238 cases and 7395 controls were included in our meta-analysis. The results indicated that the FGB-455G/A polymorphism is associated with the risk of IS when compared with the dominant model (OR = 1.518, 95%CI = 1.279-1.802 for AA + GA vs. GG). In the subgroup analysis by ethnicity, significantly elevated risks were associated with the A allele in Asians (OR = 1.700, 95%CI = 1.417-2.040), but not in Caucasians (OR = 0.942, 95%CI = 0.813-1.091). Both the hypertension and non-hypertension subgroups reached significant results, but no significance was found when stratified according to sex or subtype of IS. Results indicate that the FGB-455G/A polymorphism is associated with CHD (OR = 1.802, 95%CI = 1.445-2.246).

Conclusion

Our meta-analysis suggests that the FGB-455G/A polymorphism contributes to susceptibility to IS and CHD.     

The –A162G polymorphism of the PON1 gene and the risk of sporadic amyotrophic lateral sclerosis

Background and purposeSporadic amyotrophic lateral sclerosis (sALS) is a devastating neurodegenerative disease, which results from complex genetic and environmental interactions. Recent studies have reported an association between several polymorphisms of the PON1 and PON2 genes and risk of sALS. The aim of the present study was to identify an association between the – A162G polymorphism of the promoter region of the human PON1 gene and the risk of sALS in a Polish population.Material and methodsWe included 259 patients with a diagnosis of definite or probable sALS (76 bulbar onset, 183 limb onset) and 694 healthy controls matched for age and sex. The diagnosis of ALS was established according to El Escorial criteria. The polymorphism was studied by Single Nucleotide Polymorphism Real-Time Polymerase Chain Reaction analysis.ResultsNo overall difference in the PONI – A162G genotype and allele distribution was seen between cases and controls (all p > 0.05). There was, however, a difference in the A allele frequency when the bulbar onset group was compared to the controls (p = 0.03), but this significance disappeared after the Bonferroni correction.ConclusionsThe results did not show that the – A162G polymorphism of the PON1 gene is a risk factor of sALS in a Polish population; it may affect, however, bulbar onset of the disease.     

APOE and LRPAP1 gene polymorphism and risk of Parkinson’s disease

Epidemiologic findings suggest that lipids and alteration in lipid metabolizing protein/gene may contribute to the development of neurodegenerative disorders. The aim of the current study was to determine the serum lipid levels and genetic variation in two lipid metabolizing genes, low-density lipoprotein receptor-related protein-associated protein (LRPAP1) and apolipoprotein E (APOE) gene in Parkinson’s disease (PD). Based on well-defined inclusion and exclusion criteria, this study included 70 patients with PD and 100 age-matched controls. LRPAP1 and APOE gene polymorphism were analyzed by polymerase chain reaction and restriction fragment length polymorphism, respectively. Fasting serum lipid levels were determined using an autoanalyser. The logistic regression analysis showed that high levels of serum cholesterol [odds ratio (OR) = 1.101, 95 % confidence interval (CI_95%) = 1.067–1.135], LRPAP1 I allelic variant alone (OR = 2.766, CI_95% = 1.137–6.752) and in combination with APOE ε4 allelic variant (OR = 4.187, CI_95% = 1.621–10.82) were significantly associated with increase in PD risk. Apart from that, the high levels of LDL cholesterol appears to have a protective role (OR = 0.931, CI_95% = 0.897–0.966) against PD. The LRPAP1 I allelic variant may be considered a candidate gene for PD, predominantly in patients having the APOE ε4 allelic variant.     

Heart healthy diet and risk of myocardial infarction and venous thromboembolism. The Tromsø Study

Prudent dietary patterns are associated with reduced risk of arterial cardiovascular diseases (CVD). Limited data exist on the relation between diet and venous thromboembolism (VTE). The aim of our prospective, population based study was to investigate the association of a heart healthy diet on risk of myocardial infarction (MI) and VTE. Information on dietary habits was available in 18,062 subjects, aged 25-69, who participated in the fourth Troms? study, 1994-1995. Dietary patterns were assessed by a slightly modified version of the validated SmartDiet score; a 13-item questionnaire producing a diet score based on the intakes of fat, fibre, fruit and vegetables. Incident events of MI (n=518) and VTE (n=172) were recorded to the end of follow-up December 31, 2005 (median follow-up 10.8 years). Cox-regression models were used to calculate hazard ratios (HR). A healthy diet score of >27 points (upper tertile) was associated with 17% reduced risk of MI (HR: 0.83, 95% confidence interval [CI]: 0.66-1.06), and no association with VTE (HR: 1.01; 95%CI: 0.66-1.56), compared to <24 points (lower tertile) in multivariable analysis. High intake of fish, fruit, vegetables and polyunsatured fat had a 23% reduced risk of MI (HR 0.77; 95%CI: 0.60-0.98), but no association with VTE (HR 0.95; 95%CI: 0.64-1.40). A heart healthy diet showed an even more favourable association with MI in obese subjects (HR: 0.62; 95%CI: 0.41-0.95), but not with VTE. Our findings suggest that a heart healthy dietary pattern is associated with moderately reduced risk of MI, but not related to risk of VTE.     

Association between interleukin-6 gene promoter −572C/G polymorphism and the risk of sporadic Alzheimer’s disease

Inflammation is a key component of Alzheimer’s disease (AD), and we have examined the effect of two polymorphisms (−174G/C and −572C/G) in the promoter of the inflammatory cytokine interleukin-6 (IL-6) gene on risk of AD in 318 AD patients. Significant differences in genotype and allele frequencies of −572C/G IL-6 promoter polymorphism were observed between AD patients and controls. The GG genotype was associated with a decreased risk of developing AD (OR 0.423, 95% CI 0.200–0.894). Similarly, logistic regression analysis revealed that G allele was a protective factor for AD (OR 0.732, 95% CI 0.567–0.945). For −174G/C variability, no C variability was found in all the subjects. The frequency of the IL-6 −174G/C promoter polymorphism is very low or no variability in Henan Han population. The −572C/G polymorphism of IL-6 gene promoter region is associated with AD, and G allele is an independent protective factor for AD.     

Is there any difference between the early age myocardial infarction and late age myocardial infarction in terms of psychiatric morbidity in patients who have survived acute myocardial infarction?

ObjectiveWe aimed to compare the rates of psychiatric morbidity in patients who had early age and late age MI in patients who have survived acute myocardial infarction?MethodsOne hundred sixteen patients who were hospitalized in the coronary care unit were included in the study. Psychiatric assessment of the patients was carried out within 1–6 months post-MI. Psychiatric interviews were conducted with the Structured Clinical Interview for DSM-IV (SCID-I). Also used were the Beck Depression Inventory (BDI), Spielberger State-Trait Anxiety Inventory (STAI), and Health Anxiety Inventory (HAI).ResultsA total of 116 patients were divided into two groups according to age as an early age myocardial infarction group (EA-MI) and a late age myocardial infarction group (LA-MI). The EA-MI group included 24 patients 45 years of age and under. The LA-MI group included 92 patients over 45 years of age. Current psychiatric disorders, lifetime psychiatric disorders and lifetime depressive disorders were significantly more frequent in the EA-MI group than in the LA-MI group.ConclusionEA-MI patients have experienced a depressive episode prior to the onset of the MI, whereas in the LA-MI group, the patients typically experienced depressive episodes after MI. Our findings suggest that depression may increase the risk of MI at an early age.     

A novel ARC gene polymorphism is associated with reduced risk of Alzheimer’s disease

Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid β (Aβ) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute Aβ application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and Aβ(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c)?=?0.005; OR?=?0.74; 95?% CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed.     

Meta-analysis of APOE ε2/ε3/ε4 polymorphism and cerebral infarction

The risk of cerebral infarction (CI) is contributed to the combination of environmental influences and genetic factors. The Apolipoprotein E (APOE) gene polymorphism as a risk factor in CI has been suggested, but direct evidence from genetic association studies remains inconclusive even in Chinese population. The purpose of this study was to identify association between the APOE ε2/ε3/ε4 polymorphism and the development of CI. Published relevant case–control studies were collected from electronic databases. Data were combined using odds ratio (OR) with 95 % confidence interval (CI). Totally, 29 studies published from 1997 to 2012, involving 2,737 CI cases and 2,689 controls in Chinese population were subjected to final analysis. The pooled results suggested that CI subjects carrying ε4 allele had an increased risk for CI (ε4 vs. ε3: OR = 2.50, 95 % CI 1.98–3.16, P < 0.001, ε4 carriers vs. E3E3 genotype: OR = 2.82, 95 % CI 2.16–3.67, P < 0.001), compared with those carrying ε3 allele. However, carriers of APOE ε2 allele had no significant increased risk for CI, compared with those carrying ε3 allele. Potential publication bias was observed in the genetic model of ε4 versus ε3, but the results might not be affected deeply by the publication bias. Using the trim and fill method, the adjusted risk estimate for ε4 allele versus ε3 allele was attenuated but remained significant (OR = 2.00, 95 % CI 1.59–2.53, P < 0.001), suggesting the stability of our results. Taken together, our study suggests that APOE ε4 allele is associated with an increased risk of developing CI in Chinese population.     

Impact of the PDE4D gene polymorphism and additional SNP–SNP and gene–smoking interaction on ischemic stroke risk in Chinese Han population

Aims: To investigate the association between phosphodiesterase 4D gene (PDE4D) gene single nucleotide polymorphisms (SNPs) and ischemic stroke (IS) risk, and impact of additional SNP- SNP and gene- smoking interaction on IS risk in Chinese population.

Methods: A total of 1228 subjects (666 males, 562 females) were selected, including 610 IS patients and 618 control subjects. Logistic regression model was used to examine the association between SNPs in PDE4D gene and IS risk. Generalized multifactor dimensionality reduction (GMDR) was employed to analyze the SNP- SNP and gene- smoking interaction.

Results: IS risks were significantly higher in carriers of A allele of rs12188950 polymorphism than those with GG genotype (GA + AA vs. GG), adjusted OR (95%CI) = 1.61 (1.26–2.19), and also significantly higher in carriers of T allele of rs966221 polymorphism than those with CC (CT + TT vs. CC), adjusted OR (95%CI) = 1.82 (1.39–2.23). We found that there was a significant SNP- SNP interaction between rs966221 and rs12188950. Subjects with CT or TT of rs966221 and GA or AA of rs12188950 genotype have the highest IS risk, compared to subjects with CC of rs966221 and GG of rs12188950 genotype, OR (95%CI) was 3.52 (2.68–4.69). We also found a significant gene–environment interaction between rs966221 and smoking. Smokers with CT or TT of rs966221 genotype have the highest IS risk, compared to never smokers with CC of rs966221 genotype, OR (95%CI) was 3.97 (2.25–5.71).

Conclusions: Our results support an important association of rs966221 and rs12188950 minor allele and its interaction with increased risk of IS risk, and additional interaction between rs966221 and smoking.     

Angiogenin gene polymorphism A risk factor for diabetic peripheral neuropathy in the northern Chinese Han population ？

Angiogenin is associated with the pathogenesis of diabetic peripheral neuropathy. Here, we se- quenced the coding region of the angiogenin gene in genomic DNA from 207 patients with type 2 diabetes mellitus （129 diabetic peripheral neuropathy patients and 78 diabetic non-neuropathy pa- tients） and 268 healthy controls. All subjects were from the Han population of northern China. No mutations were found. We then compared the genotype and allele frequencies of the angiogenin synonymous single nucleotide polymorphism rs11701 between the diabetic peripheral neuropathy patients and controls, and between the diabetic neuropathy and non-neuropathy patients, using a case-control design. We detected no statistically significant genetic associations. Angiogenin may not be associated with genetic susceptibility to diabetic peripheral neuropathy in the Han population of northern China.     

A functional polymorphism of the µ-opioid receptor gene is associated with completed suicides

Summary. A recent linkage study suggested that a putative locus for suicidal behavior independent of psychiatric disease phenotypes lies at 5′ upstream of the μ-opioid receptor (OPRM1) gene. We explored an association between suicide and genetic variations of the OPRM1 using a case-control study of 183 completed suicides and 374 control subjects. We genotyped four single nucleotide polymorphisms (SNPs) including a common A118G SNP. The genotypic and allelic distributions of the A118G SNP were significantly different between the completed suicide and control groups (P = 0.014 and 0.039, respectively). A dominant model analysis of the A118G SNP showed an enhanced association with suicide (P = 0.0041, Odds ratio 0.575) and this significant association was observed with a logistic regression analysis that takes sex and age factors into account (P = 0.021). Our results raise the possibility that the A118G SNP of the OPRM1 gene is associated with suicide. Correspondence: Akitoyo Hishimoto, Division of Psychiatry and Neurology, Department of Environmental Health and Safety, Faculty of Medical Sciences, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho Chuo-ku, Kobe 650-0017, Japan     

CSF β-endorphin and leu-enkephalin levels in the acute and chronic stages of cerebral infarction

Summary To investigate the role of endogenous opioid peptides in the pathophysiology of cerebral ischaemia, the CSF levels of immunoreactive -endorphin and leu-enkephalin in 16 patients with cerebral infarction were measured. Both the CSF -endorphin and leu-enkephalin levels in the acute stage of cerebral infarction were significantly higher than the values in the chronic stage. The CSF concentrations of the two peoptides revealed a positive correlation in the acute but not the chronic stage. The increased endogenous opioid peptides in the CSF in the acute stage may modify the evolution of cerebral infarction.     

Is the dentate gyrus an independent generator of in vitro recorded theta rhythm?

In this study we investigated the ability of the dentate gyrus to independently generate cholinergically induced theta rhythm in vitro. Two different experiments were performed. In Experiment I, new laminar profiles of theta phase, amplitude, and current sources and sinks were constructed. In this experiment a gradual phase shift of theta waves in the CA1 stratum radiatum was observed. Simultaneously, two amplitude maxima were detected: the first in the CA1 stratum oriens, and the second in the CA1 stratum lacunosum-moleculare. Moreover, during the positive peak of theta in the CA1 stratum oriens, two large sinks were observed: the first localized in the stratum oriens and the second in the stratum lacunosum-moleculare. In Experiment II the EEG activity of three different transected hippocampal slices (CA1 transected slices, CA3c transected slices, and DG transected slices) was recorded. It was demonstrated that the dentate gyrus granular cell body layer was not able to independently produce in vitro theta rhythm. Data obtained in both experiments provide strong evidence that in cholinegically treated hippocampal formation maintained in vitro there is no independent generator of theta rhythm in the region of the dentate gyrus granular cell layer.