Association of PDE4D and IL-1 gene polymorphism with ischemic stroke in a Han Chinese population

Background

The single-nucleotide polymorphisms (SNPs) of the phosphodiesterase 4D (PDE4D) and interleukin-1 (IL-1) genes are associated with increased risk for the development of ischemic stroke (IS) in whites. However, little is known about whether this association could also occur in Han Chinese.

Method

A total of 371 patients with IS and unrelated healthy controls were recruited and the SNPs of the PDE4D (83T/C), (87T/C), IL-1 (−889C/T) and IL-1 (−511C/T) were characterized, respectively, by polymerase chain reactions-restriction fragment length polymorphism (PCR-RFLP). The genotype and allele frequencies of these SNPs in this population were statistically analyzed.

Results

The genotype and allele frequencies of the PDE4D (87T/C) and IL-1 (−511C/T) were similar between IS patients and controls. In contrast, the frequencies of CC genotype and C allele of the PDE4D (83T/C) and the T allele frequency of IL-1 (−889C/T) in IS patients were significantly higher than that in healthy controls (p = 0.001, p = 0.003 and p = 0.02, respectively), independent of the conventional risk factors. The values of odds ratio (OR) reached at OR = 1.603; 95%CI = 1.032-2.489; p = 0.036 for the CC genotype of the PDE4D (83T/C) and OR = 1.913; 95%CI = 1.621-2.375; p = 0.034 for the TT genotype of the IL-1 (−889C/T), respectively.

Conclusions

the SNPs of the PDE4D (83T/C) and IL-1 (−889C/T) were associated with increased risk for the development of IS in Northern Han Chinese.     

5-脂氧合酶激活蛋白基因和白介素-1A基因多态与缺血性脑卒中的相关性

目的 探讨中国北方地区汉族人群5-脂氧合酶激活蛋白(ALOX5AP)基因和白介素-1A(IL-1A)基因多态与缺血性脑卒中(IS)的相关性.方法 采用病例-对照研究,检测构建ALOX5AP基因单倍型HapA的4个位点:SG13S25、SG13S32、SG13S89、SG13S114和IL-1A基因-889位点在对照组、IS组及IS亚组中多态的分布.结果 ALOXSAP基因SG13S114位点AA基因型可能是血栓性脑梗死独立的风险因素(OR=1.479,95% CI 1.024～2.135,P=0.037),且其风险性主要来源于A等位基因(OR=1.313,95% CI 1.017～1.693,P=0.036);IL-IA基因-889位点T等位基因可能是血栓性脑梗死的易患等位基因(OR=1.540,95% CI 1.075～2.204,P=0.023).HapA单倍型和IS没有相关性,GCGA单倍型可能是IS的危险单倍型(OR=1.683,95% CI 1.138～2.487,P=0.008).同时携带ALOX5AP基因GCGA单倍型和IL-1A-889T等位基因的个体患IS的风险性显著增加(OR=1.608,95% CI 1.607～2.423,P=0.022).结论 ALOXSAP基因、IL-1A基因的多态与IS具有相关性,二者的协同作用可显著增加IS的患病风险.     

Association of E-selectin gene polymorphisms with ischemic stroke in a Chinese Han population

The E-selectin gene, a member of the selectin superfamily of adhesion molecules, plays an important role in the pathogenesis of thrombovascular diseases. The present study was designed to investigate the potential relationship between E-selectin gene polymorphisms and ischemic stroke in a Chinese Han population. Three hundred fourteen ischemic stroke patients and 389 unrelated healthy controls were recruited for the study. Three single-nucleotide polymorphisms (SNPs)-rs1805193(G98T), rs5361(A561C), and rs5355(C1839T)-in the exon region of the E-selectin gene, were genotyped using a Multiplex SNaPshot sequencing assay. The data showed that the genotype and allele frequencies of G98T and C1839T SNP were similar in both ischemic stroke patients and the controls. In contrast, the frequency of both the AC genotype and the C allele of A561C was significantly higher in ischemic stroke patients than in healthy controls (P = 0.001, P < 0.001, respectively). After adjusting for other risk factors (such as hypertension, diabetes, tobacco smoking, and alcohol consumption), the E-selectin gene AC genotype and C allele of A561C were still associated with a risk of ischemic stroke (odds ratio [OR] = 2.73, 95% confidence interval (CI): 1.29-5.76, P = 0.008; OR = 2.80, 95% CI: 1.58-4.94, P < 0.001, respectively). Our current study demonstrates that the E-selectin SNP A561C is associated with increased risk for the development of ischemic stroke in this subset of the Han Chinese population.     

Interleukin-1alpha and -1beta promoter polymorphisms in Taiwanese patients with dementia

BACKGROUND: Inflammatory events may contribute to the pathogenesis of dementia and interleukin-1 (IL-1) may exert both neurotoxic and neuroprotective effects. We investigated whether IL-1alpha -889 C/T and IL-1beta -511 C/T promoter polymorphisms are associated with the risk of Alzheimer's disease (AD) and vascular dementia (VaD). METHODS: AD patients (n = 219) and VaD patients (n = 82), who fulfilled the criteria of the NINCDS-ADRDA and NINDS-AIREN, and ethnic-matched and nondemented controls (n = 209) were analyzed by means of genotype association method. RESULTS: No significant difference in the genotype distribution of the analyzed single nucleotide polymorphisms was found between AD or VaD cases and controls. However, the frequency of the IL-1alpha -889 CT genotype was notably lower in VaD patients aged over 70 years than the age-matched controls (9.1 vs. 22.9%, p = 0.036) andtheIL-1alpha -889 CT genotype demonstrated a trend toward decrease in risk of developing VaD (odds ratio: 0.34; 95% confidence interval: 0.12-0.83, p = 0.026). Multivariate analysis revealed that the IL-1beta -511T-carrying genotype slightly strengthens the negative association of the IL-1alpha -889 CT genotype with VaD (odds ratio: 0.26; 95% confidence interval: 0.08-0.79, p = 0.024). CONCLUSION: Our data suggest a protective role of the IL-1alpha -889 CT genotype in VaD susceptibility among Taiwanese aged over 70 years.     

白细胞介素-10启动子基因多态性与缺血性卒中相关性的Meta分析

目的 系统评价IL-10启动子基因（IL-10-1082A/G、IL-10-819T/C ）多态性与缺血性卒中（i s chemi c stroke,IS）发病风险的相关性。 方法 计算机检索Pubmed、Embase、Web of Science、万方数据库及中国知网数据库发表的有关IL-10启 动子基因多态性与IS发病风险相关性的研究,检索时限为从建库至2019年2月,由2名评价者按照纳入 与排除标准选择研究、提取资料。采用RevMan 5.3软件进行荟萃分析。 结果 共纳入13篇病例对照研究,其中12篇文献研究了IL-10-1082A/G 基因多态性与I S的易感性,6 篇文献研究了IL-10-819T/C 基因多态性与I S的易感性。结果显示,在总体人群中,IL-10-1082A/G基因多 态性与I S发病风险之间存在相关性（G vs A：OR 0.71,95%CI 0.59～0.86,P＜0.001;GG vs AA：OR 0.61, 95%CI 0.49～0.76,P＜0.001;AG vs AA：OR 0.72,95%CI 0.55～0.94,P =0.020;GG+AG vs AA：OR 0.68, 95%CI 0.53～0.87,P =0.002;GG vs AG+AA：OR 0.68,95%CI 0.52～0.89,P =0.005）;而IL-10-819T/C 基因多态性与IS发病风险无明显相关性（P＞0.05）。对中国人群进行亚组分析后,Meta分析结果与总 体人群一致。 结论 IL-10-1082A/G基因的多态性与IS风险显著相关,该基因是卒中易感基因;而IL-10-819T/C基因 多态性与IS的发病风险无明显关联。     

Meta-Analysis of Homogeneous Subgroups Reveals Association between PDE4D Gene Variants and Ischemic Stroke

Background: An Icelandic study showed a significant positive association between phosphodiesterase 4D (PDE4D) gene variants and stroke. However, subsequent studies reported conflicting results, possibly due to small sample sizes and the heterogeneity of the studies. Method: We performed a meta-analysis on 6 SNPs of the PDE4D gene to investigate the association between this gene and ischemic stroke by integrating the results of previous studies, comprising 11,834 cases and 15,233 controls. A pooled genotypic odds ratio (OR) for each SNP was determined under 3 genetic models (i.e. dominant, recessive, and codominant) using both fixed- and random-effects models with consideration for heterogeneity and publication bias across studies. Results: Among the SNPs included in this study, SNP56 (rs702553) showed the most significant association with ischemic stroke in a meta-analysis comprised of 7 homogenous studies. The overall OR of the TT genotype compared to the AA genotype was 1.29 (95% CI 1.03-1.61; p = 0.022). For SNP83 (rs966221), a protective effect of the ancestral allele T was observed only in Asian populations (ORTT 0.79, 95% CI 0.69-0.90; p = 0.0005). This meta-analysis revealed a significant association of PDE4D gene variants with the risk of ischemic stroke, and further investigations are warranted to evaluate possible ethnic-specific effects.     

PDE4D and ALOX5AP genetic variants and risk for Ischemic Cerebrovascular Disease in Sweden

BACKGROUND: Genetic variants in Phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP) have been shown to confer risk of Ischemic Cerebrovascular Disease (ICVD) in Iceland. We investigated whether these variants associate with ICVD in Sweden. METHODS: Previously published PDE4D and ALOX5AP gene variants were genotyped for cases (685) and controls (751). In PDE4D this consisted of SNP41, SNP45 and microsatellite AC008818-1 and in ALOX5AP four SNPs that define the HapA haplotype. RESULTS: The PDE4D SNPs, showed a non-significant risk in the ICVD group which increased for the Large Artery Atherosclerosis subtype (SNP45: RR=1.43, P=0.063, SNP41: RR=1.57, P=0.018). The SNP haplotype GA (SNP45, SNP41) showed an increased risk for LAA (RR=1.58, P=0.016) and the combined LAA and Cardioembolism (CE) (RR=1.34, P=0.031) subgroups. As the SNPs are in strong LD, this haplotype corresponds to the complement of the protective haplotype in the Icelandic study. No allele of the microsatellite marker, showed association to stroke or any subtype and nor did the Icelandic PDE4D at-risk haplotype (GA0). We did not confirm the association between ALOX5AP HapA haplotype and ICVD, but a non-significant risk was observed in the LAA subtype. CONCLUSION: Our PDE4D findings although non-significant considering the number of markers and phenotypes tested, are consistent with the association observed in the original study, with a trend observed in the whole ICVD group, which was strengthened in the stroke subtype LAA and the combined group of LAA and CE stroke. This supports the notion that PDE4D contributes to the risk of developing stroke.     

Interleukin-1A ?889C/T polymorphism and risk of Alzheimer’s disease: a meta-analysis based on 32 case–control studies

The Interleukin-1A (IL-1A) -889C/T polymorphism has been reported to be associated with Alzheimer's disease (AD) susceptibility, but the results of these previous studies have been inconsistent. The aim of this study was to explore whether the IL-1A -889C/T polymorphism confers susceptibility to AD. All studies published up to July 2011 on the association between the IL-1A -889C/T polymorphism and AD risk were identified by searching electronic databases PubMed, Embase and Alzgene. The association between the IL-1A -889C/T polymorphism and AD risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). A total of 32 case-control studies including 7,046 AD cases and 7,534 controls were eventually identified. Overall, positive associations of the IL-1A -889C/T polymorphism with AD risk were found in allele comparison T versus C (OR = 1.019, 95% CI= 1.027-1.198), recessive model TT versus CT + CC (OR = 1.278, 95% CI = 1.073-1.522) and dominant model TT + CT versus CC (OR = 1.102, 95% CI = 1.013-1.200). In subgroup analysis stratified by ethnicity, significant associations were demonstrated in Caucasians but not in Asians. In subgroup analysis according to the age of onset, no significant association was detected. The present meta-analysis suggests that the IL-1A is a candidate gene for AD susceptibility. The IL-1A -889C/T889C/T polymorphism may be a risk factor for AD in Caucasians. Further investigations taking the APOE ε4 status and other confirmed genetic factors and potential gene-gene and gene-environmental interactions into consideration for this polymorphism should be conducted.     

Genetic associations of fatigue and other symptom domains of the acute sickness response to infection

The acute sickness response to infection is a conserved set of changes in physiology and behaviour, featuring fever, fatigue, musculo-skeletal pain, disturbed mood, and cognitive difficulties. The manifestations differ somewhat between individuals, including those infected with pathogens which do not have genetic variability--suggesting host determinants. Principal components analysis (PCA) was applied to acute phase, self-report symptom data from subjects in the Dubbo Infection Outcomes Study (n=296) to empirically derive indices of fatigue, pain, neurocognitive difficulties, and mood disturbance, as well as overall illness severity. Associations were sought with functional single nucleotide polymorphisms (SNPs) in the cytokine genes, interleukin (IL)-6, tumour necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-10. The summed individual symptom indices correlated with overall severity and also with functional status. The relative contribution of individual symptom domains to the overall illness was stable over time within subjects, but varied between subjects with the same infection. The T allele of the IFN-γ +874 T/A SNP was associated with increased fatigue (p=0.0003; OR: 3.3). The C allele of the IL-10 -592 C/A SNP exerted a protective effect on neurocognitive difficulties (p=0.017; OR: 0.52); while the A allele for the IL-10 -592 SNP was associated with increased mood disturbance (p=0.044; OR: 1.83), as was the G allele of the IL-6 -174 G/C SNP (p=0.051; OR: 1.83). The acute sickness response has discrete symptom domains including fatigue, which have unique genetic associations. These data provide novel insights into the pathophysiology of fatigue states.     

Interleukin-10 is associated with resistance to febrile seizures: Genetic association and experimental animal studies

Purpose:   Febrile seizures (FS) are the most common form of childhood convulsions. Many reports have shown that a proinflammatory cytokine, interleukin-1 (IL-1) β, may have a facilitatory effect on the development of FS. We have previously shown that the IL1B -511C/T single nucleotide polymorphism (SNP) is associated with simple FS of sporadic occurrence. The balance between pro- and antiinflammatory cytokines influences the regulation of infections and could, therefore, play a role in the pathogenesis of FS. Here, to determine whether pro- and antiinflammatory cytokine genes are responsible for the susceptibility to FS, we have performed an association study on functional SNPs of cytokine genes in FS patients and controls.
Methods:   The promoter SNPs of four inflammatory cytokine genes ( IL6 -572C/G, IL8 -251A/T, IL10 -592A/C and TNFA -1037C/T) were examined in 249 patients with FS (186 simple and 63 complex FS) and 225 controls. Because the IL10 -592 SNP showed a positive association with FS, two additional SNPs ( IL10 -1082A/G and -819T/C) were subjected to haplotype analysis. Furthermore, we examined the in vivo role of IL-10 in hyperthermia-induced seizures using immature animal models.
Results:   The frequencies of the IL10 -592C allele and -1082A/-819C/-592C haplotype were significantly decreased in FS as compared with in controls (p = 0.014 and 0.013, respectively). The seizure threshold temperature in the IL-10–administered rats was significantly higher than that in the saline-treated control ones (p = 0.027).
Conclusions:   The present study suggests that IL-10 is genetically associated with FS and, contrary to IL-1β, confers resistance to FS.     

NOS2A基因启动子区基因多态性与缺血性脑卒中关系的研究

目的以SNPs为遗传标记,探讨NOS2A基因多态性与缺血性脑卒中的关系。方法以NOS2A启动子区-969G/C,-1173C/T的两个位点为遗传标记,通过对NOS2A基因启动子区进行全长测序以分析这两个位点的基因型。结果 -969G/C,-1173C/T不是中国北方汉族人的SNP位点,NOS2A-969C位点的等位基因均为T,NOS2A-1173C位点的等位基因均为G。我们在NOS2A基因启动子区检测到了rs2779248位点,关联分析表明rs2779248位点与缺血性脑卒中无相关性。结论 NOS2A基因启动子区与缺血性脑卒中的发病无明显相关。     

ALOX5AP和PDE4D基因与中国江苏南京地区腔隙性脑梗死发病的易感性：一项病例对照研究

The genes for 5-lipoxygenase activating protein (ALOX5AP) and phosphodiesterase 4D (PDE4D) have been demonstrated as susceptibility genes for lacunar in the Icelandic and Pakistani populations,but little is known about the role of these genes in Chinese populations.The present study utilized polymerase chain reaction and ligase detection reaction to detect single nucleotide polymorphisms (SNPs) in 280 consecutive stroke patients and 258 unrelated population-based controls from Nanjing,Jiangsu Province,China.The allele frequency,genotypes,and haplotypes of the two SNPs (rs456009 and rs966221) in PDE4D were similar between the two groups.However,A allele frequency of rs4073259 (A/G) and rs4769055 (A/C) in the ALOX5AP gene exhibited differences in two groups,and especially the haplotype of the SNP was significantly different between the two groups.Results suggested that the ALOX5AP gene might be involved in lacunar infarct,while PDE4D gene was not a risk factor for lacunar infarct in individuals from Jiangsu Province,China.     

白细胞介素-10启动子基因多态性与缺血性卒中相关性的Meta分析

目的 系统评价IL-10启动子基因（IL-10-1082A/G、IL-10-819T/C ）多态性与缺血性卒中（i s chemi c
stroke，IS）发病风险的相关性。
方法 计算机检索Pubmed、Embase、Web of Science、万方数据库及中国知网数据库发表的有关IL-10启
动子基因多态性与IS发病风险相关性的研究，检索时限为从建库至2019年2月，由2名评价者按照纳入
与排除标准选择研究、提取资料。采用RevMan 5.3软件进行荟萃分析。
结果 共纳入13篇病例对照研究，其中12篇文献研究了IL-10-1082A/G 基因多态性与I S的易感性，6
篇文献研究了IL-10-819T/C 基因多态性与I S的易感性。结果显示，在总体人群中，IL-10-1082A/G基因多
态性与I S发病风险之间存在相关性（G vs A：OR 0.71，95%CI 0.59～0.86，P＜0.001；GG vs AA：OR 0.61，
95%CI 0.49～0.76，P＜0.001；AG vs AA：OR 0.72，95%CI 0.55～0.94，P =0.020；GG+AG vs AA：OR 0.68，
95%CI 0.53～0.87，P =0.002；GG vs AG+AA：OR 0.68，95%CI 0.52～0.89，P =0.005）；而IL-10-819T/C
基因多态性与IS发病风险无明显相关性（P＞0.05）。对中国人群进行亚组分析后，Meta分析结果与总
体人群一致。
结论 IL-10-1082A/G基因的多态性与IS风险显著相关，该基因是卒中易感基因；而IL-10-819T/C基因
多态性与IS的发病风险无明显关联。     

Polymorphisms at the osteoprotegerin and interleukin-6 genes in relation to first-ever stroke

BACKGROUND: Arterial calcification and osteoporosis often coexist, especially in postmenopausal women. Osteoporosis associates with a substantially increased risk of stroke in elderly women, suggesting that impaired estrogen signaling may link stroke and osteoporosis. Osteoprotegerin (OPG, TNFRSF11B) and interleukin-6 (IL-6, IL6) are putative target genes for estrogen signaling and have been implicated in both cardiovascular diseases and osteoporosis. We hypothesized that specific polymorphisms in these genes may be associated with increased risk of ischemic stroke or intracerebral hemorrhage (ICH). METHODS: We performed a population-based prospective nested case-control study, in which the relationships between polymorphisms (OPG-1181G/C, OPG-950T/C and IL6-174G/C) and ischemic stroke and ICH were examined. Definitive first-ever stroke events (n = 388), i.e. ischemic stroke (n = 320), ICH (n = 61) and unspecified stroke (n = 7) cases, and controls without cardiovascular disease (n = 773), matched for age, sex and geographical region were studied. Univariate and multivariate models using conditional logistic regression, which included traditional risk factors, were used to test for association. RESULTS: Carriers of the OPG-1181C/C genotype had a significantly (p = 0.018) increased risk of ICH (OR, 2.69; 95% CI, 1.19-6.12) in the univariate analysis. After adjustments (hypertension, diabetes, BMI and triglycerides), this genotype remained significantly (p = 0.005) associated with ICH (OR, 6.04; 95% CI, 1.71-21.29). By contrast, no correlations were found between this genotype and ischemic stroke, nor between the OPG-950T/C or IL6-174G/C polymorphisms and stroke subtypes. CONCLUSIONS: In this population, the OPG-1181C/C genotype associates with first-ever ICH, implying that alterations in OPG-mediated signaling in the vasculature may be involved in the pathophysiology of this disease.     

Polymorphisms in the promoter region of the alpha1A-adrenoceptor gene are associated with schizophrenia/schizoaffective disorder in a Spanish isolate population.

BACKGROUND: Animal models have implicated the alpha(1)-adrenergic subtypes in cognitive functions relevant to schizophrenia, but no consensus exists with regard to the status of noradrenergic receptor populations in psychiatric patients. We focused on one alpha(1)-adrenergic subtype, the alpha(1A)-adrenergic receptor, and proposed that genetic variants within the regulatory region of this gene (ADRA1A) alter the expression of this receptor, influencing susceptibility toward schizophrenia. METHODS: This study examined this proposal by testing the hypothesis that single nucleotide polymorphisms (SNPs) in the promoter region of the alpha(1A)-adrenergic gene were associated with schizophrenia by performing case-control association analysis on SNPs found in a 5' upstream region, which included the putative promoter region and 5' untranslated region. Our sample consisted of 103 schizophrenia and 14 schizoaffective disorder patients and 176 control subjects. All recruits were from a Spanish population isolate of Basque origin that is characterized by low heterogeneity, which was selected with the intent that it might facilitate the identification of disease-related polymorphisms. RESULTS: A total of eight SNPs (-9625 G/A, -7255 A/G, -6274 C/T, -4884 A/G, -4155 C/G, -2760 A/C, -1873 G/A, and -563 C/T) were confirmed at a rare allele frequency of >5%. Association with schizophrenia and schizoaffective disorder was found for the -563 C/T SNP (p = .0005 for allele and p = .007 for genotype, Bonferroni corrected) and -9625 G/A SNP (p = .02 for allele and p = .03 for genotype, Bonferroni corrected). Significant differences in the 54 haplotypes formed by these eight SNPs were also found between patients and control subjects (p = .008, Bonferroni corrected). CONCLUSIONS: Because of the strength of these results and the location of these SNPs in the regulatory region of this gene, functional studies investigating the possible influence of these SNPs on receptor expression levels in schizophrenia are warranted.     

Association of phosphodiesterase 4D gene G0 haplotype and ischaemic stroke in a Greek population

We have examined the association of phosphodiesterase 4D ( PDE4D ) single nucleotide polymorphism (SNP45) and microsatellite marker AC008818-1 with ischaemic stroke, in an independent cohort of Greek patients and control individuals with no clinical manifestations of vascular disease. Significantly different distributions were observed with respect to the AC008818-1 alleles, with allele 148 associating with an increased risk of stroke incidence, and allele 144 with a protective effect. In addition, the haplotype defined by allele 148 and G allele of SNP45 was found to be significantly increased in patients even though no statistically significant differences emerged with respect to SNP45 alone. The previously established association of a PDE4D gene haplotype with ischaemic stroke in a population from Iceland was independently confirmed in our Greek population, suggesting that PDE4D may be involved in the aetiology and pathogenesis of stroke.     

Relationship of phosphodiesterase 4D (PDE4D) gene polymorphisms with risk of ischemic stroke: a hospital based case-control study

Background: Stroke remains a leading cause of death and disability worldwide. Ischemic stroke (IS) accounts for around 80–85% of total stroke and is a complex polygenic multi-factorial disorder which is affected by a complex combination of vascular, environmental, and genetic factors.

Objective: The study was conducted with an aim to examine the relationship of single nucleotide polymorphisms (SNPs) of PDE4D (T83C, C87T, and C45T) gene with increasing risk of IS in patients in North Indian population.

Methods: In this hospital-based case-control study, 250 IS subjects and 250 age-and sex-matched control subjects were enrolled from the Neurosciences Centre, A.I.I.M.S., New Delhi, India. Deoxyribonucleic acids (DNAs) were extracted using the conventional Phenol–Chloroform isolation method. Different genotypes were determined by Polymerase chain reaction– Restriction fragment length polymorphism method. Odds ratio (OR) and 95% Confidence Interval (CI) of relationship of polymorphisms with risk of IS were calculated by conditional multivariable regression analysis.

Results: High blood pressure, low socioeconomic status, dyslipidemia, diabetes, and family history of stroke were observed to be statistically significant risk factors for IS. Multivariable adjusted analysis demonstrated a statistically significant relationship between SNP 83 of PDE4D gene polymorphism and increasing odds of IS under the dominant model of inheritance (OR, 1.59; 95% CI, 1.02 to 2.50; p value = 0.04) after adjustment of potential confounding variables. Stratified analysis on the basis of TOAST classification demonstrated a statistically significant association for increasing 2.73 times odds for developing large vessel disease stroke as compared to controls (OR, 2.73; 95% CI, 1.16 to 0.02; p value = 0.02). We did not find any significant association of SNPs (C87T and C45T) of the PDE4D gene with the risk of IS.

Conclusion: SNP 83 of PDE4D gene may increase the risk for developing IS whereas SNP 87 and SNP45 of PDE4D may not be associated with the risk of IS in the North Indian population. Prospective cohort studies are required to corroborate these findings.     

C-reactive protein, interleukin-6 and tumor necrosis factor alpha as predictors of incident coronary and cardiovascular events and total mortality. A population-based, prospective study

Previous studies have shown an association between serum C-reactive protein (CRP) and cardiovascular disease (CVD) risk. The roles of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) are less well established. The aim of the present study was to analyze the associations of CRP, IL-6 and TNFalpha with incident coronary heart disease (CHD) events, CVD events, and total mortality. A random population sample, including men and women aged 25-64 years was examined in Finland in 1992. The sample size was 7,927 and 6,051 (76%) participated. The cohort was followed up until the end of 2001. During the follow-up, 151 incident CHD events, 205 CVD events and 183 deaths from any cause were observed. A stratified random subsample (n=313) was used as the comparison group. After adjustment for conventional CVD risk factors, CRP showed a significant association with CHD risk in men (HR=2.39, 1.08-5.28, comparing fourth quartile to the first quartile). This association remained significant after further adjustment for TNFalpha. TNFalpha also was a significant predictor of CHD among men, but the association was nonlinear (HR=2.21, 1.18-4.14 comparing the three upper quartiles to the first quartile). Further adjustment for CRP did not change this association substantially. Both CRP and TNFalpha predicted also all CVD events and total mortality among men. Among women the findings were nonsignificant. In conclusion, CRP and TNFalpha were significant, independent predictors of CHD and CVD events and total mortality among men. These findings provide further support to the important role of inflammation in the pathogenesis of CVD.     

The relationship between protein C, protein S and cytokines in acute ischemic stroke

OBJECTIVE: The role of inflammation in the pathogenesis of acute ischemic stroke is well known, but its association with the clinical picture is as yet unclear. MATERIAL AND METHODS: In our study, we measured the serum levels of the proinflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) within the first 50 h of stroke in 60 acute stroke patients, and examined the association with the natural anticoagulants protein C and free protein S. We compared the results with a control group that consisted of 30 volunteers. We also correlated their levels with the clinical outcomes by using the Canadian Neurological Scale (CNS). RESULTS: Neither stroke patients nor the control group had any elevations in IL-1beta serum levels. However, the levels of serum IL-6 were significantly higher in stroke patients (13.7 +/- 19.46 vs. 4.3 +/- 15.88, p = 0.002). In addition, the protein S levels of patients were lower than those of the controls (84.36 +/- 27.97 vs. 95.9 +/- 25.64, p = 0.007). Although IL-6 showed negative correlation with protein S (r = -0.504, p = 0.000), the other studied cytokines TNFalpha and IL-1beta did not correlate with these natural anticoagulants. Another negative correlation was found between IL-6 and CNS scores (r = -0.451, p = 0.000). In addition, both protein C and protein S positively correlated with CNS (r = 0.263, p = 0.042; r = 0.381, p = 0.003). There was also a positive correlation between protein C and protein S (r = 0.408, p = 0.001). CONCLUSIONS: Our results suggest that TNFalpha and IL1beta serum levels are not elevated in the acute phase of stroke and have no correlation with the natural anticoagulants protein C and protein S. However, a decrease in free protein S may be related to elevated IL-6 levels. In addition, increased levels of IL-6 and reduced levels of protein C and protein S may play a role in acute ischemic stroke severity.