0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Neurological Review |

Meta-analysis of Genetic Studies in Ischemic Stroke:  Thirty-two Genes Involving Approximately 18 000 Cases and 58 000 Controls FREE

Juan P. Casas, MD; Aroon D. Hingorani, MRCP, PhD; Leonelo E. Bautista, MD, MPH, DrPh; Pankaj Sharma, MD, PhD
[+] Author Affiliations

Author Affiliations: Centre for Clinical Pharmacology, British Heart Foundation Laboratories at University College London, London, England (Drs Casas and Hingorani); Department of Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, Bethesda, Md (Dr Bautista); and Hammersmith Hospitals Acute Stroke Unit and Department of Cellular and Molecular Neuroscience, Imperial College, University of London (Dr Sharma).


Section Editor: David E. Pleasure, MD

More Author Information
Arch Neurol. 2004;61(11):1652-1661. doi:10.1001/archneur.61.11.1652.
Text Size: A A A
Published online

Ischemic stroke is thought to have a polygenic basis, but identification of stroke susceptibility genes and quantification of associated risks have been hampered by conflicting results from underpowered case-control studies. We performed a meta-analysis of all candidate gene association studies in ischemic stroke. Electronic databases were searched up until January 2003 for all case-control and nested case–control studies in English-language journals relating to the investigation of any candidate gene for ischemic stroke in humans. Cases were required to have neuroimaging evidence of the diagnosis. To maintain genetic homogeneity, only studies in white adults were included. Studies that evaluated quantitative traits or intermediate phenotypes were excluded. Data from 120 case-control studies were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) from random- and fixed-effects models were calculated. Of 32 genes studied, 15 polymorphisms were identified for which at least 3 studies had been conducted. Statistically significant associations with ischemic stroke were identified for factor V Leiden Arg506Gln (OR, 1.33; 95% CI, 1.12-1.58), methylenetetrahydrofolate reductase C677T (OR, 1.24; 95% CI, 1.08-1.42), prothrombin G20210A (OR, 1.44; 95% CI, 1.11-1.86), and angiotensin-converting enzyme insertion/deletion (OR, 1.21; 95% CI, 1.08-1.35). These were also the most investigated candidate genes, including 4588, 3387, 3028, and 2990 cases, respectively. No statistically significant association with ischemic stroke was detected for the 3 next most investigated genes (factor XIII, apolipoprotein E, and human platelet antigen type 1). There is a genetic component to common stroke. No single gene with major effect was identified; rather, common variants in several genes, each exerting a modest effect, contribute to the risk of stroke. These findings have important implications for the design of future genetic studies and for predictive genetic testing for stroke and other multifactorial diseases.

Figures in this Article

According to the World Health Organization, stroke is the third most common cause of death in developed countries.1 In the United States there are more than 700 000 incident strokes annually and 4.4 million stroke survivors every year.2 The economic burden of stroke has been estimated to be $51.2 billion annually.3 Because treatments for stroke are limited, the best approach to reducing the burden of disease is primary prevention through modification of acquired risk factors (diabetes mellitus, smoking, high blood pressure, and atrial fibrillation),4 particularly in persons at elevated risk. Stroke cases cluster in families,5 and there is a nearly 5-fold difference in stroke prevalence among monozygotic vs dizygotic twins.6 Epidemiologic studies suggest a polygenic basis for stroke,79 and the favored model for the pathogenesis of stroke is an interaction between genetic and acquired risk factors.10

In theory, identification of stroke susceptibility genes might enhance prediction of disease risk. However, the lack of reproducibility of genetic case-control studies has led to uncertainty about the nature and number of genes contributing to stroke risk. There is concern, on one hand, that positive associations might be spurious and, on the other hand, that the negative findings from some studies might be a consequence of inadequate statistical power.

With a case-control design, sample sizes of thousands are required to have adequate power to detect genes of small to moderate effect whose allele frequencies range from 5% to 10%. Few individual studies conducted to date have been of this size. By using all available published data to increase statistical power, meta-analysis might allow plausible candidate genes to be excluded, causative genes to be identified with reliability, and genetic risks to be quantified with more precision. Therefore, we undertook a comprehensive meta-analysis of all genetic case-control studies in ischemic stroke to date.

DATA SOURCES

Electronic databases (MEDLINE, EMBASE, and BIDS [Bath Information and Data Services]) were searched up until January 2003 for all case-control studies evaluating any candidate gene and stroke in humans. Letters and abstracts were included in the meta-analysis. The Medical Subject Headings terms and text words used for the search were cerebrovascular disease, stroke, brain infarction, and cerebral ischemia in combination with genetic, polymorphism(s), mutation,genotype, or genes. The search results were limited to human. All languages were searched initially, but only English-language articles were selected. The references of all computer-identified publications were searched for any additional studies, and the MEDLINE option related articles was used for all the relevant articles. In addition, a search to identify previous genetic meta-analyses in stroke was also performed.

STUDY SELECTION

Studies were selected if neuroimaging (magnetic resonance imaging or computed tomography) had been used to confirm the diagnosis of ischemic stroke, and, to maintain homogeneity of genetic background, only studies of white patients were included. Studies were excluded if (1) the patients were children (aged <18 years), (2) quantitative traits or intermediate phenotypes were being investigated, or (3) genotype frequency was not reported. For duplicate publications, the smaller data set was discarded.

DATA EXTRACTION

The primary search generated 155 potentially relevant articles, of which 120 met the inclusion criteria. Data for analysis were extracted independently and entered into separate databases by 2 of us (J.P.C. and P.S.). The results were compared, and disagreements were resolved by consensus.

STATISTICAL ANALYSIS

Data were analyzed using software for preparing and maintaining Cochrane reviews (Review Manager, version 4.1; Cochrane Collaboration, Syracuse, NY) and statistical analysis software (Stata 8.0; Stata Corp, College Station, Tex). For each genetic marker (polymorphism) for which data were available for at least 3 studies, a meta-analysis was carried out. For each gene variant, a pooled odds ratio (OR) was calculated using fixed- and random-effects models, along with the 95% confidence interval (CI) to measure the strength ofthe genetic association. Fixed-effects summary ORs were calculated using the Mantel-Haenszel method,11,12 and the DerSimonian and Laird method was used to calculate random-effects summary ORs.13

Tests for heterogeneity were performed for each meta-analysis (with significance set at P < .05).14 For assessment of publication bias, we used the funnel plot and the Egger regression asymmetry test.15 In addition, the effect of individual studies on the summary OR was evaluated by reestimating and plotting the summary OR in the absence of each study.

The proportion of stroke cases in the population that could be attributed to a particular genetic variant (population-attributable risk [PAR]) was estimated as follows:

PAR = 100 × [Prevalence (OR − 1)/Prevalence (OR − 1) + 1].

For this calculation, we used the fixed-effects model, and we estimated the prevalence of exposure as the genotype frequency among control subjects.

DATA SYNTHESIS

One hundred twenty candidate gene case-control studies in which the presence or absence of stroke was analyzed in a dichotomous manner were identified. In total, 51 polymorphisms in 32 genes were identified. Of these, data were available from at least 3 studies for 15 polymorphisms in 13 genes. For another 6 polymorphisms, 2 studies per genetic marker were identified, and, in the case of 30 polymorphisms, only 1 study per genetic marker was identified that met the selection criteria. From the 15 polymorphisms analyzed in detail (representing 18 123 cases and 57 579 controls), the mean number of studies per candidate gene was 9 (95% CI, 4.3-12.8). Eight (53%) of the 15 meta-analyses had more than 1000 cases, and 7 (47%) had at least 1 study with a total sample size greater than 1000 (Table).

Table Graphic Jump LocationTable. Candidate Genes and Ischemic Stroke

The Table shows the genotypic ORs for the 15 polymorphisms evaluated. Of those candidate genes with statistically significant associations, the summary ORs varied from 1.21 (95% CI, 1.08-1.35) for angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism to 1.88 (95% CI, 1.28-2.76) for the polymorphism of the glycoprotein Ib-α (GPIBA) Kozak sequence (Table).

The factor V Leiden mutation has been by far the most investigated, with 26 studies1641 that included 4588 cases and 13 798 controls. Carriers of the factor V Gln506 allele were 1.33 times more likely to develop stroke (95% CI, 1.12-1.58; P = .001) (Table and Figure 1). However, significant interstudy OR heterogeneity was observed (χ2 = 39.78; P for heterogeneity [PHet] = .03). A sensitivity analysis revealed that the study by Margaglione et al30 was mainly responsible for the heterogeneity observed. After excluding this study from the analysis, the heterogeneity was no longer significant (χ2 = 18.87; PHet = .76), but the OR was attenuated and of marginal significance (OR, 1.18; 95% CI, 0.98-1.42; P = .08). Nevertheless, a random-effects model that takes into account the intrastudy and interstudy variability resulted in a similar overall estimate (OR, 1.31; 95% CI, 1.02-1.68; P = .03), although the 95% CIs are wide, leading to some uncertainty about the size of the effect. The distribution of the OR in relation to its standard deviation in the funnel plot was symmetrical, and the Egger test result was not significant (P = .89), suggesting a low probability of publication bias.

Place holder to copy figure label and caption
Figure 1.

Results of published studies of the association between the factor V Leiden mutation and ischemic stroke. Odds ratios for the outcome compared carriers of the Gln506 allele vs wild type (Arg/Arg). CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location

A total of 22 studies20,2830,34,38,40,4256 (3387 cases and 4597 controls) were identified that evaluated the polymorphism in the gene encoding methylenetetrahydrofolate reductase where cytosine is replaced by thymidine at base position 677 of the gene (MTHRF C677T). A summary OR, under the fixed-effects model, of 1.24 (95% CI, 1.08-1.42; P = .002) was observed for individuals homozygous for the T allele compared with C allele carriers (C/T plus C/C) (Figure 2). The funnel plot distribution was symmetrical and the Egger test was not significant (P = .08), indicating a low probability of publication bias. No significant interstudy heterogeneity was observed (χ2 = 25.64; PHet = .22), and no individual study had an undue effect on the summary OR.

Place holder to copy figure label and caption
Figure 2.

Results of published studies of the association between the methylenetetrahydrofolate reductase C677T polymorphism and ischemic stroke. Odds ratios for the outcome compared individuals homozygous for the T allele (T/T) with those heterozygous individuals (C/T) plus wild type (C/C). CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location

The prothrombin G20210A mutation was evaluated in 19 studies,17,20,22,23,26,2830,32,34,38,40,5763 with a total of 3028 cases and 7131 controls. The summary OR under a fixed-effects model showed that carriers of the mutation were 1.44 times more likely to develop stroke (95% CI, 1.11-1.86; P = .006) (Figure 3). No significant interstudy heterogeneity was observed (χ2 = 10.59; PHet = .91). The distribution of theORs from individual studies in relation to their respective standard deviations (funnel plot) was symmetrical, and the Egger test result suggested a low probability of publication bias (P = .13). Again, no individual study had an undue effect on the summary OR.

Place holder to copy figure label and caption
Figure 3.

Results of published studies of the association between the prothrombin G20210A polymorphism and ischemic stroke. Odds ratios for the outcome compared carriers of the A allele with those with wild type (G/G). CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location

The ACE I/D polymorphism was evaluated in 11 studies38,6473 (2990 cases and 11 305 controls), and a summary OR of 1.21 (95% CI, 1.08-1.35; P<.001), under a fixed-effects model, was observed for individuals homozygous for the D allele compared with heterozygous (D/I) and homozygous (I/I) individuals combined (Figure 4). The funnel plot showed a symmetrical distribution of the OR in relation to its standard deviation, and the Egger test result did not suggest the presence of publication bias (P = .22). No significant interstudy heterogeneity was observed (χ2 = 9.71; PHet = .47), and as for MTHFR C677T and prothrombin G20210A, no individual study had an undue effect on the summary OR.

Place holder to copy figure label and caption
Figure 4.

Results of published studies of the association between the ACE I/D polymorphism and ischemic stroke. Odds ratios for the outcome compared individuals homozygous for the D allele with those with the heterozygous (D/I) plus wild type (I/I). CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location

The PARs for the 4 positive and most investigated candidates—ACE I/D, MTHFR C677T, factor V Leiden, and prothrombin G20210A—following the models of inheritance shown in the Table were 4.54%, 3.31%, 2.16%, and 1.30%, respectively.

Other genetic markers associated with an increase in the risk of stroke but for which the data set was much smaller were glycoprotein Ib-α Thr→Met or human platelet antigen (HPA) type 2 (HPA2) (4 studies88,91,102,104 with 564 cases; OR, 1.55; 95% CI, 1.14-2.11; P = .006), and plasminogen activator inhibitor 1 (PAI1) promoter 4G/5G I/D (4 studies74,99101 with 842 cases; OR, 1.47; 95% CI, 1.13-1.92; P = .004), with no evidence for heterogeneity in either meta-analysis. Meta-analysis of studies of GPIBA Kozak sequence was positive (3 studies102,107,108 with 350 cases; OR, 1.88; 95% CI, 1.28-2.76; P = .001) (Table), but studies were highly heterogeneous.

Of the remaining 8 polymorphisms studied, no significant associations were observed for 3 genes with large data sets: apolipoprotein E ε4, ε3, ε2 (10 studies50,56,8087 and 1805 cases; OR, 0.96; 95% CI, 0.84-1.11; P = .60) (Figure 5), factor XIII Val→Leu (6 studies7479 with 2166 cases; OR, 0.97; 95% CI, 0.75-1.25; P = .80) (Figure 6), and glycoprotein IIIa Leu33Pro or HPA1 (9 studies23,8895 with 1467 cases; OR, 1.11; 95% CI, 0.95-1.28; P = .20) (Figure 7) polymorphisms (Table). Five of the remaining negative meta-analyses each had a small sample size (endothelial nitric oxide synthase [eNOS] Glu298Asp, 1086 cases; GPIBA variable number tandem repeat [VNTR], 816 cases; glycoprotein IIb Ile→Ser, 770 cases; factor VII A1/A2, 545 cases; and lipoprotein lipase [LPL] Asn291Ser, 452 cases). Overall, these 8 negative meta-analyses included fewer cases than the 7 meta-analyses in which significant associations were detected (mean number of cases: 1138 [95% CI, 621-1655] vs 2250 [95% CI, 723-3776]; P value for difference = .046).

Place holder to copy figure label and caption
Figure 5.

Results of published studies of the association between the apolipoprotein E polymorphism and ischemic stroke. Odds ratios for the outcome compared carriers of the ε4 allele with those with the ε3 and ε2 alleles. CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 6.

Results of published studies of the association between the factor XIII polymorphism and ischemic stroke. Odds ratios for the outcome compared individuals homozygous for the Leu34 allele (Leu/Leu) with those with the heterozygous (Val/Leu) plus wild type (Val/Val). CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 7.

Results of published studies of the association between the glycoprotein IIIa polymorphism and ischemic stroke. Odds ratios for the outcome compared individuals homozygous for the Pro allele with those with the heterozygous (Leu/Pro) plus wild type (Leu/Leu). CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location

In this comprehensive meta-analysis, 7 (47%) of the 15 candidate polymorphisms analyzed significantly increased the risk of stroke among individuals of European ancestry. In 4 of these meta-analyses (ACE I/D, factor V Leiden, MTHFR C677T, and prothrombin G20210A), the mean number of cases included per gene was more than 3000, allowing more precise estimates to be made of the effect of these genes than from any single study. However, the individual risk provided by any one of these candidate genes was moderate (OR, 1.21-1.44). This is in agreement with previous studies112114 in other complex diseases, such as ischemic heart disease.

Most candidate genes assessed in stroke thus far have been evaluated initially for their potential role in ischemic heart disease. Therefore, up to now, most genetic studies (73% of the meta-analyses described in this article) have focused on genes involved in thrombosis and coagulation, whereas genes regulating other well-established risk factors for stroke (eg, hypertension, diabetes mellitus, and hyperlipidemia) have received relatively limited attention. Thus, it is possible that several additional genes with similar risks may exist but have yet to be evaluated.

For the genes with positive associations and large data sets, mechanistic studies have indicated the processes by which risk alleles might alter the expression or activity of the encoded protein and contribute to disease pathogenesis. The factor V Leiden mutation causes activated protein C resistance.115 Activated protein C limits clot formation by proteolytic inactivation of factors Va and VIIIa, and the single point mutation in the gene for factor V (1691G→A) studied predicts replacement of arginine by glycine at position 506 in the activated protein C cleavage site. After activation, the mutated factor V is less efficiently degraded by activated protein C than normal factor V, resulting in increased thrombin generation and a hypercoagulable state, which may explain the increased risk of stroke in carriers of this mutation observed in this study.116 A sequence variation in the 3′-untranslated region of the prothrombin gene (G20210A), which alters messenger RNA stability, is associated with elevated prothrombin levels117,118 and thrombin formation117 and may similarly lead to a procoagulant state.

Plasma and intracellular levels of ACE have been shown to be partly determined by the presence of the ACE I/D polymorphism in healthy individuals and in patients with stroke.119,120 Individuals homozygous for the D allele have a 56% increase in ACE activity compared with I allele homozygotes.121 Angiotensin-converting enzyme converts angiotensin I to angiotensin II, which is known to be involved in vascular hypertrophy, vasoconstriction, and atherosclerotic processes.122 Also, ACE is responsible for degradation of bradykinin, a vasoactive peptide that has been suggested to stimulate vasodilator nitric oxide production.122

Long-term differences of 5 μmol/L in the serum concentration of homocysteine are associated with a 59% increase in the risk of stroke.112 The C677T mutation in the MTHFR gene, which encodes an amino acid substitution (A222V), renders the enzyme thermolabile and reduces metabolism of homocysteine.123 A recent meta-analysis124 in coronary heart disease showed that, on average, patients homozygous for the T allele had a 2.2-μmol/L higher serum level of homocysteine than patients with the C/C genotype and have a 1.16-fold increased risk of developing coronary heart disease. Findings from the present meta-analysis suggest that this variant is associated with a similar increase in the risk of stroke.

Taken together, the evidence from these meta-analyses, the molecular studies, and the effects of these genes on other cardiovascular phenotypes supports a role for variants in factor V, prothrombin, MTHFR, and ACE genes in susceptibility to stroke, but verification will be required from larger studies.

The PARs for these polymorphisms ranged from 1.30% for prothrombin G20210A to 4.54% for ACE I/D, values that are far lower than those reported for well-established acquired risk factors for ischemic stroke (eg, hypertension, smoking, and diabetes mellitus).4 This low level of PAR is not surprising, because the genetic contribution of any single gene toward a complex disease is unlikely to act in a simple mendelian fashion but rather with epistatic (gene-gene or gene-environmental interaction) effects. Nevertheless, given the high incidence of stroke, if these estimates are correct, they suggest that variants in 4 common genes may contribute to 9000 to 32 000 strokes in the United States each year.

Meta-analyses of 3 gene variants—apolipoprotein E ε4, ε3, ε2 (1805 cases), factor XIII Val→Leu (2166 cases), and glycoprotein IIIa Leu33Pro (1467 cases)—has so far failed to provide evidence of increased stroke susceptibility. The sample sizes of these meta-analyses allowed exclusion of ORs as low as 1.14, 1.20, and 1.35, respectively, with 80% power at P = .05. It seems unlikely, therefore, that carriers of the apolipoprotein E ε4 allele, which affects serum cholesterol, and which has been associated with a moderate increase in the risk of coronary heart disease,114 are at a substantially higher risk of stroke. Of the remaining 8 meta-analyses with relatively small data sets, 3 (PAI14G/5G [842 cases], HPA2 Thr→Met [564 cases], and GPIBA Kozak sequence [350 cases]) identified significant associations. However, additional larger studies are required to confirm or refute these findings.

The interpretation of any meta-analysis must be made within the context of its limitations, including study selection, publication bias, and variability in the methodological quality of the included studies. The present meta-analyses were restricted to studies published in the English language, but our overall computer search identified only a few non-English studies.125129 Although publication bias cannot be excluded, this is an unlikely explanation for our findings. Many of the individual studies included in our meta-analysis were not statistically significant and were interpreted by their authors as negative studies. In addition, the Egger asymmetry test and the funnel plot showed no substantialevidence of publication bias in the 7 largest (N>3000) meta-analyses (ACE I/D; factor V Leiden; MTHFR C677T; prothrombin G20210A; apolipoprotein E ε4, ε3, ε2; factor XIII Val→Leu; and glycoprotein IIIa Leu33Pro). Moreover, rigorous selection criteria (neuroimaging and ethnic homogeneity) enriched the meta-analyses for studies with comparable selection of participants. Thus, lack of specificity, by the inclusion of individuals with hemorrhagic stroke or those with a clinical diagnosis of stroke but without neuroimaging evidence, was avoided.

Although it is not possible to exclude the future identification of 1 or more genes with a more substantial effect on stroke risk, our findings suggest that several genes, each with a small to moderate effect, are likely to act individually, together, or in combination with environmental determinants to cause stroke. One implication of these findings is that predictive genetic tests that use any single variant are unlikely individually to have much value. However, tests that combine genotyping for 1 or more risk alleles and that integrate the results with established risk prediction tools based on acquired risk factors (eg, the Framingham risk equation) may have greater utility.130 Another important consequence for future research is that very large case-control studies with several thousand participants will be required to detect new risk alleles with small to moderate effects of the size identified in our review, and to confirm or refute our findings. Because recruitment of data sets of this size may be difficult for a single medical center, a complementary approach has been suggested that involves the recruitment and genotyping of fewer patients and controls from many centers according to uniform criteria and submission of the data (whether nominally positive or negative) to a common Web-based repository for online, continuously updated and cumulative meta-analysis,131 which reduces the potential for publication bias.

In summary, our study confirms the existence of a genetic cause for common stroke but with no single common “stroke gene” exerting a major effect. Instead, several stroke susceptibility alleles are likely to act individually, together, or in combination with environmental determinants to cause stroke. 

Correspondence: Pankaj Sharma, MD, PhD, Hammersmith Hospitals Acute Stroke Unit, Imperial College, Fulham Palace Road, London W6 8RF, England (psharma@hgmp.mrc.ac.uk).

Accepted for Publication: March 23, 2004.

Author Contributions:Study concept and design: Casas, Hingorani, and Sharma. Acquisition of data: Casas, Hingorani, and Sharma. Analysis and interpretation of data: Casas, Hingorani, Bautista, and Sharma. Drafting of the manuscript: Casas, Hingorani, Bautista, and Sharma. Critical revision of the manuscript for important intellectual content: Hingorani, Bautista, and Sharma. Statistical analysis: Casas, Hingorani, Bautista, and Sharma. Obtained funding: Hingorani and Sharma. Administrative, technical, and material support: Hingorani and Sharma. Study supervision: Sharma.

Funding/Support: Dr Hingorani holds a Senior Fellowship from the British Heart Foundation, London.

World Health Organization The World Health Report 2002: Reducing Risks, Promoting Healthy Life.  Geneva, Switzerland: World Health Organization; 2002
National Heart, Lung, and Blood Institute Morbidity & Mortality: 2002 Chartbook on Cardiovascular, Lung, and Blood Diseases.  Bethesda, Md: National Institutes of Health; 2002
American Heart Association Economic cost of cardiovascular diseases.  Available at: http://www.americanheart.org/statistics/10econom.html. Accessed June 15, 2003
Goldstein  LBAdams  RBecker  K  et al.  Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation 2001;103163- 182
PubMed
Hrubec  ZRobinette  CD The study of human twins in medical research. N Engl J Med 1984;310435- 441
PubMed
Brass  LMIsaacsohn  JLMerikangas  KR  et al.  A study of twins and stroke. Stroke 1992;23221- 223
PubMed
Rubattu  SVolpe  MKreutz  RGanten  UGanten  DLindpaintner  K Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. Nat Genet 1996;13429- 434
PubMed
Kiely  DKWolf  PACupples  LA  et al.  Familial aggregation of stroke: the Framingham Study. Stroke 1993;241366- 1371
PubMed
Sharma  P Genes for ischaemic stroke: strategies for their detection. J Hypertens 1996;14277- 285
PubMed
Liao  DMyers  RHunt  S  et al.  Familial history of stroke and stroke risk: the Family Heart Study. Stroke 1997;281908- 1912
PubMed
Mantel  NHaenszel  W Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22719- 748
PubMed
Robins  JGreenland  SBreslow  NE A general estimator of the variance of the Mantel-Haenszel odds ratio. Am J Epidemiol 1986;124719- 723
PubMed
DerSimonian  RLaird  NM Meta-analysis in clinical trials. Control Clin Trials 1986;7177- 188
PubMed
Deeks  JJAltman  DGBradburn  MJ Statistical methods for examining heterogeneity and combining results from several studies in a meta-analysis.  In: Egger  M, Davey  Smith G, Altman  DG, eds. Systematic Reviews in Health Care: Meta-analysis in Context. Annapolis Junction, Md: BMJ Publishing Group; 2001
Egger  MDavey Smith  GSchneider  M  et al.  Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315629- 634
Albucher  JFGuiraud-Chaumeil  BChollet  FCadroy  YSie  P Frequency of resistance to activated protein C due to factor V mutation in young patients with ischemic stroke. Stroke 1996;27766- 767
PubMed
Bentolila  SRipoll  LDrouet  LMazoyer  EWoimant  F Thrombophilia due to 20210 G→A prothrombin polymorphism and cerebral ischemia in the young. Stroke 1997;281846- 1847
PubMed
Catto  ACarter  AIreland  H  et al.  Factor V Leiden gene mutation and thrombin generation in relation to the development of acute stroke. Arterioscler Thromb Vasc Biol 1995;15783- 785
PubMed
Chimowitz  MMansbach  HSchmaier  ANichols  WGinsburg  D Factor V mutation and cryptogenic stroke in the young [abstract]. Stroke 1996;27188
De Stefano  VChiusolo  PPaciaroni  K  et al.  Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood 1998;913562- 3565
PubMed
Halbmayer  WMHaushofer  AAngerer  VFinsterer  JFischer  MVienna Thrombophilia in Stroke Study Group (VITISS), APC resistance and factor V Leiden (FV:Q506) mutation in patients with ischemic cerebral events. Blood Coagul Fibrinolysis 1997;8361- 364
PubMed
Hankey  GJEikelboom  JWvan Bockxmeer  FMLofthouse  EStaples  NBaker  RI Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke 2001;321793- 1799
PubMed
Iniesta  JACorral  JGonzalez-Conejero  RRivera  JVicente  V Prothrombotic genetic risk factors in patients with coexisting migraine and ischemic cerebrovascular disease. Headache 1999;39486- 489
PubMed
Juul  KTybjaerg-Hansen  ASteffensen  RKofoed  SJensen  GNordestgaard  BG Factor V Leiden: the Copenhagen City Heart Study and 2 meta-analyses. Blood 2002;1003- 10
PubMed
Kontula  KYlikorkala  AMiettinen  H  et al.  Arg506Gln factor V mutation (factor V Leiden) in patients with ischaemic cerebrovascular disease and survivors of myocardial infarction. Thromb Haemost 1995;73558- 560
PubMed
Lalouschek  WAull  SSeries  WZeiler  KMannhalter  C The prothrombin G20210A mutation and factor V Leiden mutation in patients with cerebrovascular disease [letter]. Blood 1998;92704- 705
PubMed
Landi  GCella  EMartinelli  ITagliabue  LMannucci  PMZerbi  D Arg506Gln factor V mutation and cerebral ischemia in the young [letter]. Stroke 1996;271697- 1698
Lopaciuk  SBykowska  KKwiecinski  H  et al.  Factor V Leiden, prothrombin gene G20210A variant, and methylenetetrahydrofolate reductase C677T genotype in young adults with ischemic stroke. Clin Appl Thromb Hemost 2001;7346- 350
PubMed
Madonna  Pde Stefano  VCoppola  A  et al.  Hyperhomocysteinemia and other inherited prothrombotic conditions in young adults with a history of ischemic stroke. Stroke 2002;3351- 56
PubMed
Margaglione  MD'Andrea  GGiuliani  N  et al.  Inherited prothrombotic conditions and premature ischemic stroke: sex difference in the association with factor V Leiden. Arterioscler Thromb Vasc Biol 1999;191751- 1756
PubMed
Markus  HSZhang  YJeffery  S Screening for the factor-V Arg 506 Gln mutation in patients with TIA and stroke. Cerebrovasc Dis 1996;6360- 362
Martinelli  IFranchi  FAkwan  SBettini  PMerati  GMannucci  PM The transition G to A at position 20210 in the 3′-untranslated region of the prothrombin gene is not associated with cerebral ischemia [letter]. Blood 1997;903806
PubMed
Nabavi  DGJunker  RWolff  E  et al.  Prevalence of factor V Leiden mutation in young adults with cerebral ischaemia: a case-control study on 225 patients. J Neurol 1998;245653- 658
PubMed
Pezzini  ADel Zotto  EMagoni  M  et al.  Inherited thrombophilic disorders in young adults with ischemic stroke and patent foramen ovale. Stroke 2003;3428- 33
PubMed
Press  RDLiu  XYBeamer  NCoull  BM Ischemic stroke in the elderly: role of the common factor V mutation causing resistance to activated protein C. Stroke 1996;2744- 48
PubMed
Ridker  PMHennekens  CHLindpaintner  KStampfer  MJEisenberg  PRMiletich  JP Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995;332912- 917
PubMed
Sanchez  JRoman  Jde la Torre  MJVelasco  FTorres  A Low prevalence of the factor V Leiden among patients with ischemic stroke. Haemostasis 1997;279- 15
PubMed
Szolnoki  ZSomogyvari  FKondacs  ASzabo  MFodor  L Evaluation of the interactions of common genetic mutations in stroke subtypes. J Neurol 2002;2491391- 1397
PubMed
van der Bom  JGBots  MLHaverkate  F  et al.  Reduced response to activated protein C is associated with increased risk for cerebrovascular disease. Ann Intern Med 1996;125265- 269
PubMed
Voetsch  BDamasceno  BPCamargo  EC  et al.  Inherited thrombophilia as a risk factor for the development of ischemic stroke in young adults. Thromb Haemost 2000;83229- 233
PubMed
Zunker  PHohenstein  CPlendl  HJ  et al.  Activated protein C resistance and acute ischaemic stroke: relation to stroke causation and age. J Neurol 2001;248701- 704
PubMed
Duca  FSacchi  ETagliabue  LTajoli  E C677T methylenetetrahydrofolate reductase (MTHFR) mutation in stroke [abstract]. Thromb Haemost 1997;78(suppl)102
Eikelboom  JWHankey  GJAnand  SSLofthouse  EStaples  NBaker  RI Association between high homocysteine and ischemic stroke due to large- and small-artery disease but not other etiologic subtypes of ischemic stroke. Stroke 2000;311069- 1075
PubMed
Gross  BAntebi  ACassel  AHonigman  S Is a mutation in the enzyme MTHFR a risk factor for stroke in young adults [abstract]? Neurology 2000;54(suppl 3)A142
Harmon  DLDoyle  RMMeleady  R  et al.  Genetic analysis of the thermolabile variant of 5, 10-methylenetetrahydrofolate reductase as a risk factor for ischemic stroke. Arterioscler Thromb Vasc Biol 1999;19208- 211
PubMed
Kostulas  KCrisby  MHuang  WX  et al.  A methylenetetrahydrofolate reductase gene polymorphism in ischaemic stroke and in carotid artery stenosis. Eur J Clin Invest 1998;28285- 289
PubMed
Kristensen  BMalm  JNilsson  TK  et al.  Hyperhomocysteinemia and hypofibrinolysis in young adults with ischemic stroke. Stroke 1999;30974- 980
PubMed
Lalouschek  WAull  SSerles  W  et al.  Genetic and nongenetic factors influencing plasma homocysteine levels in patients with ischemic cerebrovascular disease and in healthy control subjects. J Lab Clin Med 1999;133575- 582
PubMed
Markus  HSAli  NSwaminathan  RSankaralingam  AMolloy  JPowell  J A common polymorphism in the methylenetetrahydrofolate reductase gene, homocysteine, and ischemic cerebrovascular disease. Stroke 1997;281739- 1743
PubMed
McIlroy  SPDynan  KBLawson  JTPatterson  CCPassmore  AP Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke 2002;332351- 2356
PubMed
Pezzini  ADel Zotto  EArchetti  S  et al.  Plasma homocysteine concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke. Stroke 2002;33664- 669
PubMed
Press  RDBeamer  NEvans  ADeLoughery  TGCoull  BM Role of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase in ischemic stroke. Diagn Mol Pathol 1999;854- 58
PubMed
Reuner  KHRuf  AKaps  MDruschky  KFPatscheke  H The mutation C677→T in the methylene tetrahydrofolate reductase gene and stroke. Thromb Haemost 1998;79450- 451
PubMed
Salooja  NCatto  ACarter  ATudenham  EGGrant  PJ Methylene tetrahydrofolate reductase C677T genotype and stroke. Clin Lab Haematol 1998;20357- 361
PubMed
Soriente  LCoppola  AMadonna  P  et al.  Homozygous C677T mutation of the 5,10 methylenetetrahydrofolate reductase gene and hyperhomocysteinemia in Italian patients with a history of early-onset ischemic stroke. Stroke 1998;29869- 871
PubMed
Topic  ETimundic  AMTtefanovic  M  et al.  Polymorphism of apoprotein E (APOE), methylenetetrahydrofolate reductase (MTHFR) and paraoxonase (PON1) genes in patients with cerebrovascular disease. Clin Chem Lab Med 2001;39346- 350
PubMed
Egan  RAKuyl  JMPress  RLutsep  HL Lack of prothrombin gene mutation in young stroke patients. J Stroke Cerebrovasc Dis 2000;9229- 231
Gomez Garcia  EBvan Goor  MPLeebeek  FWBrouwers  GJKoudstaal  PJDippel  DW Elevated prothrombin is a risk factor for cerebral arterial ischemia in young adults. Clin Neurol Neurosurg 2002;104285- 288
PubMed
Halbmayer  WMHaushofer  AHermann  KMFischer  M The 20210A allele of the prothrombin gene: a risk factor for juvenile stroke? result of a pilot study [letter]. Blood Coagul Fibrinolysis 1998;9209- 210
Lichy  CReuner  KHBuggle  F  et al Prothrombin g20210a mutation, but not factor V Leiden, is a risk factor in patients with cerebral ischemia associated with persistent foramen ovale.  Paper presented at: 16th International Congress on Fibrinolysis and Proteolysis in conjunction with the 17th International Fibrinogen Workshop; September 8-13, 2002; Munich, Germany
Reuner  KHRuf  AGrau  A  et al.  Prothrombin gene G20210→A transition is a risk factor for cerebral venous thrombosis. Stroke 1998;291765- 1769
PubMed
Ridker  PMHennekens  CHMiletich  JP G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation 1999;99999- 1004
PubMed
Smiles  AMJenny  NSTang  ZArnold  ACushman  MTracy  RP No association of plasma prothrombin concentration or the G20210A mutation with incident cardiovascular disease: results from the Cardiovascular Health Study. Thromb Haemost 2002;87614- 621
PubMed
Agerholm-Larsen  BTybjaerg-Hansen  AFrikke-Schmidt  RGronholdt  MLJensen  GNordestgaard  BG ACE gene polymorphism as a risk factor for ischemic cerebrovascular disease. Ann Intern Med 1997;127346- 355
PubMed
Catto  ACarter  AMBarrett  JH  et al.  Angiotensin-converting enzyme insertion/deletion polymorphism and cerebrovascular disease. Stroke 1996;27435- 440
PubMed
Kostulas  KHuang  WXCrisby  M  et al.  An angiotensin-converting enzyme gene polymorphism suggests a genetic distinction between ischaemic stroke and carotid stenosis. Eur J Clin Invest 1999;29478- 483
PubMed
Margaglione  MCelentano  EGrandone  E  et al.  Deletion polymorphism in the angiotensin-converting enzyme gene in patients with a history of ischemic stroke. Arterioscler Thromb Vasc Biol 1996;16304- 309
PubMed
Markus  HSBarley  JLunt  R  et al.  Angiotensin-converting enzyme gene deletion polymorphism: a new risk factor for lacunar stroke but not carotid atheroma. Stroke 1995;261329- 1333
PubMed
Peterlin  BPetrovic  DZorc  MKeber  I Deletion/insertion polymorphism in the angiotension-converting enzyme gene as a risk factor in the Slovenian patients with coronary heart disease. Pflugers Arch 2000;439(suppl)R40- R41
PubMed
Pfohl  MFetter  MKoch  MBarth  CMRudiger  WHaring  HU Association between angiotensin I–converting enzyme genotypes, extracranial artery stenosis, and stroke. Atherosclerosis 1998;140161- 166
PubMed
Sharma  PCarter  NDBarley  JBrown  MM Molecular approach to assessing the genetic risk of cerebral infarction: deletion polymorphism in the gene encoding angiotensin 1–converting enzyme. J Hum Hypertens 1994;8645- 648
PubMed
Ueda  SWeir  CJInglis  GCMurray  GDMuir  KWLees  KR Lack of association between angiotensin converting enzyme gene insertion/deletion polymorphism and stroke. J Hypertens 1995;131597- 1601
PubMed
Zee  RYRidker  PMStampfer  MJHennekens  CHLindpaintner  K Prospective evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of stroke. Circulation 1999;99340- 343
PubMed
Catto  AJKohler  HPBannan  SStickland  MCarter  AGrant  PJ Factor XIII Val 34 Leu: a novel association with primary intracerebral hemorrhage. Stroke 1998;29813- 816
PubMed
Corral  JGonzalez-Conejero  RIniesta  JARivera  JMartinez  CVicente  V The FXIII Val34Leu polymorphism in venous and arterial thromboembolism. Haematologica 2000;85293- 297
PubMed
Elbaz  APoirier  OCanaple  SChedru  FCambien  FAmarenco  P The association between the Val34Leu polymorphism in the factor XIII gene and brain infarction. Blood 2000;95586- 591
PubMed
Endler  GFunk  MHaering  D  et al.  Is the factor XIII 34Val/Leu polymorphism a protective factor for cerebrovascular disease? Br J Haematol 2003;120310- 314
PubMed
Gemmati  DSerino  MLOngaro  A  et al.  A common mutation in the gene for coagulation factor XIII-A (VAL34Leu): a risk factor for primary intracerebral hemorrhage is protective against atherothrombotic diseases. Am J Hematol 2001;67183- 188
PubMed
Reiner  APFrank  MBSchwartz  SM  et al.  Coagulation factor XIII polymorphisms and the risk of myocardial infarction and ischaemic stroke in young women. Br J Haematol 2002;116376- 382
PubMed
Basun  HCorder  EHGuo  Z  et al.  Apolipoprotein E polymorphism and stroke in a population sample aged 75 years or more. Stroke 1996;271310- 1315
PubMed
Catto  AJMcCormack  LJMansfield  MW  et al.  Apolipoprotein E polymorphism in cerebrovascular disease. Acta Neurol Scand 2000;101399- 404
PubMed
Couderc  RMahieux  FBailleul  SFenelon  GMary  RFermanian  J Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease: a case-control study. Stroke 1993;24661- 664
PubMed
Frikke-Schmidt  RNordestgaard  BGThudium  DMoes Gronholdt  MLTybjaerg-Hansen  A APOE genotype predicts AD and other dementia but not ischemic cerebrovascular disease. Neurology 2001;56194- 200
PubMed
Hachinski  VGraffagnino  CBeaudry  M  et al.  Lipids and stroke: a paradox resolved. Arch Neurol 1996;53303- 308
PubMed
Kessler  CSpitzer  CStauske  D  et al.  The apolipoprotein E and β-fibrinogen G/A-455 gene polymorphisms are associated with ischemic stroke involving large-vessel disease. Arterioscler Thromb Vasc Biol 1997;172880- 2884
PubMed
MacLeod  MJDe Lange  RPBreen  GMeiklejohn  DLemmon  HClair  DS Lack of association between apolipoprotein E genotype and ischaemic stroke in a Scottish population. Eur J Clin Invest 2001;31570- 573
PubMed
Margaglione  MSeripa  DGravina  C  et al.  Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke: an Italian Case-Control Study. Stroke 1998;29399- 403
PubMed
Carlsson  LEGreinacher  ASpitzer  CWalther  RKessler  C Polymorphisms of the human platelet antigens HPA-1, HPA-2, HPA-3, and HPA-5 on the platelet receptors for fibrinogen (GPIIb/IIIa), von Willebrand factor (GPIb/IX), and collagen (GPIa/IIa) are not correlated with an increased risk for stroke. Stroke 1997;281392- 1395
PubMed
Carter  AMCatto  AJBamford  JMGrant  PJ Association of the platelet glycoprotein IIb HPA-3 polymorphism with survival after acute ischemic stroke. Stroke 1999;302606- 2611
PubMed
Kekomaki  SHamalainen  LKauppinen-Makelin  RPalomaki  HKaste  MKontula  K Genetic polymorphism of platelet glycoprotein IIIa in patients with acute myocardial infarction and acute ischaemic stroke. J Cardiovasc Risk 1999;613- 17
PubMed
Reiner  APKumar  PNSchwartz  SM  et al.  Genetic variants of platelet glycoprotein receptors and risk of stroke in young women. Stroke 2000;311628- 1633
PubMed
Reuner  KHElgas  MKaps  MRuf  APatscheke  H The human platelet antigen HPA-1a/1b (PI(A1)/PI(A2)) polymorphism and cerebral ischaemia [letter]. Thromb Haemost 1997;78964- 965
Ridker  PMHennekens  CHSchmitz  CStampfer  MJLindpaintner  K PIA1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis. Lancet 1997;349385- 388
PubMed
van Goor  MLGomez Garcia  EBrouwers  GJLeebeek  FWKoudstaal  PJDippel  DW PLA1/A2 polymorphism of the platelet glycoprotein receptor IIb/IIIa in young patients with cryptogenic TIA or ischemic stroke. Thromb Res 2002;10863- 65
PubMed
Wagner  KRGiles  WHJohnson  CJ  et al.  Platelet glycoprotein receptor IIIa polymorphism P1A2 and ischemic stroke risk: the Stroke Prevention in Young Women Study. Stroke 1998;29581- 585
PubMed
Elbaz  APoirier  OMoulin  T  et al.  Association between the Glu298Asp polymorphism in the endothelial constitutive nitric oxide synthase gene and brain infarction. Stroke 2000;311634- 1639
PubMed
MacLeod  MJDahiyat  MTCumming  AMeiklejohn  DShaw  DSt Clair  D No association between Glu/Asp polymorphism of NOS3 gene and ischemic stroke. Neurology 1999;53418- 420
PubMed
Markus  HSRuigrok  YAli  NPowell  JF Endothelial nitric oxide synthase exon 7 polymorphism, ischemic cerebrovascular disease, and carotid atheroma. Stroke 1998;291908- 1911
PubMed
Endler  GLalouschek  WExner  MMitterbauer  GHaring  DMannhalter  C The 4G/4G genotype at nucleotide position −675 in the promotor region of the plasminogen activator inhibitor 1 (PAI−1) gene is less frequent in young patients with minor stroke than in controls. Br J Haematol 2000;110469- 471
PubMed
Hindorff  LASchwartz  SMSiscovick  DSPsaty  BMLongstreth  WT  JrReiner  AP The association of PAI-1 promoter 4G/5G insertion/deletion polymorphism with myocardial infarction and stroke in young women. J Cardiovasc Risk 2002;9131- 137
PubMed
Roest  Mvan der Schouw  YTBanga  JD  et al.  Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women. Circulation 2000;10167- 70
PubMed
Baker  RIEikelboom  JLofthouse  E  et al.  Platelet glycoprotein Ibα Kozak polymorphism is associated with an increased risk of ischemic stroke. Blood 2001;9836- 40
PubMed
Carter  AMCatto  AJBamford  JMGrant  PJ Platelet GP IIIa PlA and GP Ib variable number tandem repeat polymorphisms and markers of platelet activation in acute stroke. Arterioscler Thromb Vasc Biol 1998;181124- 1131
PubMed
Gonzalez-Conejero  RLozano  MLRivera  J  et al.  Polymorphisms of platelet membrane glycoprotein Ib associated with arterial thrombotic disease. Blood 1998;922771- 2776
PubMed
Corral  JGonzalez-Conejero  RLozano  MLRivera  JVicente  V Genetic polymorphisms of factor VII are not associated with arterial thrombosis. Blood Coagul Fibrinolysis 1998;9267- 272
PubMed
Heywood  DMCarter  AMCatto  AJBamford  JMGrant  PJ Polymorphisms of the factor VII gene and circulating FVII:C levels in relation to acute cerebrovascular disease and poststroke mortality. Stroke 1997;28816- 821
PubMed
Corral  JLozano  MLGonzalez-Conejero  R  et al.  A common polymorphism flanking the ATG initiator codon of GPIb α does not affect expression and is not a major risk factor for arterial thrombosis. Thromb Haemost 2000;8323- 28
PubMed
Frank  MBReiner  APSchwartz  SM  et al.  The Kozak sequence polymorphism of platelet glycoprotein Ibα and risk of nonfatal myocardial infarction and nonfatal stroke in young women. Blood 2001;97875- 879
PubMed
Huang  PKostulas  KHuang  WXCrisby  MKostulas  VHillert  J Lipoprotein lipase gene polymorphisms in ischaemic stroke and carotid stenosis. Eur J Clin Invest 1997;27740- 742
PubMed
Myllykangas  LPolvikoski  TSulkava  R  et al.  Association of lipoprotein lipase Ser447Ter polymorphism with brain infarction: a population-based neuropathological study. Ann Med 2001;33486- 492
PubMed
Wittrup  HHNordestgaard  BGSillesen  HSchnohr  PTybjaerg-Hansen  A A common mutation in lipoprotein lipase confers a 2-fold increase in risk of ischemic cerebrovascular disease in women but not in men. Circulation 2000;1012393- 2397
PubMed
Wald  DSLaw  MMorris  JK Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;3251202- 1206
PubMed
Keavney  BMcKenzie  CParish  S  et al. International Studies of Infarct Survival (ISIS) Collaborators, Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. Lancet 2000;355434- 442
PubMed
Keavney  BParish  SPalmer  A  et al.  Large-scale evidence that the cardiotoxicity of smoking is not significantly modified by the apolipoprotein E ε2/ε3/ε4 genotype. Lancet 2003;361396- 398
PubMed
Bertina  RMKoeleman  BPKoster  T  et al.  Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;36964- 67
PubMed
Dahlback  B New molecular insights into the genetics of thrombophilia: resistance to activated protein C caused by Arg506 to Gln mutation in factor V as a pathogenic risk factor for venous thrombosis. Thromb Haemost 1995;74139- 148
PubMed
Franco  RFTrip  MDten Cate  H  et al.  the 20210 G→A mutation in the 3′-untranslated region of the prothrombin gene and the risk for arterial thrombotic disease. Br J Haematol 1999;10450- 54
PubMed
Cattaneo  MChantarangkul  VTaioli  ESantos  JHTagliabue  L The G20210A mutation of the prothrombin gene in patients with previous first episodes of deep-vein thrombosis: prevalence and association with factor V G1691A, methylenetetrahydrofolate reductase C677T and plasma prothrombin levels. Thromb Res 1999;931- 8
PubMed
Tiret  LRigat  BVisvikis  S  et al.  Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I–converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 1992;51197- 205
PubMed
Sharma  PCarter  NDBarley  JLunt  RSeymour  CABrown  MM Polymorphisms in the gene encoding angiotensin 1–converting enzyme and relationship to its post-translational product in cerebral infarction. J Hum Hypertens 1994;8633- 634
PubMed
Agerholm-Larsen  BNordestgaard  BGTybjaerg-Hansen  A ACE gene polymorphism in cardiovascular disease: meta-analyses of small and large studies in whites. Arterioscler Thromb Vasc Biol 2000;20484- 492
PubMed
Kim  SIwao  H Molecular and cellular mechanisms of angiotensin II–mediated cardiovascular and renal diseases. Pharmacol Rev 2000;5211- 34
PubMed
Frosst  PBlom  HJMilos  R  et al.  A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10111- 113
PubMed
Klerk  MVerhoef  PClarke  R  et al. MTHFR Studies Collaboration Group, MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002;2882023- 2031
PubMed
Lellouche  FDorval  IDewilde  JVan Walleghem  E Presence of G1691A mutation on the gene of factor V in arterial thrombosis [letter] [in French]. Presse Med 1995;24869
PubMed
Moliaka  IuKPetruk  SVKir’ianov  SA  et al.  Association analysis of polymorphism in angiotensin-converting enzyme gene in ischemic stroke [in Russian]. Zh Nevrol Psikhiatr Im S S Korsakova 1998;9835- 37
PubMed
Pongracz  ETordai  ACsornai  MNagy  Z Genetics of blood coagulation in young stroke patients [in Hungarian]. Ideggyogy Sz 2002;55111- 117
Pongracz  ETordai  ACsornai  MNagy  Z Investigation of insertion/deletion polymorphism of the ACE gene in stroke patients [in Hungarian]. Ideggyogy Sz 2002;55157- 163
Pongracz  ETordai  ACsornai  MNagy  Z Platelet glycoprotein IIb/IIIa (LeuPro 33) polymorphism in stroke patients [in Hungarian]. Orv Hetil 2001;142781- 785
Yang  QKhoury  MJBotto  L  et al.  Improving the prediction of complex diseases by testing for multiple disease-susceptibility genes. Am J Hum Genet 2003;72636- 649
PubMed
Colhoun  HMMcKeigue  PMDavey Smith  G Problems of reporting genetic associations with complex outcomes. Lancet 2003;361865- 872
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Results of published studies of the association between the factor V Leiden mutation and ischemic stroke. Odds ratios for the outcome compared carriers of the Gln506 allele vs wild type (Arg/Arg). CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Results of published studies of the association between the methylenetetrahydrofolate reductase C677T polymorphism and ischemic stroke. Odds ratios for the outcome compared individuals homozygous for the T allele (T/T) with those heterozygous individuals (C/T) plus wild type (C/C). CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Results of published studies of the association between the prothrombin G20210A polymorphism and ischemic stroke. Odds ratios for the outcome compared carriers of the A allele with those with wild type (G/G). CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Results of published studies of the association between the ACE I/D polymorphism and ischemic stroke. Odds ratios for the outcome compared individuals homozygous for the D allele with those with the heterozygous (D/I) plus wild type (I/I). CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Results of published studies of the association between the apolipoprotein E polymorphism and ischemic stroke. Odds ratios for the outcome compared carriers of the ε4 allele with those with the ε3 and ε2 alleles. CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 6.

Results of published studies of the association between the factor XIII polymorphism and ischemic stroke. Odds ratios for the outcome compared individuals homozygous for the Leu34 allele (Leu/Leu) with those with the heterozygous (Val/Leu) plus wild type (Val/Val). CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 7.

Results of published studies of the association between the glycoprotein IIIa polymorphism and ischemic stroke. Odds ratios for the outcome compared individuals homozygous for the Pro allele with those with the heterozygous (Leu/Pro) plus wild type (Leu/Leu). CI indicates confidence interval. The size of the box is porportional to the weight of the study.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Candidate Genes and Ischemic Stroke

References

World Health Organization The World Health Report 2002: Reducing Risks, Promoting Healthy Life.  Geneva, Switzerland: World Health Organization; 2002
National Heart, Lung, and Blood Institute Morbidity & Mortality: 2002 Chartbook on Cardiovascular, Lung, and Blood Diseases.  Bethesda, Md: National Institutes of Health; 2002
American Heart Association Economic cost of cardiovascular diseases.  Available at: http://www.americanheart.org/statistics/10econom.html. Accessed June 15, 2003
Goldstein  LBAdams  RBecker  K  et al.  Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation 2001;103163- 182
PubMed
Hrubec  ZRobinette  CD The study of human twins in medical research. N Engl J Med 1984;310435- 441
PubMed
Brass  LMIsaacsohn  JLMerikangas  KR  et al.  A study of twins and stroke. Stroke 1992;23221- 223
PubMed
Rubattu  SVolpe  MKreutz  RGanten  UGanten  DLindpaintner  K Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. Nat Genet 1996;13429- 434
PubMed
Kiely  DKWolf  PACupples  LA  et al.  Familial aggregation of stroke: the Framingham Study. Stroke 1993;241366- 1371
PubMed
Sharma  P Genes for ischaemic stroke: strategies for their detection. J Hypertens 1996;14277- 285
PubMed
Liao  DMyers  RHunt  S  et al.  Familial history of stroke and stroke risk: the Family Heart Study. Stroke 1997;281908- 1912
PubMed
Mantel  NHaenszel  W Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22719- 748
PubMed
Robins  JGreenland  SBreslow  NE A general estimator of the variance of the Mantel-Haenszel odds ratio. Am J Epidemiol 1986;124719- 723
PubMed
DerSimonian  RLaird  NM Meta-analysis in clinical trials. Control Clin Trials 1986;7177- 188
PubMed
Deeks  JJAltman  DGBradburn  MJ Statistical methods for examining heterogeneity and combining results from several studies in a meta-analysis.  In: Egger  M, Davey  Smith G, Altman  DG, eds. Systematic Reviews in Health Care: Meta-analysis in Context. Annapolis Junction, Md: BMJ Publishing Group; 2001
Egger  MDavey Smith  GSchneider  M  et al.  Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315629- 634
Albucher  JFGuiraud-Chaumeil  BChollet  FCadroy  YSie  P Frequency of resistance to activated protein C due to factor V mutation in young patients with ischemic stroke. Stroke 1996;27766- 767
PubMed
Bentolila  SRipoll  LDrouet  LMazoyer  EWoimant  F Thrombophilia due to 20210 G→A prothrombin polymorphism and cerebral ischemia in the young. Stroke 1997;281846- 1847
PubMed
Catto  ACarter  AIreland  H  et al.  Factor V Leiden gene mutation and thrombin generation in relation to the development of acute stroke. Arterioscler Thromb Vasc Biol 1995;15783- 785
PubMed
Chimowitz  MMansbach  HSchmaier  ANichols  WGinsburg  D Factor V mutation and cryptogenic stroke in the young [abstract]. Stroke 1996;27188
De Stefano  VChiusolo  PPaciaroni  K  et al.  Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood 1998;913562- 3565
PubMed
Halbmayer  WMHaushofer  AAngerer  VFinsterer  JFischer  MVienna Thrombophilia in Stroke Study Group (VITISS), APC resistance and factor V Leiden (FV:Q506) mutation in patients with ischemic cerebral events. Blood Coagul Fibrinolysis 1997;8361- 364
PubMed
Hankey  GJEikelboom  JWvan Bockxmeer  FMLofthouse  EStaples  NBaker  RI Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke 2001;321793- 1799
PubMed
Iniesta  JACorral  JGonzalez-Conejero  RRivera  JVicente  V Prothrombotic genetic risk factors in patients with coexisting migraine and ischemic cerebrovascular disease. Headache 1999;39486- 489
PubMed
Juul  KTybjaerg-Hansen  ASteffensen  RKofoed  SJensen  GNordestgaard  BG Factor V Leiden: the Copenhagen City Heart Study and 2 meta-analyses. Blood 2002;1003- 10
PubMed
Kontula  KYlikorkala  AMiettinen  H  et al.  Arg506Gln factor V mutation (factor V Leiden) in patients with ischaemic cerebrovascular disease and survivors of myocardial infarction. Thromb Haemost 1995;73558- 560
PubMed
Lalouschek  WAull  SSeries  WZeiler  KMannhalter  C The prothrombin G20210A mutation and factor V Leiden mutation in patients with cerebrovascular disease [letter]. Blood 1998;92704- 705
PubMed
Landi  GCella  EMartinelli  ITagliabue  LMannucci  PMZerbi  D Arg506Gln factor V mutation and cerebral ischemia in the young [letter]. Stroke 1996;271697- 1698
Lopaciuk  SBykowska  KKwiecinski  H  et al.  Factor V Leiden, prothrombin gene G20210A variant, and methylenetetrahydrofolate reductase C677T genotype in young adults with ischemic stroke. Clin Appl Thromb Hemost 2001;7346- 350
PubMed
Madonna  Pde Stefano  VCoppola  A  et al.  Hyperhomocysteinemia and other inherited prothrombotic conditions in young adults with a history of ischemic stroke. Stroke 2002;3351- 56
PubMed
Margaglione  MD'Andrea  GGiuliani  N  et al.  Inherited prothrombotic conditions and premature ischemic stroke: sex difference in the association with factor V Leiden. Arterioscler Thromb Vasc Biol 1999;191751- 1756
PubMed
Markus  HSZhang  YJeffery  S Screening for the factor-V Arg 506 Gln mutation in patients with TIA and stroke. Cerebrovasc Dis 1996;6360- 362
Martinelli  IFranchi  FAkwan  SBettini  PMerati  GMannucci  PM The transition G to A at position 20210 in the 3′-untranslated region of the prothrombin gene is not associated with cerebral ischemia [letter]. Blood 1997;903806
PubMed
Nabavi  DGJunker  RWolff  E  et al.  Prevalence of factor V Leiden mutation in young adults with cerebral ischaemia: a case-control study on 225 patients. J Neurol 1998;245653- 658
PubMed
Pezzini  ADel Zotto  EMagoni  M  et al.  Inherited thrombophilic disorders in young adults with ischemic stroke and patent foramen ovale. Stroke 2003;3428- 33
PubMed
Press  RDLiu  XYBeamer  NCoull  BM Ischemic stroke in the elderly: role of the common factor V mutation causing resistance to activated protein C. Stroke 1996;2744- 48
PubMed
Ridker  PMHennekens  CHLindpaintner  KStampfer  MJEisenberg  PRMiletich  JP Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995;332912- 917
PubMed
Sanchez  JRoman  Jde la Torre  MJVelasco  FTorres  A Low prevalence of the factor V Leiden among patients with ischemic stroke. Haemostasis 1997;279- 15
PubMed
Szolnoki  ZSomogyvari  FKondacs  ASzabo  MFodor  L Evaluation of the interactions of common genetic mutations in stroke subtypes. J Neurol 2002;2491391- 1397
PubMed
van der Bom  JGBots  MLHaverkate  F  et al.  Reduced response to activated protein C is associated with increased risk for cerebrovascular disease. Ann Intern Med 1996;125265- 269
PubMed
Voetsch  BDamasceno  BPCamargo  EC  et al.  Inherited thrombophilia as a risk factor for the development of ischemic stroke in young adults. Thromb Haemost 2000;83229- 233
PubMed
Zunker  PHohenstein  CPlendl  HJ  et al.  Activated protein C resistance and acute ischaemic stroke: relation to stroke causation and age. J Neurol 2001;248701- 704
PubMed
Duca  FSacchi  ETagliabue  LTajoli  E C677T methylenetetrahydrofolate reductase (MTHFR) mutation in stroke [abstract]. Thromb Haemost 1997;78(suppl)102
Eikelboom  JWHankey  GJAnand  SSLofthouse  EStaples  NBaker  RI Association between high homocysteine and ischemic stroke due to large- and small-artery disease but not other etiologic subtypes of ischemic stroke. Stroke 2000;311069- 1075
PubMed
Gross  BAntebi  ACassel  AHonigman  S Is a mutation in the enzyme MTHFR a risk factor for stroke in young adults [abstract]? Neurology 2000;54(suppl 3)A142
Harmon  DLDoyle  RMMeleady  R  et al.  Genetic analysis of the thermolabile variant of 5, 10-methylenetetrahydrofolate reductase as a risk factor for ischemic stroke. Arterioscler Thromb Vasc Biol 1999;19208- 211
PubMed
Kostulas  KCrisby  MHuang  WX  et al.  A methylenetetrahydrofolate reductase gene polymorphism in ischaemic stroke and in carotid artery stenosis. Eur J Clin Invest 1998;28285- 289
PubMed
Kristensen  BMalm  JNilsson  TK  et al.  Hyperhomocysteinemia and hypofibrinolysis in young adults with ischemic stroke. Stroke 1999;30974- 980
PubMed
Lalouschek  WAull  SSerles  W  et al.  Genetic and nongenetic factors influencing plasma homocysteine levels in patients with ischemic cerebrovascular disease and in healthy control subjects. J Lab Clin Med 1999;133575- 582
PubMed
Markus  HSAli  NSwaminathan  RSankaralingam  AMolloy  JPowell  J A common polymorphism in the methylenetetrahydrofolate reductase gene, homocysteine, and ischemic cerebrovascular disease. Stroke 1997;281739- 1743
PubMed
McIlroy  SPDynan  KBLawson  JTPatterson  CCPassmore  AP Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke 2002;332351- 2356
PubMed
Pezzini  ADel Zotto  EArchetti  S  et al.  Plasma homocysteine concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke. Stroke 2002;33664- 669
PubMed
Press  RDBeamer  NEvans  ADeLoughery  TGCoull  BM Role of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase in ischemic stroke. Diagn Mol Pathol 1999;854- 58
PubMed
Reuner  KHRuf  AKaps  MDruschky  KFPatscheke  H The mutation C677→T in the methylene tetrahydrofolate reductase gene and stroke. Thromb Haemost 1998;79450- 451
PubMed
Salooja  NCatto  ACarter  ATudenham  EGGrant  PJ Methylene tetrahydrofolate reductase C677T genotype and stroke. Clin Lab Haematol 1998;20357- 361
PubMed
Soriente  LCoppola  AMadonna  P  et al.  Homozygous C677T mutation of the 5,10 methylenetetrahydrofolate reductase gene and hyperhomocysteinemia in Italian patients with a history of early-onset ischemic stroke. Stroke 1998;29869- 871
PubMed
Topic  ETimundic  AMTtefanovic  M  et al.  Polymorphism of apoprotein E (APOE), methylenetetrahydrofolate reductase (MTHFR) and paraoxonase (PON1) genes in patients with cerebrovascular disease. Clin Chem Lab Med 2001;39346- 350
PubMed
Egan  RAKuyl  JMPress  RLutsep  HL Lack of prothrombin gene mutation in young stroke patients. J Stroke Cerebrovasc Dis 2000;9229- 231
Gomez Garcia  EBvan Goor  MPLeebeek  FWBrouwers  GJKoudstaal  PJDippel  DW Elevated prothrombin is a risk factor for cerebral arterial ischemia in young adults. Clin Neurol Neurosurg 2002;104285- 288
PubMed
Halbmayer  WMHaushofer  AHermann  KMFischer  M The 20210A allele of the prothrombin gene: a risk factor for juvenile stroke? result of a pilot study [letter]. Blood Coagul Fibrinolysis 1998;9209- 210
Lichy  CReuner  KHBuggle  F  et al Prothrombin g20210a mutation, but not factor V Leiden, is a risk factor in patients with cerebral ischemia associated with persistent foramen ovale.  Paper presented at: 16th International Congress on Fibrinolysis and Proteolysis in conjunction with the 17th International Fibrinogen Workshop; September 8-13, 2002; Munich, Germany
Reuner  KHRuf  AGrau  A  et al.  Prothrombin gene G20210→A transition is a risk factor for cerebral venous thrombosis. Stroke 1998;291765- 1769
PubMed
Ridker  PMHennekens  CHMiletich  JP G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation 1999;99999- 1004
PubMed
Smiles  AMJenny  NSTang  ZArnold  ACushman  MTracy  RP No association of plasma prothrombin concentration or the G20210A mutation with incident cardiovascular disease: results from the Cardiovascular Health Study. Thromb Haemost 2002;87614- 621
PubMed
Agerholm-Larsen  BTybjaerg-Hansen  AFrikke-Schmidt  RGronholdt  MLJensen  GNordestgaard  BG ACE gene polymorphism as a risk factor for ischemic cerebrovascular disease. Ann Intern Med 1997;127346- 355
PubMed
Catto  ACarter  AMBarrett  JH  et al.  Angiotensin-converting enzyme insertion/deletion polymorphism and cerebrovascular disease. Stroke 1996;27435- 440
PubMed
Kostulas  KHuang  WXCrisby  M  et al.  An angiotensin-converting enzyme gene polymorphism suggests a genetic distinction between ischaemic stroke and carotid stenosis. Eur J Clin Invest 1999;29478- 483
PubMed
Margaglione  MCelentano  EGrandone  E  et al.  Deletion polymorphism in the angiotensin-converting enzyme gene in patients with a history of ischemic stroke. Arterioscler Thromb Vasc Biol 1996;16304- 309
PubMed
Markus  HSBarley  JLunt  R  et al.  Angiotensin-converting enzyme gene deletion polymorphism: a new risk factor for lacunar stroke but not carotid atheroma. Stroke 1995;261329- 1333
PubMed
Peterlin  BPetrovic  DZorc  MKeber  I Deletion/insertion polymorphism in the angiotension-converting enzyme gene as a risk factor in the Slovenian patients with coronary heart disease. Pflugers Arch 2000;439(suppl)R40- R41
PubMed
Pfohl  MFetter  MKoch  MBarth  CMRudiger  WHaring  HU Association between angiotensin I–converting enzyme genotypes, extracranial artery stenosis, and stroke. Atherosclerosis 1998;140161- 166
PubMed
Sharma  PCarter  NDBarley  JBrown  MM Molecular approach to assessing the genetic risk of cerebral infarction: deletion polymorphism in the gene encoding angiotensin 1–converting enzyme. J Hum Hypertens 1994;8645- 648
PubMed
Ueda  SWeir  CJInglis  GCMurray  GDMuir  KWLees  KR Lack of association between angiotensin converting enzyme gene insertion/deletion polymorphism and stroke. J Hypertens 1995;131597- 1601
PubMed
Zee  RYRidker  PMStampfer  MJHennekens  CHLindpaintner  K Prospective evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of stroke. Circulation 1999;99340- 343
PubMed
Catto  AJKohler  HPBannan  SStickland  MCarter  AGrant  PJ Factor XIII Val 34 Leu: a novel association with primary intracerebral hemorrhage. Stroke 1998;29813- 816
PubMed
Corral  JGonzalez-Conejero  RIniesta  JARivera  JMartinez  CVicente  V The FXIII Val34Leu polymorphism in venous and arterial thromboembolism. Haematologica 2000;85293- 297
PubMed
Elbaz  APoirier  OCanaple  SChedru  FCambien  FAmarenco  P The association between the Val34Leu polymorphism in the factor XIII gene and brain infarction. Blood 2000;95586- 591
PubMed
Endler  GFunk  MHaering  D  et al.  Is the factor XIII 34Val/Leu polymorphism a protective factor for cerebrovascular disease? Br J Haematol 2003;120310- 314
PubMed
Gemmati  DSerino  MLOngaro  A  et al.  A common mutation in the gene for coagulation factor XIII-A (VAL34Leu): a risk factor for primary intracerebral hemorrhage is protective against atherothrombotic diseases. Am J Hematol 2001;67183- 188
PubMed
Reiner  APFrank  MBSchwartz  SM  et al.  Coagulation factor XIII polymorphisms and the risk of myocardial infarction and ischaemic stroke in young women. Br J Haematol 2002;116376- 382
PubMed
Basun  HCorder  EHGuo  Z  et al.  Apolipoprotein E polymorphism and stroke in a population sample aged 75 years or more. Stroke 1996;271310- 1315
PubMed
Catto  AJMcCormack  LJMansfield  MW  et al.  Apolipoprotein E polymorphism in cerebrovascular disease. Acta Neurol Scand 2000;101399- 404
PubMed
Couderc  RMahieux  FBailleul  SFenelon  GMary  RFermanian  J Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease: a case-control study. Stroke 1993;24661- 664
PubMed
Frikke-Schmidt  RNordestgaard  BGThudium  DMoes Gronholdt  MLTybjaerg-Hansen  A APOE genotype predicts AD and other dementia but not ischemic cerebrovascular disease. Neurology 2001;56194- 200
PubMed
Hachinski  VGraffagnino  CBeaudry  M  et al.  Lipids and stroke: a paradox resolved. Arch Neurol 1996;53303- 308
PubMed
Kessler  CSpitzer  CStauske  D  et al.  The apolipoprotein E and β-fibrinogen G/A-455 gene polymorphisms are associated with ischemic stroke involving large-vessel disease. Arterioscler Thromb Vasc Biol 1997;172880- 2884
PubMed
MacLeod  MJDe Lange  RPBreen  GMeiklejohn  DLemmon  HClair  DS Lack of association between apolipoprotein E genotype and ischaemic stroke in a Scottish population. Eur J Clin Invest 2001;31570- 573
PubMed
Margaglione  MSeripa  DGravina  C  et al.  Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke: an Italian Case-Control Study. Stroke 1998;29399- 403
PubMed
Carlsson  LEGreinacher  ASpitzer  CWalther  RKessler  C Polymorphisms of the human platelet antigens HPA-1, HPA-2, HPA-3, and HPA-5 on the platelet receptors for fibrinogen (GPIIb/IIIa), von Willebrand factor (GPIb/IX), and collagen (GPIa/IIa) are not correlated with an increased risk for stroke. Stroke 1997;281392- 1395
PubMed
Carter  AMCatto  AJBamford  JMGrant  PJ Association of the platelet glycoprotein IIb HPA-3 polymorphism with survival after acute ischemic stroke. Stroke 1999;302606- 2611
PubMed
Kekomaki  SHamalainen  LKauppinen-Makelin  RPalomaki  HKaste  MKontula  K Genetic polymorphism of platelet glycoprotein IIIa in patients with acute myocardial infarction and acute ischaemic stroke. J Cardiovasc Risk 1999;613- 17
PubMed
Reiner  APKumar  PNSchwartz  SM  et al.  Genetic variants of platelet glycoprotein receptors and risk of stroke in young women. Stroke 2000;311628- 1633
PubMed
Reuner  KHElgas  MKaps  MRuf  APatscheke  H The human platelet antigen HPA-1a/1b (PI(A1)/PI(A2)) polymorphism and cerebral ischaemia [letter]. Thromb Haemost 1997;78964- 965
Ridker  PMHennekens  CHSchmitz  CStampfer  MJLindpaintner  K PIA1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis. Lancet 1997;349385- 388
PubMed
van Goor  MLGomez Garcia  EBrouwers  GJLeebeek  FWKoudstaal  PJDippel  DW PLA1/A2 polymorphism of the platelet glycoprotein receptor IIb/IIIa in young patients with cryptogenic TIA or ischemic stroke. Thromb Res 2002;10863- 65
PubMed
Wagner  KRGiles  WHJohnson  CJ  et al.  Platelet glycoprotein receptor IIIa polymorphism P1A2 and ischemic stroke risk: the Stroke Prevention in Young Women Study. Stroke 1998;29581- 585
PubMed
Elbaz  APoirier  OMoulin  T  et al.  Association between the Glu298Asp polymorphism in the endothelial constitutive nitric oxide synthase gene and brain infarction. Stroke 2000;311634- 1639
PubMed
MacLeod  MJDahiyat  MTCumming  AMeiklejohn  DShaw  DSt Clair  D No association between Glu/Asp polymorphism of NOS3 gene and ischemic stroke. Neurology 1999;53418- 420
PubMed
Markus  HSRuigrok  YAli  NPowell  JF Endothelial nitric oxide synthase exon 7 polymorphism, ischemic cerebrovascular disease, and carotid atheroma. Stroke 1998;291908- 1911
PubMed
Endler  GLalouschek  WExner  MMitterbauer  GHaring  DMannhalter  C The 4G/4G genotype at nucleotide position −675 in the promotor region of the plasminogen activator inhibitor 1 (PAI−1) gene is less frequent in young patients with minor stroke than in controls. Br J Haematol 2000;110469- 471
PubMed
Hindorff  LASchwartz  SMSiscovick  DSPsaty  BMLongstreth  WT  JrReiner  AP The association of PAI-1 promoter 4G/5G insertion/deletion polymorphism with myocardial infarction and stroke in young women. J Cardiovasc Risk 2002;9131- 137
PubMed
Roest  Mvan der Schouw  YTBanga  JD  et al.  Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women. Circulation 2000;10167- 70
PubMed
Baker  RIEikelboom  JLofthouse  E  et al.  Platelet glycoprotein Ibα Kozak polymorphism is associated with an increased risk of ischemic stroke. Blood 2001;9836- 40
PubMed
Carter  AMCatto  AJBamford  JMGrant  PJ Platelet GP IIIa PlA and GP Ib variable number tandem repeat polymorphisms and markers of platelet activation in acute stroke. Arterioscler Thromb Vasc Biol 1998;181124- 1131
PubMed
Gonzalez-Conejero  RLozano  MLRivera  J  et al.  Polymorphisms of platelet membrane glycoprotein Ib associated with arterial thrombotic disease. Blood 1998;922771- 2776
PubMed
Corral  JGonzalez-Conejero  RLozano  MLRivera  JVicente  V Genetic polymorphisms of factor VII are not associated with arterial thrombosis. Blood Coagul Fibrinolysis 1998;9267- 272
PubMed
Heywood  DMCarter  AMCatto  AJBamford  JMGrant  PJ Polymorphisms of the factor VII gene and circulating FVII:C levels in relation to acute cerebrovascular disease and poststroke mortality. Stroke 1997;28816- 821
PubMed
Corral  JLozano  MLGonzalez-Conejero  R  et al.  A common polymorphism flanking the ATG initiator codon of GPIb α does not affect expression and is not a major risk factor for arterial thrombosis. Thromb Haemost 2000;8323- 28
PubMed
Frank  MBReiner  APSchwartz  SM  et al.  The Kozak sequence polymorphism of platelet glycoprotein Ibα and risk of nonfatal myocardial infarction and nonfatal stroke in young women. Blood 2001;97875- 879
PubMed
Huang  PKostulas  KHuang  WXCrisby  MKostulas  VHillert  J Lipoprotein lipase gene polymorphisms in ischaemic stroke and carotid stenosis. Eur J Clin Invest 1997;27740- 742
PubMed
Myllykangas  LPolvikoski  TSulkava  R  et al.  Association of lipoprotein lipase Ser447Ter polymorphism with brain infarction: a population-based neuropathological study. Ann Med 2001;33486- 492
PubMed
Wittrup  HHNordestgaard  BGSillesen  HSchnohr  PTybjaerg-Hansen  A A common mutation in lipoprotein lipase confers a 2-fold increase in risk of ischemic cerebrovascular disease in women but not in men. Circulation 2000;1012393- 2397
PubMed
Wald  DSLaw  MMorris  JK Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;3251202- 1206
PubMed
Keavney  BMcKenzie  CParish  S  et al. International Studies of Infarct Survival (ISIS) Collaborators, Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. Lancet 2000;355434- 442
PubMed
Keavney  BParish  SPalmer  A  et al.  Large-scale evidence that the cardiotoxicity of smoking is not significantly modified by the apolipoprotein E ε2/ε3/ε4 genotype. Lancet 2003;361396- 398
PubMed
Bertina  RMKoeleman  BPKoster  T  et al.  Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;36964- 67
PubMed
Dahlback  B New molecular insights into the genetics of thrombophilia: resistance to activated protein C caused by Arg506 to Gln mutation in factor V as a pathogenic risk factor for venous thrombosis. Thromb Haemost 1995;74139- 148
PubMed
Franco  RFTrip  MDten Cate  H  et al.  the 20210 G→A mutation in the 3′-untranslated region of the prothrombin gene and the risk for arterial thrombotic disease. Br J Haematol 1999;10450- 54
PubMed
Cattaneo  MChantarangkul  VTaioli  ESantos  JHTagliabue  L The G20210A mutation of the prothrombin gene in patients with previous first episodes of deep-vein thrombosis: prevalence and association with factor V G1691A, methylenetetrahydrofolate reductase C677T and plasma prothrombin levels. Thromb Res 1999;931- 8
PubMed
Tiret  LRigat  BVisvikis  S  et al.  Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I–converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 1992;51197- 205
PubMed
Sharma  PCarter  NDBarley  JLunt  RSeymour  CABrown  MM Polymorphisms in the gene encoding angiotensin 1–converting enzyme and relationship to its post-translational product in cerebral infarction. J Hum Hypertens 1994;8633- 634
PubMed
Agerholm-Larsen  BNordestgaard  BGTybjaerg-Hansen  A ACE gene polymorphism in cardiovascular disease: meta-analyses of small and large studies in whites. Arterioscler Thromb Vasc Biol 2000;20484- 492
PubMed
Kim  SIwao  H Molecular and cellular mechanisms of angiotensin II–mediated cardiovascular and renal diseases. Pharmacol Rev 2000;5211- 34
PubMed
Frosst  PBlom  HJMilos  R  et al.  A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10111- 113
PubMed
Klerk  MVerhoef  PClarke  R  et al. MTHFR Studies Collaboration Group, MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002;2882023- 2031
PubMed
Lellouche  FDorval  IDewilde  JVan Walleghem  E Presence of G1691A mutation on the gene of factor V in arterial thrombosis [letter] [in French]. Presse Med 1995;24869
PubMed
Moliaka  IuKPetruk  SVKir’ianov  SA  et al.  Association analysis of polymorphism in angiotensin-converting enzyme gene in ischemic stroke [in Russian]. Zh Nevrol Psikhiatr Im S S Korsakova 1998;9835- 37
PubMed
Pongracz  ETordai  ACsornai  MNagy  Z Genetics of blood coagulation in young stroke patients [in Hungarian]. Ideggyogy Sz 2002;55111- 117
Pongracz  ETordai  ACsornai  MNagy  Z Investigation of insertion/deletion polymorphism of the ACE gene in stroke patients [in Hungarian]. Ideggyogy Sz 2002;55157- 163
Pongracz  ETordai  ACsornai  MNagy  Z Platelet glycoprotein IIb/IIIa (LeuPro 33) polymorphism in stroke patients [in Hungarian]. Orv Hetil 2001;142781- 785
Yang  QKhoury  MJBotto  L  et al.  Improving the prediction of complex diseases by testing for multiple disease-susceptibility genes. Am J Hum Genet 2003;72636- 649
PubMed
Colhoun  HMMcKeigue  PMDavey Smith  G Problems of reporting genetic associations with complex outcomes. Lancet 2003;361865- 872
PubMed

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
Table 9.2-3 Refuted Evidence From Observational Studiesa

The Rational Clinical Examination
Quick Reference