***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    ***EXAMPLES*** 
    Input: The genetic background of complex diseases is proposed to consist of several low-penetrance risk loci . Addressing this complexity likely requires both large sample size and simultaneous analysis of different predisposing variants . We investigated the role of four thrombosis genes :  coagulation factor V ( F5 ) ,  intercellular adhesion molecule 1 ( ICAM1 ) ,  protein C ( PROC ) , and thrombomodulin ( THBD ) in cardiovascular diseases . Single allelic gene variants and their pair-wise combinations were analyzed in two independently sample d population cohorts from Finl and . From among 14,140 FINRISK participants ( FINRISK-92 , n = 5,999 and FINRISK-97 , n = 8,141 ) , we selected for genotyping a sample of 2,222 , including 528 incident cardiovascular disease ( CVD ) cases and r and om subcohorts totaling 786 . To cover all known common haplotypes ( > 10 % ) , 54 single nucleotide polymorphisms ( SNPs ) were genotyped . Classification-tree analysis identified 11 SNPs that were further analyzed in Cox 's proportional hazard model as single variants and pair-wise combinations . Multiple testing was controlled by use of two independent cohorts and with false-discovery rate . Several CVD risk variants were identified : In women , the combination of F5 rs7542281 × THBD rs1042580 , together with three single F5 SNPs , was associated with CVD events . Among men , PROC rs1041296 , when combined with either ICAM1 rs5030341 or F5 rs2269648 , was associated with total mortality . As a single variant , PROC rs1401296 , together with the F5 Leiden mutation , was associated with ischemic stroke events . Our strategy to combine the classification-tree analysis with more traditional genetic models was successful in identifying SNPs — acting either in combination or as single variants — predisposing to CVD , and produced consistent results in two independent cohorts . These results suggest that variants in these four thrombosis genes contribute to arterial cardiovascular events at population level BACKGROUND AND PURPOSE Factor V Leiden and a prothrombin gene variant , G20210A , are mutations associated with a thrombotic risk . The aim of our study was to assess whether these mutations increase the risk of stroke in women under 45 years of age . METHODS We conducted a case-control study in western Washington state . Case patients were women aged 18 to 44 years with a first stroke ( n = 106 ) . Control subjects were women without stroke recruited from the same region by use of r and om-digit telephone dialing ( n = 391 ) . All were interviewed and provided blood specimens , which were genotyped for these mutations . RESULTS Factor V Leiden was found in 0.9 % of case patients , a single patient with a subarachnoid hemorrhage , and in 4.1 % of control subjects . The odds ratio ( OR ) for any stroke was 0.2 ( 95 % confidence interval [ CI ] , 0.03 to 1.7 ) . The prothrombin variant was found in 1.9 % of case patients , 1 with a venous stroke and 1 with an ischemic stroke , and in 1.6 % of control subjects . The OR for any stroke was 1.48 ( 95 % CI , 0.14 to 9.17 ) . ORs for stroke types were also not statistically significant . CONCLUSIONS In this study , neither factor V Leiden nor the prothrombin variant ( G20210A ) was an important risk factor for stroke in young women . In this setting , screening for these mutations can not be recommended . Unanswered by this study is whether screening would be useful in select patients , such as those with a strong family history of thrombophilia or those with venous strokes Background and Purpose s— Abnormalities in blood coagulation and the fibrinolytic system have been associated with increased risk of stroke , but few prospect i ve studies have studied the associations in older adults . We have examined the associations between fibrin D-dimer , tissue-type plasminogen activator , and  von Willebr and factor ( vWF )  and risk of stroke in older men and examined their predictive roles separately in normotensive and hypertensive men . Methods — Prospect i ve study of 3358 men aged 60 to 79 years with no previous diagnosis of myocardial infa rct ion or stroke and without atrial fibrillation followed-up for an average of 9 years , during which there were 187 incident stroke events . Results — Increased levels of D-dimer and vWF were associated with significantly increased risk of major stroke events after adjustment for potential confounders , including systolic blood pressure ( adjusted hazard ratios and 95 % confidence interval per st and ard deviation increase in D-dimer and vWF were 1.24 [ 95 % confidence interval , 1.08–1.44 ] and 1.25 [ 95 % confidence interval , 1.09–1.45 ] , respectively ) . No associations were seen with tPA after adjustment . The positive associations between D-dimer and vWF and incident stroke remained after additional adjustment for markers of inflammation ( C-reactive protein , IL-6 ) . D-dimer was associated with stroke in both normotensive and hypertensive men ; vWF showed stronger associations in normotensive than in hypertensive men ( test for interaction : P=0.52 for D-dimer ; P<0.01 for vWF ) . Conclusions — Fibrin D-dimer and vWF are associated with increased risk of stroke in older men . These associations were not explained by their associations with inflammation . D-dimer may be a useful marker to identify those at high risk for stroke among hypertensive men Little is known about the prospect i ve associations of fibrinogen , factor VII , or factor VIII with  cardiovascular disease ( CVD ) and mortality in the elderly . At baseline in the Cardiovascular Health Study ( 5888 white and African American men and women ; aged > /=65 years ) , we measured  fibrinogen , factor VIII , and factor VII .  We used sex-stratified stepwise Cox survival analysis to determine relative risks ( RRs ) for CVD events and all-cause mortality ( up to 5 years of follow-up ) , both unadjusted and adjusted for CVD risk factors and sub clinical CVD . After adjustment , comparing the fifth quintile to the first , fibrinogen was significantly associated in men with coronary heart disease events ( RR=2.1 ) and stroke or transient ischemic attack ( RR=1.3 ) , and also with mortality within 2.5 years of follow-up ( RR=5.8 ) and later ( RR=1.7 ) . Factor VIII was significantly associated in men with coronary heart disease events ( RR=1.5 ) and mortality ( RR=1.8 ) , and in women with stroke/transient ischemic attack ( RR=1.4 ) . For both factors , values were higher in those who died , whether causes were CVD-related or non-CVD-related , but highest in CVD death . Factor VII exhibited associations with incident angina ( RR=1.44 ) in men and with death in women ( RR , middle quintile compared with first=0.66 ) . However , in general , factor VII was not consistently associated with CVD events in this population . We conclude that , if confirmed in other studies , the measurement of fibrinogen and /or factor VIII may help identify older individuals at higher risk for CVD events and mortality Using specimens from a population -based case control study among women ages 18 to 44 years in western Washington , we assessed the relationship between carriership of a genetic clotting factor II variant ( 20210 G-->A ) and myocardial infa rct ion ( MI ) . The factor II variant was previously shown to be present in 1 % to 2 % of the population , to increase the levels of factor II , and to be associated with venous thrombotic disease . Personal interviews and blood sample s were obtained from 79 women with a first myocardial infa rct ion and 381 control women identified through r and om-digit telephone dialing . Polymerase chain reaction ( PCR ) method was used to determine the factor II genotypes . The factor II 20210 G to A transition was present more often in women with MI ( 5.1 % ) than among control women ( 1.6 % ) . The age-adjusted odds ratio for MI was 4.0 ( 95 % confidence interval 1.1 to 15.1 ) . The relative risk was high when another major cardiovascular risk factor was also present , such as smoking ( odds ratio 43.3 , 95 % confidence interval 6.7 to 281 ) , and the risk seemed limited to those with other risk factors . These results , in which the effect of major coronary risk factors is enhanced fourfold to sixfold by the prothrombin variant , are similar to those previously reported for another genetic clotting abnormality , factor V Leiden . We conclude that factor II 20210 G to A increases the risk of myocardial infa rct ion in young women , especially in the women with other major risk factors for coronary heart disease To determine the presence of a ' hypercoagulable state ' as assessed by indices of thrombin and plasmin generation and of the amount of fibrin that is lysed , in patients with stable coronary , cerebral and peripheral arterial disease a population -based cross-sectional study was performed . From a population -based cohort comprising 7983 men and women aged 55 years and over , we r and omly selected 127 subjects with a history of myocardial infa rct ion , 124 with a history of stroke and /or transient ischemic attack , 131 patients with peripheral arterial disease and 263 control subjects in the same age group without arterial disease . Subjects using anticoagulant drugs were not selected . F1 + 2 , TAT , and PAP were not associated with a history of cardiovascular events , nor with peripheral arterial disease . In contrast , positive associations were found for D-Dimer . Mean D-Dimer level was 40 microg/l ( 95 % CI 35 , 44 ) in control subjects ; 53 microg/l ( 47 , 61 ) in those with a history of myocardial infa rct ion and 51 microg/l ( 45 , 58 ) in those with a history of stroke and or transient ischemic attack . D-Dimer increased gradually with increasing severity of peripheral atherosclerosis ; a decrease in ankle/arm systolic blood pressure ratio of 0.1 was associated with an increase in D-Dimer of 3.9 microg/l ( p<0.01 ) . This was more pronounced in subjects with higher F1 + 2 , TAT and PAP concentration . In conclusion , the markers of onset of coagulation F1 + 2 , TAT and PAP are not associated with the presence of arterial disease , but increased levels of these markers are necessary for the positive association between D-Dimer and arterial disease BACKGROUND A single base pair mutation in the prothrombin gene has recently been identified that is associated with increased prothrombin levels . Whether this mutation increases the risks of arterial and venous thrombosis among healthy individuals is controversial . METHODS AND RESULTS In a prospect i ve cohort of 14 916 men , we determined the prevalence of the G20210A prothrombin gene variant in 833 men who subsequently developed myocardial infa rct ion , stroke , or venous thrombosis ( cases ) and in 1774 age- and smoking status-matched men who remained free of thrombosis during a 10-year follow-up ( control subjects ) .  Gene sequencing was used to confirm mutation status in a subgroup of participants . Overall , carrier rates for the G20210A mutation were similar among case and control subjects ; the relative risk of developing any thrombotic event in association with the 20210A allele was 1.05 ( 95 % CI , 0.7 to 1.6 ; P=0.8 ) . We observed no evidence of association between mutation and myocardial infa rct ion ( RR=0.8 , P=0.4 ) or stroke ( RR=1.1 , P=0.8 ) . For venous thrombosis , a modest nonsignificant increase in risk was observed ( RR=1.7 , P=0.08 ) that was smaller in magnitude than that associated with factor V Leiden ( RR=3.0 , P<0 . 001 ) . Nine individuals carried both the prothrombin mutation and factor V Leiden ( 5 controls and 4 cases ) . One individual , a control subject , was homozygous for the prothrombin mutation . CONCLUSIONS In a large cohort of US men , the G20210A prothrombin gene variant was not associated with increased risk of myocardial infa rct ion or stroke . For venous thrombosis , risk estimates associated with the G20210A mutation were smaller in magnitude than risk estimates associated with factor V Leiden Background and Purpose The etiology of ischemic stroke affects prognosis , outcome , and management . Trials of therapies for patients with acute stroke should include measurements of responses as influenced by subtype of ischemic stroke . A system for categorization of subtypes of ischemic stroke mainly based on etiology has been developed for the Trial of Org 10172 in Acute Stroke Treatment ( TOAST ) . Methods A classification of subtypes was prepared using clinical features and the results of ancillary diagnostic studies . “ Possible ” and “ probable ” diagnoses can be made based on the physician 's certainty of diagnosis . The usefulness and interrater agreement of the classification were tested by two neurologists who had not participated in 
    Output:
    
These results suggest that hypercoagulability has a more pronounced effect on the risk of IS than that of MI