亚甲基四氢叶酸还原酶基因rs4846049 G/T多态性与中国汉族人群缺血性卒中的相关性

目的：探讨亚甲基四氢叶酸还原酶(methylenetetrahydrofolatereductase, MTHFR)基因3'-非翻译区rs4846049 G/T多态性与中国汉族人群缺血性卒中发病风险的相关性。方法采用病例对照研究设计,选取396例缺血性卒中患者和378名健康体检者(对照组),病例组大动脉粥样硬化和小动脉闭塞型分别为268例和128例。采用聚合酶链反应-限制性片段长度多态性和直接测序法检测MTHFR 基因rs4846049 G/T多态性。结果以GG基因型为参照,TT基因型使缺血性卒中发病风险显著增高[优势比(odds ratio, OR)2．87,95%可信区间(confidence interval, CI)1．43~5．76;P=0．003];与G 等位基因比较,T 等位基因使发病风险显著增高( OR 1．62,95% CI 1．28~2．06;P<0．001)。亚组分析显示, rs4846049 G/T 多态性可显著增高 LAA 和 SAO 亚型卒中的发病风险(P均<0．05)。结论 MTHFR基因rs4846049 G/T多态性可能与中国汉族人群缺血性卒中易感性增高有关,T等位基因可能是中国汉族人群缺血性卒中的遗传危险因素。     

The association of PAI-1 promoter 4G/5G insertion/deletion polymorphism with myocardial infarction and stroke in young women

BACKGROUND: The plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G insertion/deletion polymorphism has been associated with increased risk of myocardial infarction (MI) and decreased risk of cerebrovascular events. Whether these results apply to young women is not known. METHODS: We genotyped 78 MI cases, 106 stroke cases and 385 age-matched controls from a population-based case-control study of MI and stroke in women < 45 years old. RESULTS: The risk of MI was significantly decreased in carriers of the 4G allele compared with 5G/5G homozygotes, and the association persisted upon adjustment for other risk factors (age- and race-adjusted OR 0.50, 95% CI 0.29-0.85). Carrying the 4G allele was not associated with stroke, either overall or according to subtype. The association of this polymorphism with MI or stroke did not vary significantly by presence or absence of established cardiovascular risk factors, assessed on either an additive or multiplicative scale. CONCLUSIONS: These data suggest a decreased risk of MI among young women carrying the 4G allele of the PAI-1 4G/5G polymorphism. Although this result contrasts with those of previous studies of older adults and young men, it may highlight the influence of genetic factors on the development of MI within the context of particular hormonal or environmental influences.     

Association Between Plasminogen Activator Inhibitor-1-675 4G/5G Insertion/Deletion Polymorphism and Chronic Obstructive Pulmonary Disease

Molecular pathology of chronic obstructive pulmonary disease (COPD) is still being investigated to discover relationships with disease pathogenesis. Evidence of plasminogen activator inhibitor-1 (PAI-1) overexpression in the sputum and the blood of COPD patients is growing. We aimed to investigate the potential relation between PAI-1 promoter 4G/5G insertion/deletion polymorphism and COPD development. In a case-control study, we genotyped 117 COPD patients and 160 control subjects for PAI-1 promoter 4G/5G polymorphism by an allele-specific polymerase chain reaction analysis. All subjects were male smokers. In the co-dominant model, there was a significant difference in the distribution of 5G/5G, 4G/5G and 4G/4G genotypes between COPD patients and controls (p = 0.002). In the recessive model, carriers of 4G/4G genotype were significantly higher in COPD patients than controls (p = 0.01). Carriers of 4G/4G genotype were at higher risk to develop COPD than those carrying 5G/5G or 4G/5G genotypes (crude odds ratio (OR) = 2.10, 95% confidence interval (CI) = 1.19–3.73, adjusted OR = 2.5, 95% CI = 1.22–3.99). In conclusion, PAI-1 4G/5G genetic variations are associated with COPD development in males.     

Lack of association between plasminogen activator inhibitor type-1 (PAI-1) gene 4G/5G polymorphism and osteoarthritis

This study was conducted in Turkish osteoarthritis patients to determine the frequency of 4G/5G polymorphism genotypes of plasminogen activator inhibitor type-1 gene and to examine the role of this polymorphism in osteoarthritis development. Genomic DNA obtained from 200 persons (140 patients with osteoarthritis and 60 healthy controls) was used in the study. DNA was amplified by polymerase chain reaction using 4G allele- and 5G allele-specific primers. Polymerase chain reaction products were assessed with CCD camera by being exposed to 2% agarose gel electrophoresis. No statistically significant difference between the groups with respect to genotype distribution was found (P > 0.05) in the study. The 4G allele frequency was indicated as 44% and 5G allele was as 56% in patients, whereas this was 45–55% in the control group. This study has established that 4G/5G polymorphism genotypes of plasminogen activator inhibitor type-1 gene do not play a role in the development of osteoarthritis in the Turkish population.     

Coagulation factor XIII gene variation, oral contraceptives, and risk of ischemic stroke

Prothrombotic conditions are associated with ischemic stroke in young women. In particular, the combination of oral contraceptive use and prothrombotic genetic variants appears to increase the risk of ischemic stroke. We performed a population-based case-control study in 190 women aged 20 to 49 years with ischemic stroke and 767 women without cardiovascular disease stratified for age, calendar year of the index event, and residence. A total of 4 variants of coagulation factor XIII subunit A and B genes (F13A1 and F13B) were investigated. The Phe allele of the F13A1 Tyr204Phe variant was present in 59 (31%) patients and 43 (6%) controls; the odds ratio for ischemic stroke was 9.1 for Phe/Phe and Phe/Tyr versus Tyr/Tyr genotype; the 95% confidence interval was 5.5 to 15. Homozygous genotypes (Phe/Phe) conferred a higher risk (odds ratio, 77; 95% confidence interval, 7.0-848) than heterozygous (Tyr/Phe) genotypes (odds ratio, 8.2; 95% confidence interval, 4.9-14). The risk of ischemic stroke was further increased in carriers of the 204Phe allele using oral contraceptives (odds ratio, 20; 95% confidence interval, 9-46) compared with nonusers with Tyr/Tyr genotype. In conclusion, the F13A1 204Phe allele was strongly associated with ischemic stroke in young women. Oral contraceptive use further increased the risk of ischemic stroke.     

807C/T polymorphism in the platelet glycoprotein Ia gene in young patients with ischemic stroke of undetermined etiology.

Platelet membrane glycoprotein receptors mediate key reactions in arterial thrombosis. The relationship between glycoprotein Ia polymorphisms and the risk of ischemic stroke, however, remains controversial. A matched case-control study was conducted to evaluate this question in young patients. Seventy patients with ischemic stroke of undetermined etiology, with ages ranging from 15 to 50 years, and 70 healthy control individuals, matched by age, gender and ethnicity, were tested for the 807C/T genotypes. Patients were excluded if they had systemic diseases known to predispose to thrombosis or any defined etiology of ischemic stroke. The frequencies of the 807T glycoprotein Ia variant and of conventional risk factors for arterial thrombosis (hypertension, smoking, diabetes mellitus, use of oral contraceptives, levels of serum cholesterol and body mass index) were compared in stroke patients and control individuals. The 807T allele was found in 61% of patients and 53% of control individuals (matched-pair odds ratio, 1.38; 95% confidence interval, 0.69-2.74; P = 0.42). Arterial hypertension and smoking were more frequent in patients than control individuals (matched-pair odds ratio, 2.83; 95% confidence interval, 1.05-8.02; P = 0.04; and odds ratio, 3.20; 95% confidence interval, 1.10-9.97, P = 0.03, respectively). In conclusion, our results do not support an independent association between the 807C/T polymorphism and stroke of undetermined etiology. The interplay of this polymorphism with arterial hypertension in the causation of ischemic stroke requires further evaluation.     

The 4G/5G polymorphism of the type 1 plasminogen activator inhibitor gene and thrombosis in patients with antiphospholipid syndrome

OBJECTIVE: To investigate the relationship between the 4G/5G polymorphism of the type 1 plasminogen activator inhibitor (PAI-1) gene and thrombotic manifestations in patients with antiphospholipid syndrome (APS). METHODS: We studied a total of 247 patients included in the following 4 groups: 70 patients with primary APS, 104 patients with systemic lupus erythematosus (40 with antiphospholipid antibodies [aPL] and clinical [secondary] APS, 13 with aPL but without clinical APS, and 51 with neither detectable aPL nor a history of thrombosis), 14 asymptomatic individuals with aPL, and 59 patients with thrombosis but without known thrombosis risk factors. A control group of 100 healthy individuals was also analyzed. PAI-1 4G/5G polymorphism was determined by polymerase chain reaction and endonuclease digestion. RESULTS: The allele frequency of 4G/5G in controls was 0.47/0.53. There were no differences in allele distribution among patient groups or between patients and controls. However, a higher frequency of the 4G allele was observed in APS patients with versus those without thrombosis (0.57 versus 0.39; P < 0.05) (odds ratio [OR] 2.83, 95% confidence interval [95% CI] 1.18-6.76). This higher frequency of the 4G allele was attributable to the higher frequency in patients with versus those without arterial thrombosis (0.64 versus 0.43; P < 0.01) (OR 5.96, 95% CI 1.67-21.32), while patients with venous thrombosis had an allele distribution similar to that of those without venous thrombosis (0.49 versus 0.50; P not significant). There was a trend toward higher PAI-1 antigen and activity levels in APS patients and controls with the 4G/4G genotype, but this did not reach statistical significance. CONCLUSION: The presence of the 4G allele of the 4G/5G polymorphism of the PAI-1 gene may be an additional risk factor for the development of arterial thrombosis in APS.     

The 4G5G polymorphism in the gene for PAI-1 and the circadian oscillation of plasma PAI-1

Plasminogen activator inhibitor type I (PAI-1) antigen concentrations follow a circadian oscillation peaking in the morning. Some individuals show no apparent circadian rhythm, while others show up to a 10-fold variation in PAI-1 over 24 hours. Results from experimental studies suggest that a polymorphism in the promoter of the gene for PAI-1 (4G5G) directly influences the circadian expression of the PAI-1 gene. We studied whether the diurnal variation of PAI-1 antigen differs for the genotypes of the 4G5G polymorphism. A population-based, cross-sectional study was performed among 263 subjects selected from the Rotterdam Study, a population-based cohort of 7983 men and women aged 55 years and older. The 4G allele was associated with a more pronounced circadian expression of PAI-1 antigen. Morning PAI-1 antigen concentrations were 79 ng/mL (95% confidence interval [CI], 68-92) in subjects homozygous for 4G, 62 ng/mL (95% CI, 54-72) in heterozygous subjects, and 59 ng/mL (95% CI, 49-71) in subjects homozygous for 5G. While respective PAI-1 antigen concentrations in the afternoon were 40 ng/mL (95% CI, 33-49), 41 ng/mL (95% CI, 37-47), and 40 ng/mL (95% CI, 49-71). These findings suggest that the morning increase in PAI-1 antigen concentration is more pronounced among subjects homozygous for the 4G allele compared with the morning increase among the other genotypes. Additionally, these findings show that homozygosity for the 4G allele is associated with increased PAI-1 levels during the morning only.     

The plasminogen activator inhibitor (PAI)-1 promoter 4G/4G genotype is not associated with ischemic stroke in a population of German children. Childhood Stroke Study Group

OBJECTIVES: To investigate the relationship between an insertion/deletion (4G/5G) polymorphism of the plasminogen activator inhibitor (PAI)-1 gene and childhood patients with a past history of ischemic stroke. METHODS: The PAI-1 4G/4G genotype and the coinheritance with lipoprotein (Lp) (a) levels, the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, and the methylene-tetrahydrofolate reductase (MTHFR) T677T genotype were studied in 198 Caucasian children with stroke and 951 controls (same age, sex and ethnical distribution). In a randomly selected subgroup of patients/controls (n=60) PAI-I activities have been investigated. RESULTS: The distribution of the 4G/5G genotypes was no different in childhood stroke patients and controls, with a 4G allele frequency of 55.8% in patients compared with 53.8% in control subjects (P=0.49). The 4G/4G genotype compared with the remaining genotypes was present in 43 cases and 167 (17.6% vs. 21.7%; OR/CI: 1.30/0.89-1.98; P=0.3). PAI-1 activity was significantly elevated (P < 0.001) in the patient group. CONCLUSIONS: Data presented here suggest that the 4G/4G genotype is not a major risk factor in the aetiology of childhood ischemic stroke.     

Reduced carriership of 4G allele of plasminogen activator inhibitor-1 4G/5G polymorphism in very young survivors of myocardial infarction

There are limited and controversial data regarding the impact of 4G/5G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene in the pathogenesis of premature myocardial infarction (MI). We explored whether 4G/5G polymorphism of the PAI-1 gene is associated with the development of MI ≤ 35 years of age. We recruited 201 consecutive patients who had survived their first acute MI ≤ 35 years of age (mean age = 32.2 ± 3.4 years). The control group consisted of 140 healthy individuals matched with cases for age and sex, without a family history of premature coronary heart disease. 4G/5G polymorphism of PAI-1 was tested with polymerase chain reaction and reverse hybridization. 4G allele carriers (4G/4G and 4G/5G genotypes) of PAI-1 were less frequent in patients than in controls (69.6 vs. 83.6%, P = 0.007). 4G carriership of the polymorphism of PAI-1 was associated with lower risk for acute MI (odds ratio 0.45, 95% confidence interval 0.23–0.88, P = 0.02) after adjusting for major cardiovascular risk factors. Patients possessing the 4G allele had higher PAI-1 plasma levels (32.2 ± 25 vs. 22.2 ± 11.3 ng/ml, P = 0.006) but lower lipoprotein(a) levels (10.1 [2.1–29.9] vs. 15.3 [8.2–57.1] mg/dl, P = 0.03) compared to 5G/5G homozygotes. Our data indicate that the 4G allele of the PAI-1 4G/5G polymorphism is less frequent among survivors of MI at very young age compared with matched controls.     

Genotype combinations of plasminogen activator inhibitor-1 and angiotensin-converting enzyme genes and risk for early onset of coronary heart disease.

BACKGROUND: Both angiotensin-converting enzyme genotype and plasminogen activator inhibitor type 1 genotype have an effect on fibrinolytic components and hence, may increase risk or advance occurrence of coronary heart disease. We examined the association of the angiotensin-converting enzyme and the plasminogen activator inhibitor type 1 genotypes, and their combinations, with early onset of coronary heart disease in a cohort of 907 patients with coronary heart disease. DESIGN AND METHODS: All patients with a coronary heart disease (International Classification of Diseases, 9th Rev. pos. 410-414), aged 30-70 years and participating in an inpatient rehabilitation program between January 1999 and May 2000 in two clinical centres in Germany were enrolled. The plasminogen activator inhibitor type 1 and the angiotensin-converting enzyme genotypes were determined by polymerase chain reaction, and the distribution was compared between patients with early (< or =55 years) and late (>55 years) onset of coronary heart disease. A multivariate analysis was employed to adjust for potentially confounding factors. RESULTS: Of the 907 included patients, 408 (45.0%) developed coronary heart disease before the age of 55 years. For the 4G/4G genotype of plasminogen activator inhibitor type 1 the odds ratio for early onset of coronary heart disease was 1.68 [95% confidence interval (CI) 1.01-2.57] and for the D/D genotype of angiotensin-converting enzyme the odds ratio was 1.22 (95% CI 0.84-1.76) after adjustment for covariates. In multivariate analysis an odds ratio of 3.10 (95% CI 1.51-6.36) was found for the association between the combined homozygosity for both polymorphisms (plasminogen activator inhibitor type 1 genotype 4G/4G and angiotensin-converting enzyme genotype D/D) and onset of coronary heart disease before the age of 55 years after controlling for sex, age, smoking, diabetes, hypertension, hyperlipidemia and school education. CONCLUSION: The co-existence of the 4G/5G polymorphism of the plasminogen activator inhibitor type 1 gene and the I/D polymorphism of the angiotensin-converting enzyme gene increases the risk for early onset of coronary heart disease in this population.     

Effect of the angiotensin-converting enzyme gene deletion polymorphism on the risk of venous thromboembolism

Allele frequencies for the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene were determined in a large case-control study of 517 unselected patients with venous thromboembolism and 478 blood donors. The D allele frequency was 0. 53 [95% confidence interval (CI) 0.50-0.56] in patients and 0.54 (95% CI 0.50-0.57) in controls, giving an odds ratio for the D allele of 0.97 (95% CI 0.81-1.16). In the same population, the odds ratio for the factor V Leiden mutation (F5G1691A) was 6.9 (95% CI 4. 0-11.9). Therefore, the ACE I/D polymorphism is not a risk factor in a representative group of unselected patients with venous thromboembolism. The possibility that the I/D polymorphism is a risk factor for venous thromboembolism specifically after hip replacement cannot be excluded.     

The Kozak sequence polymorphism of platelet glycoprotein Ibalpha and risk of nonfatal myocardial infarction and nonfatal stroke in young women

Several platelet membrane glycoprotein polymorphisms have been identified as potential risk factors for cardiovascular disease. Recently a nucleotide -5T/C dimorphism in the translation initiation site (Kozak sequence) of the platelet glycoprotein Ibalpha (GPIbalpha) gene was associated with increased platelet surface levels of the GPIb-IX-V receptor complex. The role of this GPIbalpha Kozak sequence polymorphism in the occurrence of arterial thrombotic disease is unknown. We performed genotype analysis of the Kozak sequence polymorphism of GPIbalpha in a population-based study of 18- to 44-year-old women with nonfatal myocardial infarction (MI) (n = 78), nonfatal stroke (n = 106), and 384 demographically similar female control subjects. Analysis of -5T/C genotypes revealed that at least one copy of the C allele was present in 14.1% of MI cases, 23.6% of stroke cases, and 23.7% of controls. The age-adjusted odds ratio for MI in women carrying at least one copy of the C allele was 0.53 (95% confidence interval [CI] 0.27-1.05). The age-adjusted odds ratio for stroke in women carrying at least one copy of the C allele was 0.99 (95% CI 0.59-1.65). Analyses stratified by stroke type (ischemic, hemorrhagic) yielded similar results. In conclusion, young women carrying the C allele of the Kozak sequence polymorphism of GPIbalpha are not at increased risk of MI or stroke. Paradoxically, the C allele may even be associated with a reduced risk of MI in this population. This finding requires further study.     

The A -844G polymorphism in the PAI-1 gene is associated with a higher risk of venous thrombosis in factor V Leiden carriers

Identification of combined genetic factors in factor V Leiden carriers is important for a more accurate risk assessment for venous thrombosis (VT). Among these individuals, we evaluated the role of polymorphisms of the plasminogen activator inhibitor-1 (PAI-1) gene in the thrombophilic phenotype. A total of 382 factor V Leiden carriers were included in the study. This population was divided into 3 groups. Group 1 (n=168) included individuals with a personal history of VT; group 2 (n=140) included individuals without personal VT but with a familial history of VT; and group 3 (n=74) included individuals without VT and with a fortuitous discovery of the factor V Leiden mutation. We compared the genotype distribution of 2 polymorphisms, A -844G and -675 4G/5G, located in the promoter region of the PAI-1 gene among these 3 groups of individuals. The A -844G allele frequency differed significantly among the 3 groups (P=0.048), the A allele being more frequent in patients who suffered from VT (61%) than in subjects without VT (52%, P=0.015), whereas no difference was observed between the 2 groups of asymptomatic individuals. The prevalence of genotype AA carriers was higher in patients with VT (38%) than in asymptomatic individuals (21%, P=0. 015), leading to an odds ratio of 1.74 (95% confidence interval, 1.3 to 3.8). Carrying the AA genotype conferred a risk of deep VT of 2. 08 (95% confidence interval, 1.28 to 3.40), whereas it did not seem to significantly influence the risk of pulmonary embolism. Concerning the -675 4G/5G polymorphism, no significant difference was observed among the 3 groups, the 4G allele frequency being 0.54 (in group 1), 0.49 (in group 2), and 0.45 (in group 3). These data suggest a role for the -A844G PAI-1 gene polymorphism in the thrombophilic phenotype of factor V Leiden carriers.     

The association of endothelial nitric oxide synthase G894T polymorphism with C-reactive protein level and metabolic syndrome in a Chinese study group

Some studies have reported a possible relationship between endothelial nitric oxide synthase (eNOS) and metabolic syndrome (MS), which is associated with an increased risk for cardiovascular disease. A recent meta-analysis study found the eNOS G894T polymorphism to be associated with ischemic heart disease. Here, we examine the association of eNOS G894T polymorphism with MS in a Chinese population (n = 397). The eNOS T+ (TT and GT) genotypes (56.92% vs 38.86%; odds ratio, 2.08; 95% confidence interval, 1.21-3.56; P = .007) and T allele (33.08% vs 23.34%; odds ratio, 1.62; 95% confidence interval, 1.08-2.44; P = .019) were significantly more frequent in subjects who had MS. Furthermore, subjects with eNOS T+ genotypes had significantly higher plasma C-reactive protein levels as compared with GG subjects (P = .004). This study shows that, in a Chinese population, eNOS G894T polymorphism is associated with an elevated C-reactive protein level and MS.     

The COX-2 G/C -765 polymorphism may modulate the occurrence of cerebrovascular ischemia.

In the atherosclerotic plaque, cyclooxygenase-2 (COX-2) catalyzes prostaglandin E formation, which acts as a pro-atherogenic factor. A polymorphism, G/C -765, within the COX-2 promoter region modulates gene expression and the risk of cerebrovascular disease. We have evaluated the relation between COX-2 G/C -765 genotypes and the occurrence of cerebrovascular ischemia. We evaluated the COX-2 G/C -765 polymorphism in 110 consecutive patients with a documented history of acute ischemic cerebrovascular disease, in 110 age-matched and sex-matched subjects without such history, and in a general population (n = 324) from the same ethnical background. The frequency of the COX-2 -765C allele in patients [0.21; 95% confidence interval (CI), 0.16-0.26] was similar to those found in controls (0.28; 95% CI, 0.22-0.34) and in the general population (0.26; 95% CI, 0.23-0.29). Carriers of the CC genotype differed between patients (0.02; 95% CI, 0.00-0.05) and controls [0.10 (95% CI, 0.04-0.16), P = 0.019; odds ratio, 0.17 (95% CI, 0.04-0.79)] or the general population [0.08 (95% CI, 0.05-0.11), P = 0.023; odds ratio, 0.22 (95% CI, 0.05-0.95)]. In a multiple logistic regression analysis adjusted for confounding variables, smoking status (P < 0.001), atrial fibrillation (P = 0.004) and COX-2 G/C-765 polymorphism (P = 0.016) independently contributed to cerebrovascular ischemia, with CC carriers exhibiting a lower risk (odds ratio, 0.07; 95% CI, 0.01-0.61). Our data show an association between the COX-2 G/C-765 gene polymorphism and cerebrovascular ischemia, suggesting that the COX-2 gene is a susceptibility locus for the risk of cerebrovascular ischemic disease.     

Association of platelet-derived growth factor-D gene polymorphism with ischemic stroke in a Chinese case-control study

Stroke is a multiple genetic disease. Platelet-derived growth factor-D has been found to be involved in the pathogenesis of atherosclerosis, suggesting possible association between platelet-derived growth factor-D and the development of ischemic stroke. However, little information on the relationship between platelet-derived growth factor-D and stroke is currently available. The aim of this study was to investigate the association between platelet-derived growth factor-D genetic variation and the risk of ischemic stroke in a Chinese population. We conducted a case-control study with 309 ischemic stroke patients and 309 sex and age (<5 years)-matched controls. DNA was extracted from the whole blood of each participant. Platelet-derived growth factor-D C/G polymorphism at position +3166 (rs7950273) was detected by TaqMan SNP genotyping assay. Overall, the combined rates of platelet-derived growth factor- D CG and GG are 51% in patients in contrast with 46% in controls. There were no significant differences in the genotype frequencies of platelet-derived growth factor-D +3166 polymorphisms between the patients and controls with history or family history of hypertension or diabetes (P = 0.770). However, among people without history or family history of hypertension or diabetes, platelet-derived growth factor-D CG/GG is significantly more frequently expressed in patients (60%) than in controls (43%) (odds ratio 1.97; 95% confidence interval 1.19-3.26). This significant association holds after adjustment for age, sex, smoking and alcohol intaking (odds ratio 1.86; 95% confidence interval 1.11-3.10) (P = 0.018). Our study found that the G allele of rs7950273 of the platelet-derived growth factor-D gene is associated with higher risk of ischemic stroke in a Chinese population without history or family history of hypertension or diabetes. Future studies with larger and ethnically diverse populations are needed to further evaluate the platelet-derived growth factor-D polymorphism and stroke association, as well as its pathophysiological mechanisms.     

Cholesterol ester transfer protein, interleukin-8, peroxisome proliferator activator receptor alpha, and Toll-like receptor 4 genetic variations and risk of incident nonfatal myocardial infarction and ischemic stroke

Variations in candidate genes participating in oxidative stress, inflammation, and their interactions are potentially associated with diseases of atherosclerotic origin. We investigated independent and joint associations of variations in cholesterol ester transfer protein (CETP), interleukin-8 (IL8), peroxisome proliferator activator receptor-alpha (PPARA), and Toll-like receptor 4 (TLR4) genes with incident nonfatal myocardial infarction (MI) or ischemic stroke. In a population-based case-control study, patients (848 with MI and 368 with ischemic stroke) and controls (2,682) were recruited from postmenopausal women and hypertensive men/women who were members of Group Health in western Washington State. Common tag single-nucleotide polymorphisms (SNPs; n=34) representing gene-wide variations were selected from gene sequencing data using pairwise linkage disequilibrium. Haplotypes were inferred using a modified expectation maximization algorithm. Multivariate logistic regression evaluated individual haplotype and SNP-disease associations in log-additive models. Global haplotype tests assessed overall gene-disease associations. Logic regression was used to evaluate gene-gene interactions. False discovery rates and permutation tests were used for multiple testing adjustment in evaluating independent associations and interactions, respectively. Overall, gene-wide variations in PPARA and TLR4 genes were associated with MI. The minor allele of the PPARA SNP, rs4253623, was associated with a higher risk of MI (odds ratio 1.25, 95% confidence interval 1.08 to 1.46), whereas the minor allele of the TLR4 SNP, rs1927911, was associated with a lower risk of MI (odds ratio 0.88, 95% confidence interval 0.77 to 0.99). No within-gene or gene-gene interaction was associated with MI or ischemic stroke risk. In conclusion, potential SNP-disease associations identified in the present study are novel and need further investigation.     

Analysis of -675 4 g/5 G SERPINE1 and C-159T CD14 polymorphisms in house dust mite-allergic asthma patients

BACKGROUND: Experimental studies indicate that endogenous plasminogen activator inhibitor-1 (PAI-1, encoded by the gene SERPINE1) modulates the immune response to lipopolysaccharide (LPS). On the other hand, LPS induces PAI-1 secretion. Activation of individual cells by LPS is facilitated by CD14. The single nucleotide polymorphisms -675 4G/5G in SERPINE1 and C-159T in CD14 are major determinants of PAI-1 and CD14 expression, respectively. OBJECTIVE: To evaluate the frequency of the -675 4G/5G SERPINE1 and C-159T CD14 polymorphisms in house dust mite (HDM) allergic asthma patients. METHODS: The polymorphisms were evaluated in unrelated inhabitants of northeastern Poland, including 372 HDM-allergic asthmatic patients and 160 healthy nonatopic control subjects using polymerase chain reaction. RESULTS: Both the C allele of CD14 and the 4G allele of SERPINE1 were more frequently encountered in HDM-allergic asthmatic patients than in healthy control individuals. When the 5G/5G-TT/CT genotype was considered as a nonrisk genotype, all other genotypes were associated with asthma. The odds ratios ranged from 3.96 (95% confidence interval, 1.56-10.1) for the 5G/5G-CC genotype to 10.7 (95% confidence interval, 5.1-24.9) for the 4G/4G-CC genotype. Bronchial reactivity to histamine and total serum immunoglobulin (Ig) E levels were predominantly associated with the 4G/5G SERPINE1 variants, while bronchial reactivity to Dermatophagoides pteronyssinus and serum concentrations of specific IgE against D pteronyssinus were predominantly associated with the C/T CD14 variants. Patients with 4G/4G-CC genotype had the lowest forced expiratory volume in 1 second and the highest bronchial reactivity. CONCLUSION: The SERPINE1 and CD14 polymorphisms studied here are associated with different aspects of bronchial reactivity and IgE response. Our results indicate that PAl-1 and CD14 may interact to affect susceptibility to allergic asthma.