Influence of polymorphisms in the factor VII gene promoter on activated factor VII levels and on the risk of myocardial infarction in advanced coronary atherosclerosis

In this study, we investigate the influence of three factor VII (FVII) gene polymorphisms on activated FVII levels (FVIIa), and also on the risk of myocardial infarction (MI) in patients with advanced coronary atherosclerotic disease (CAD). The -323A2 allele in the promoter is known to be associated with low FVII levels, and has been suggested to protect against MI in some studies. The -402GA promoter polymorphism, that in vitro has been associated with having opposite effect, is less well studied clinically. For this study, plasma FVIIa levels and three FVII gene polymorphisms were assessed in 934 subjects of both sexes, all with an angiographic documentation of coronary vessels. Our results show that two promoter polymorphisms, plasma cholesterol, and gender, were significant predictors of FVIIa levels. The -402A allele was associated to a significant increase of FVIIa levels in males (by 19.2%). In a selected clinical model including the patients with severe CAD, with or without a thrombotic complication (MI), male carriers of the -402A had an increased risk of MI (OR=1.79; 95% CI 1.15-2.80). The -323A2 allele was associated to a significant decrease in FVIIa (by 36.02% in males, and 39.7% in females). Male carriers of the -323A2 were protected from MI (OR=0.6; 95% CI 0.39-0.94), but only after correction for the confounding effect of combined heterozygosity for the promoter polymorphisms. We can conclude that FVII gene polymorphisms with an opposite effect on FVIIa levels may modulate the risk of MI in males with advanced CAD. This study highlights a "within-gene" interaction, and the need to explore polymorphisms in candidate gene(s) in detail.     

Influence of factor VII gene polymorphisms and environmental factors on plasma coagulation factor VII concentrations in middle-aged women with and without manifest coronary heart disease

Plasma concentrations of coagulation factorVII (FVII) are determined by environmental and genetic factors. The influence of functional polymorphisms in the FVII gene (-670A>C, -402G>A, -401G>T and R353Q) and of established cardiovascular risk factors on plasma concentrations of FVII were investigated in a representative sample of middle-aged women with (n=238) and without (n=220) coronary heart disease (CHD). Specific and sensitive assays were used to measure FVII antigen (VIIag) and activated factorVII (VIIa). The effect of genotypes was markedly stronger on VIIa than on VIIag, with the percentage variation in FVII levels accounted for by genotypes being greater in controls than in patients. Of the four polymorphisms examined, only the R353Q contributed to the variation inVIIa (24.1% in patients and 30.3% in controls). The -401G>T and -670A>C promoter polymorphisms together accounted for 12.2% of the variation in VIIag amongst patients whereas the -401G>T polymorphism alone contributed 19.7% of the variation in VIIag in controls. Serum triglycerides exerted a major influence onVIIag in both patients (13.0%) and controls (7.2%). Three main haplotypes emerged from the four polymorphisms which accounted for 98% of all haplotypes. Large-scale prospective studies of CHD including FVII haplotypes and sensitive and specific FVII measurements are needed in women.     

Polymorphic changes in the 5' flanking region of factor VII have a combined effect on promoter strength

Polymorphic differences in the 5' flanking region of the gene encoding procoagulant protein Factor VII (FVII) are associated with variations in FVII coagulant activity (FVII:C) and FVII antigen (FVII:Ag) levels. A decanucleotide insert polymorphism (CCTATATCCT) at 323 bp upstream of the start site of translation correlates with a decrease of approximately 20% FVII: C levels per allele containing this insert. However, linkage disequilibrium of the decanucleotide polymorphism with two single nucleotide polymorphisms (SNPs) at -122 and -401 have made it difficult to pinpoint the functional role, if any, of these genetic changes in lowering FVII levels. In vitro reporter gene studies in HepG2 cells analyzing the 8 possible combinations of polymorphic sites at -401, -323, and -122 reveal the necessity of the presence of the three concurrent polymorphic changes to maximally decrease promoter strength. In addition, these in vitro results are supported by in vivo studies in 89 individuals of African heritage, 34% of whom display a new haplotype that shows the polymorphic changes at -323 and -401 but lacks the change at -122.     

The -323Ins10 polymorphism for factor VII is not associated with coronary atherosclerosis in symptomatic men. The REGRESS study group

Elevated factor VII coagulant activity (FVII:C) has been associated with an increased risk of ischaemic heart disease, particularly for fatal events. Results of studies on the association between FVII:C and atherosclerosis are not consistent. FVII:C levels are influenced by several environmental factors and by genetic factors. One of the genetic factors is the -323Ins10 polymorphism in the promoter region of the factor VII gene, which is strongly related to FVII:C, and thus may be associated with ischaemic heart disease. We studied the association of this polymorphism with the severity and progression of atherosclerosis. In 511 male patients of the Regression Growth Evaluation Statin Study, the genotype for the -323Ins10 polymorphism was determined. The minimum obstruction diameter and the mean segment diameter were determined at baseline and after a 2-year follow-up period, and new lesion formation was assessed as well. Cardiovascular events were recorded. No relationship was observed between the -323Ins10 polymorphism and angiographic measures of disease progression, nor on the risk of new cardiovascular events. The results suggest that there is no association between the -323Ins10 polymorphism for factor VII and the severity or progression of coronary atherosclerosis in male patients with symptomatic coronary artery disease.     

Polymorphism in the sorbin and SH3-domain-containing-1 (SORBS1) gene and the risk of brain infarction in the Japanese population: the Fukuoka Stroke Registry and the Hisayama study

Background and purpose:  Sorbin and SH3-domain-containing-1 (SORBS1) is an important adaptor protein in insulin-signalling pathway, and its genetic polymorphism may regulate the activity of insulin resistance. We investigated the association between the SORBS1 T228A polymorphism and ischaemic stroke.
Methods:  Genotyping was achieved by a rapid-cycle PCR and melting curve analysis using fluorescent probes in 1049 incident cases of ischaemic stroke and 1049 age- and sex-matched control subjects recruited from the Hisayama study.
Results:  The allele distributions of the SORBS1 T228A polymorphism were similar amongst cases and controls. The multivariate-adjusted odds ratio (OR) of the AA genotype for ischaemic stroke was 2.897 (95% CI, 0.907–8.018) compared with the TT genotype. In terms of stroke subtype, there was a trend toward a difference in the AA genotypes for lacunar infarction, compared with the TT genotype (OR = 8.740, P  = 0.0510), and combined TT and TA genotypes (OR = 8.768, P  = 0.0505). The other polymorphisms genotyped were not associated with any subtypes of ischaemic stroke. T228A polymorphism of SORBS1 was not associated with the prevalence of diabetes.
Conclusions:  The AA genotype of SORBS1 T228A polymorphism may play a role in lacunar infarction in the Japanese population.     

Gene–gene interaction between 14-3-3 zeta and butyrylcholinesterase modulates Alzheimer's disease risk

A loss in the regulatory mechanism that controls tau phosphorylation in normal brain is suggested to cause tau hyperphosphorylation in Alzheimer's disease (AD) brain and the development of neurofibrillary tangles (NFT). 14-3-3 zeta protein and butyrylcholinesterase (BCHE) are associated with NFT in AD brain and stimulate tau phosphorylation. In a case–control study in 231 AD patients and 221 healthy controls, we examined whether the combined effects between 14-3-3 zeta (rs964917 and rs983583) and BCHE (K variant) polymorphisms might be responsible for susceptibility to AD. Subjects carrying both the BCHE K allele and the 14-3-3 zeta rs964917 G/G genotype (OR = 0.44, 95% CI = 0.20–0.95, P  = 0.03), or 14-3-3 zeta rs983583 G/G genotype (OR = 0.46, 95% CI = 0.21–1.00, P  = 0.05) had a lower risk of developing AD than subjects without these risk genotypes. Considering synergistic effects between polymorphisms in tau phosphorylation relate-genes may help in determining the risk profile for AD.     

Apolipoprotein H gene polymorphisms and risk of primary cerebral hemorrhage in a Chinese population

BACKGROUND AND PURPOSE: Apolipoprotein H (ApoH) has been implicated in several physiologic pathways including lipid metabolism, coagulation and the production of hypertension, which are related to the pathogenesis of primary cerebral hemorrhage (PICH). The gene coding for ApoH is polymorphic, with the occurrence of several common alleles in the general population. This genetically determined variation can effect lipid metabolism and the production of hypertension. We determined the distribution of ApoH gene polymorphisms in Chinese people and investigated whether these polymorphisms were associated with increased risk of PICH in a Chinese population. METHODS: We studied polymorphisms of the ApoH gene by the polymerase chain reaction-single strand conformation polymorphism technique and DNA sequencing in 140 PICH patients and 100 healthy control subjects. Serum antiphospholipid antibodies and lipid levels were also examined in all subjects. RESULTS: Four polymorphisms of the ApoH gene have been identified in Chinese people. No difference in genotype frequencies of G817T (Leu247Val) polymorphism, G1025C (Try316Ser) polymorphism and C1080T polymorphism was observed between PICH patients and control subjects (p > 0.05). The G341A (Ser88Asn) polymorphism correlated significantly with PICH. The frequencies of the A allele were significantly higher in PICH patients than in controls, especially in PICH patients with hypertension and a family history of stroke. CONCLUSIONS: Our results suggest that the G341A (Ser88Asn) polymorphism might be associated with increased risk of PICH in a Chinese population. The association appeared to be mediated by the generation of hypertension.     

DNA-polymorphisms and plasma levels of vascular disease risk factors in Greenland Inuit--is there a relation with the low risk of cardiovascular disease in the Inuit?

Greenland Inuit are a population with a low risk of cardiovascular disease. Recently, we stated that frequencies of potentially high risk alleles of the apolipoproteins, fibrinogen, factor V, glycoprotein IIIa and factor VII (FVII) genes have different allele frequencies in the Inuit when compared with Caucasian populations. We have extended this study and evaluated whether or not this was also true for the genetic polymorphisms of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), angiotensin-converting enzyme (ACE) and angiotensinogen in a group of 133 Greenland Inuit, aged 30-34 gamma. In addition, we compared the plasma levels of these factors and those of C-reactive protein (CRP) and D-Dimer in Inuit and in Danes, comparable for age and gender. Frequencies (f) were assessed of the alleles that are known as the potential high risk alleles in Caucasians. In the Inuit, the f(insertion allele) of the t-PA intron8ins311 polymorphism was 0.37 (CI 0.32-0.43), the f(4G allele) of the PAI-1 promoter polymorphism was 0.88 (CI 0.83-0.91), the f(deletion allele) of the ACE intron16ins287 polymorphism was 0.40 (CI 0.33-0.47) and the f(M-allele) of the angiotensinogen M/T353 polymorphism was 0.30(CI 0.25-0.38). As for fibrinogen and FVII polymorphisms, these frequencies are all significantly different from what is reported for Caucasian populations. In the Inuit, plasma levels of fibrinogen and D-Dimer were higher than in the Danes, the PAI-1 levels were lower and FVII, t-PA and CRP levels were comparable. The observed allele frequencies of the polymorphisms of t-PA, fibrinogen, FVII, ACE, angiotensinogen and the plasma levels of PAI-1 and D-Dimer were in accordance with the low CVD risk in the Inuit, considering the observed associations between these measures and CVD risk in Caucasian populations, but for other measures this was not the case (allele frequencies of the PAI-1 polymorphism, and plasma levels of fibrinogen, FVII and t-PA). In conclusion there are clear differences in genetic background and plasma levels of risk factors in Greenland Inuit compared with Caucasian populations, and these differences were sometimes, but not always, in accordance with the observed low cardiovascular disease risk of the Inuit population.     

Meta-analysis of genetic variability in the beta-amyloid production, aggregation and degradation metabolic pathways and the risk of Alzheimer's disease

Background –  Variants in genes encoding enzymes involved in production, aggregation or degradation of β-amyloid are potential risk factors for sporadic Alzheimer's disease (AD).
Methods –  Meta-analyses on AD association with BACE1 exon 5, BACE1 intron 5, FE65 intron 13, CYP46 intron 2, α₁-antichymotrypsine Ala17Thr, bleomycin hydrolase I443V, lectin-like oxidized low-density lipoprotein receptor (OLR1) 3'-UTR (+1071) and (+1073), and very-low-density lipoprotein receptor (VLDLR) 5'-UTR (CGG-repeat) polymorphisms.
Results –  In BACE1 exon 5, genotype CC+CT acts as a protective factor in Apolipoprotein E (ApoE) ε4 carriers [odds ratio (OR) = 0.57; 95% confidence interval (CI): 0.38–0.88], and as a risk factor in ApoE ε4 non-carriers (OR = 1.33; 95% CI: 1.00–1.78). OLR1 3'-UTR (+1073) allele C is associated with increased risk (OR = 1.23; 95% CI: 1.01–1.50). VLDLR 5'-UTR genotype 2 is associated with increased risk (OR = 1.70; 95% CI: 1.09–2.63) in the Asian population and is protective (OR = 0.48; 95% CI: 0.26–0.86) in the non-Asian population. Other studied polymorphisms are not associated with AD.
Conclusions –  The overall impact on AD risk of the genes for which meta-analyses are now available is rather limited. Additional meta-analyses of other different genes encoding for Aβ production, aggregation and degradation mediators might help in determining the risk profile for AD.     

Genetic association of BDNF val66met and GSK-3β-50T/C polymorphisms with tardive dyskinesia

Aims:  Neurodegenerative processes may be involved in the pathogenesis of tardive dyskinesia (TD), and a growing body of evidence suggests that brain-derived neurotrophic factor (BDNF) plays a role in both the antipsychotic effects and the pathogenesis of TD. BDNF and glycogen synthase kinase (GSK)-3β are important in neuronal survival, and thus abnormal regulation of BDNF and GSK-3β may contribute to TD pathophysiology. This study investigated the relationship between two polymorphisms, val66met in the BDNF coding region and -50T/C in the GSK-3β promoter, and susceptibility to TD among a matched sample of patients having schizophrenia with TD ( n  = 83), patients with schizophrenia without TD ( n  = 78), and normal control subjects ( n  = 93).
Methods:  All subjects were Korean. The BDNF val66met and GSK-3β-50T/C genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism analyses.
Results:  Polymerase chain reaction analysis revealed no significant difference in the occurrence of the polymorphisms among the TD, non-TD, and control subjects, but a significant interaction was observed among the groups possessing BDNF val allele in compound genotypes ( P  = 0.001). We found that the schizophrenic subjects with the C/C GSK-3β genotype, who carry the val allele of the BDNF gene, are expected to have a decreased risk of developing neuroleptic-induced tardive dyskinesia ( P  < 0.001).
Conclusions:  Our results demonstrate that the GSK-3β C/C genotype with the BDNF val allele is associated with patients having schizophrenia without TD. This study also suggests that the BDNF and GSK-3β gene polymorphisms work in combination, but not individually, in predisposing patients with schizophrenia to TD.     

Relevance of the genetic polymorphism of NOD1 in Chlamydia pneumoniae seropositive stroke patients

Background and purpose:  Chronic infections with certain pathogens, such as Chlamydia pneumoniae , and genetic parameters that influence inflammatory reactions have been suggested to contribute to ischaemic stroke. NOD1 is a potent cytosolic receptor for C. pneumoniae. The aim of this study was to investigate the genetic polymorphism of NOD1 from the aspect of the development of stroke.
Materials and methods:  A total of 280 patients with ischaemic stroke were enrolled in the study; 150 healthy blood donors served as controls. The G796A (E266K) NOD1 polymorphism was determined by restriction fragment length polymorphism. Chlamydia pneumoniae seropositivity was tested by ELISA.
Results:  There was a significant difference in NOD1 G796A genotype distribution between the controls and the stroke patients with C. pneumoniae seropositivity. The AA homozygote and GA heterozygote mutant variants were detected in 16% (25 of 152) and in 50% (77 of 152) of the C. pneumoniae- positive stroke patients, as compared with 8% (6 of 84), and 28% (24 of 84), respectively, in the C. pneumoniae- positive healthy controls. (OR = 2.559; 95% CI = 1.105–6.517, P  = 0.04 and OR = 2.567; 95% CI = 1.451–4.540 P  < 0.001, respectively). The stroke patients with the large vessel pathology exhibited the highest frequency of the mutant allele A (51%). In contrast, amongst the C. pneumoniae- negative subjects, no difference in genotype frequency was observed between the stroke patients and the controls.
Conclusion:  Polymorphism in NOD1 G796A alone did not prove to be a risk factor for stroke in general, but in association with C. pneumoniae infection it appeared to be accompanied by an increased risk of the development of stroke.     

The -141C Ins/Del and Taq1A polymorphism in the dopamine D2 receptor gene may confer susceptibility to schizophrenia in Asian populations

It has been reported that two single nucleotide polymorphisms (SNP) Taq1A and -141C Ins/Del in the DRD2 gene may be associated with susceptibility to schizophrenia. Due to inconclusive and mixed results, a meta-analysis was conducted to further clarify the relationship between the two SNP and schizophrenia susceptibility. A systematic literature search for the association of these two SNP with schizophrenia susceptibility was conducted using PubMed, ScienceDirect, Chinese Biomedical Literature Database, and Chinese National Knowledge Infrastructure. Odds ratios (OR) with 95% confidence intervals (CI) were used to assess the strength of the associations reported. A total of 5558 schizophrenic patients and 6792 healthy controls from 31 articles were included in this study. Evidence regarding the association between -141C Ins/Del polymorphism and schizophrenia was found in the allele frequency comparison (Ins versus Del: OR 1.29, 95% CI 1.06–1.57; p = 0.01, P_raw = 0.1, P_{False Discovery Rate} = 0.023). In ethnic subgroup analysis, the result revealed that the 141C Ins/Del polymorphism was associated with schizophrenia in all genetic models in Asians, but not in Caucasians. For Taq1A polymorphism, a significant association was found in the allele frequency (A1 versus A2: OR 0.71, 95% CI 0.52–0.98, p = 0.03). Stratification by ethnicity indicated an association between the Taq1A polymorphism and schizophrenia in Asians, but not Caucasians. The present study suggests that the -141C Ins/Del polymorphism carries a significantly increased risk of schizophrenia, while the Taq1A polymorphism carries a significantly decreased risk of schizophrenia susceptibility in Asians.     

Hormone replacement therapy and headache prevalence in postmenopausal women. The Head-HUNT study

Conflicting evidence exists whether hormone replacement therapy (HRT) is a risk factor for headache. The aim of the study was to examine the prevalence of headache and migraine amongst postmenopausal women using HRT. In the Nord-Trøndelag Health Study 1995–97 (HUNT 2), 18 323 (62%) out of 29 679 women aged 40 years or more responded to headache questions (Head-HUNT). Amongst the 6007 postmenopausal women, 5507 (92%) responded to questions regarding use of HRT (2375 used or had used it) and questions related to headache (2407 had complaints). There was a significant association between headache and present use of HRT, both with local [odds ratio (OR) = 1.4, 95% confidence intervals (CI) 1.1–1.7] and systemic (OR = 1.6, 95% CI 1.4–1.9) application. This was found for non-migrainous headache (OR = 1.3, 95% CI 1.1–1.5) and migraine (OR = 1.6, 95% CI 1.4–1.9). Both migraine and non-migrainous headache were more probably amongst users of postmenopausal HRT than amongst those who had never used HRT. Whether HRT caused headache or was used partly because of headache cannot be determined in this cross-sectional study.     

Polymorphism of the MDR1/ABCB1 C3435T drug-transporter and resistance to anticonvulsant drugs: A meta-analysis

Background:   Approximately one-third of patients with epilepsy patients have recurrent seizures despite therapy. It has been suggested that therapeutic failure is associated with high expression of the multidrug efflux ABCB1 (MDR1) drug-transporter; specifically, that patients with the 3435CC genotype have higher efflux of anticonvulsants out of brain tissue, with correspondingly lower concentrations in the central nervous system.
Methods:   We conducted a meta-analysis to examine the association between MDR1 polymorphisms and the response to anticonvulsants. We included all published studies until September 2007, in which patients with responsive and unresponsive seizure disorders underwent genotyping for ABCB1 C3435T. Individual and summary odds ratios were calculated using a random effects model. A secondary analysis was also performed, stratifying the studies by their ethnic distribution to account for genetic heterogeneity. We also performed a cumulative analysis by date of publication for the included studies using a random effects model.
Results:   We identified 11 case-control studies involving 3,371 patients (1,646 patients with drug-resistant epilepsy and 1,725 controls). We identified no significant association between anticonvulsant drug resistance and MDR1 polymorphism [odds ratio 1.15; 95% confidence interval (CI) 0.78–1.70; p = 0.48). Subanalysis of studies according to ethnicity yielded similar findings [European cohort: OR = 1.31; 95% CI 0.89–1.94, p = 0.18; Asian cohort: OR = 0.99; 95% CI 0.51–1.89, p = 0.96).
Conclusions:   We found no association between ABCB1 genotype and response to anticonvulsant drugs. At the present time, genetic typing for MDR1 polymorphism is not warranted for patients with drug-resistant epilepsy.     

Elevated factor VII as a risk factor for recurrent fetal loss. Relationship to factor VII gene polymorphisms

Haemostatic abnormalities can be detected in a portion of the women who have recurrent fetal loss. We measured factor VII coagulant activity (FVII:C) in 65 women with 3 or more fetal losses (recurrent cases), 31 women with one 2nd or 3rd trimester loss (late loss cases), and 81 women with only live births (controls). FVII:C was greater than 2 standard deviations above the mean for controls in 9 recurrent cases (13.8%) and 2 controls (2.5%) for an odds ratio of 6.35 (95% CI 1.32-30.52, p=0.012). In recurrent cases, mean levels were significantly higher than controls for FVII:C (p=0.003), FVII antigen (p=0.024), and FVIIa (p=0.001). Late loss cases had an odds ratio of 4.23 (95% CI 0.67-26.67, p=0.098) with FVII:C, FVII antigen, and FVIIa not significantly different from the controls. DNA was examined for the presence of mutations or polymorphisms in the promoter region of the FVII gene, using denaturing HPLC. Abnormal patterns were confirmed with direct sequencing. A previously reported polymorphism, -402 G>A, was found to be present in 11/14 subjects with elevated FVII:C (79%) and 43% of those with normal levels (p=0.029). FVII:C, FVII antigen and FVIIa varied significantly with genotype; however, genotype frequencies did not differ between controls and either case group. No other promoter polymorphisms were identified. This is the first report of a significant elevation of FVII in a population with recurrent fetal loss. These data suggest the need for further investigation of this potential risk factor.     

Emergency perception and other variables associated with extra-hospital delay in stroke patients in the Maresme region (Spain)

Delay in arrival to the emergency room (ER) may negatively influence outcome of stroke patients. We aim to analyze factors that influence extra-hospital delay in stroke patients. Two hundred and ninety-two consecutive stroke patients admitted in the ER were prospectively studied. Analysis was made to identify variables associated with <1- and <3 h delays from onset. About 18.8% of patients arrived before 1 h and 57.5% before 3 h. Factors independently associated with <3 h delay were decision to go immediately to ER (OR = 8.17; 95% IC = 4.47–18.8), ambulance transportation (OR = 2.35; 1.36–4.05) and total anterior circulation syndrome (TACS) (OR = 3.74; 1.51–9.24). History of >1 vascular risk factor was associated with a greater delay (OR = 0.47; 0.26–0.86). Factors associated with a <1 h delay were: (i) immediate decision to attend the ER (OR = 3.55; 1.85–6.81), (ii) stroke on Sunday (OR = 3.46; 1.56–7.66), (iii) aphasia (OR = 2.41; 1.23–4.74), (iv) absence of stairs at home (OR = 0.37; 0.17–0.81) and (v) absence of diabetes mellitus (OR = 0.42; 0.20–0.88). In our area, nearly 60% of stroke patients arrive to ER before 3 h from onset. Immediate decision to attend the ER has the strongest association with a short delay. Patients with TACS arrived mainly before 3 h and those with isolated aphasia arrived before 1 h. Patients with vascular risk factors attended the hospital later. Ambulance transportation is associated with <3 h delay, but not with <1 h.     

Effects of coagulation Factor VII polymorphisms on the coronary artery disease in Japanese: Factor VII polymorphism and coronary disease

We investigated the relationships among Factor VII coagulant activity (FVIIc), genetic polymorphisms of Factor VII (FVII) and coronary artery disease (CAD) in 380 unrelated Japanese individuals (mean 64 years) who underwent coronary angiography and whose cholesterol levels were within normal range. CAD subjects were defined as those in whom one of the three major coronary arteries showed >50% narrowing after nitroglycerin administration. FVIIc was measured and the following polymorphisms of FVII were determined: R353Q polymorphism (M1, M2 alleles), −323 0/10 bp polymorphism (0, 10 alleles), hypervariable region 4 of intron 7 (HVR4; H5, H6, H7 alleles). FVIIc was slightly lower in M1M2/M2M2 than M1M1 (89.5±8.9%, 93.4±17.8%). Those with M2 and/or 10 allele have less chance of developing CAD (M2: OR 0.36, 95% CI 0.18–0.69, 10: OR 0.50, 95% CI 0.26–0.97). However, both alleles did not associate with myocardial infarction (MI). HVR4 was unrelated with CAD, nor with MI. In conclusion, M2 and/or 10 allele has protective effects on the developing CAD in individuals with a normal cholesterol level.     

Acute ischemic stroke and transient ischemic attack in the very old – risk factor profile and stroke subtype between patients older than 80 years and patients aged less than 80 years

Old age groups have different risk profile and stroke features compared to younger groups. Our aim was to examine the risk factor profile and stroke subtype in patients older than 80 years with ischemic stroke. Data of 535 patients with ischemic stroke or transient ischemic attack (TIA) were prospectively recorded. Cardiovascular risk factors and stroke subtype in individuals aged 80 years or older were compared with patients under 80. Of 535 patients a total of 179 were over 80 years (33.5%). The mean age was 84.4 ± 4.4 years (61.8%; 111 women). The most common risk factors included hypertension (82.7%) and hyperlipidemia (40.2%). Lacunar stroke was the most frequent subtype of stroke (41.7%). When the groups were compared, we observed the following risk factors more frequently in the group older than 80: female patients ( P  = <0.001), hypertension (OR = 1.62), atrial fibrillation (OR = 2.64); whereas diabetes (OR = 0.54), hyperlipidemia (OR = 0.57), smoking (OR = 0.17) and obesity (OR = 0.58) were more frequent in the group younger than 80. In the old group we found a high incidence of ischemic stroke in women. We also found a higher frequency of hypertension and atrial fibrillation. The available and future epidemiological data will provide a better knowledge about the effect of typical risk factors in old people.     

Polymorphisms of APOE and LRP genes in Brazilian individuals with Alzheimer disease

Alzheimer disease (AD) is the most frequent cause of dementia in Western countries. Putative genetic risk factors for AD are polymorphisms in the apolipoprotein E (APOE) gene and in the low-density lipoprotein receptor-related protein (LRP) gene. Our objective was to investigate the role of the APOE coding region polymorphisms epsilon 2, epsilon 3, and epsilon 4 and APOE promoter variants A/T at position -491 and G/T at -219, as well as LRP polymorphism C/T, as risk factors for AD in Brazilian individuals. One hundred and twenty patients with probable AD, along with 120 controls were analyzed. A significant difference between patients and controls for epsilon 4 alleles was observed: frequency of this allele in AD was 0.31, and 0.10 in controls. Individuals with 2 epsilon 4 alleles had a higher risk for AD than subjects with only 1 such allele; presence of 1 epsilon 2 allele proved protective. The presence of the T allele of the -219 polymorphism was also associated with an increased risk of AD, but this polymorphism is in linkage disequilibrium with APOE epsilon polymorphisms. No significant differences between patients and controls were observed for -491 APOE or LRP polymorphisms. In this Brazilian population, both the epsilon 4 allele and T -219 polymorphism were associated with an increased risk for AD.     

Brain-derived neurotrophic factor (BDNF) genetic polymorphism greatly increases risk of leucine-rich repeat kinase 2 (LRRK2) for Parkinson's disease

Parkinson's disease (PD) is a complex neurodegenerative disorder. Although the p.G2385R allele of leucine-rich repeat kinase 2 (LRRK2) has been recently reported as a common genetic variant that increases the risk for typical PD exclusively among Asian population, its genetic modifiers is yet to be studied. Brain-derived neurotrophic factor (BDNF) has been shown to play an important role in the survival of dopaminergic neurons and its genetic polymorphism was associated with an increased risk for PD at an older age onset. The current case–control study was performed to investigate the interaction between LRRK2 p.G2385R and BDNF p.V66M in a Chinese PD cohort. A total of 464 PD patients and 549 controls were involved in this study. LRRK2 p.G2385R variant (odds ratio [OR] = 3.2; 95% confidence interval [CI] = 1.96–5.15, p < 0.0001), not BDNF p.V66M alone significantly increased the risk of PD. However, the simultaneous presence of both LRRK2 and BDNF variants significantly enhanced the risk for PD (OR = 4.033; 95% CI = 2.188–7.435, p < 0.0001), particularly in patients with an onset age of older than 60 (OR = 6.439; 95% CI = 3.096–13.389, p < 0.0001). Our results further support that LRRK2 variants are an independent genetic risk factor for typical PD, but BDNF variants can greatly increase LRRK2-induced risk for patients with an onset age of older than 60 indicating an additive effect between the 2 genes, which might aid in studying the mechanism underlying LRRK2 parkinsonism and developing potential therapeutic strategies.