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      Thrombomodulin Ala455Val Polymorphism and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study

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          The genes encoding proteins in the thrombomodulin-protein C pathway are promising candidate genes for stroke susceptibility because of their importance in thrombosis regulation and inflammatory response. Several published studies have shown that the Ala455Val thrombomodulin polymorphism is associated with ischemic heart disease, but none has examined the association with stroke. Using data from the Stroke Prevention in Young Women Study, we sought to determine the association between the Ala455Val thrombomodulin polymorphism and the occurrence of ischemic stroke in young women.


          All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. We compared 141 cases of first ischemic stroke (44% black) among women 15 to 44 years of age with 210 control subjects (35% black) who were identified by random digit dialing and frequency matched to the cases by age and geographical region of residence. Data on historical risk factors were collected by standardized interview. Genotyping of the thrombomodulin Ala455Val polymorphism was performed by pyrosequencing.


          The A allele (frequency = 0.85) was associated with stroke under the recessive model. After adjustment for age, race, cigarette smoking, hypertension, and diabetes, the AA genotype, compared with the AV and VV genotypes combined, was significantly associated with stroke (odds ratio 1.9, 95% CI 1.1–3.3). The AA genotype was more common among black than white control subjects (81% versus 68%) but there was no significant interaction between the risk genotype and race (adjusted odds ratio 2.7 for blacks and 1.6 for whites). A secondary analysis removing all probable (n = 16) and possible (n = 15) cardioembolic strokes demonstrated an increased association (odds ratio 2.2, 95% CI 1.2–4.2).


          Among women aged 15 to 44 years, the AA genotype is more prevalent among blacks than whites and is associated with increased risk of early onset ischemic stroke. Removing strokes potentially related to cardioembolic phenomena increased this association. Further studies are needed to determine whether this polymorphism is functionally related to thrombomodulin expression or whether the association is due to population stratification or linkage to a nearby functional polymorphism.

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          Most cited references 25

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          Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases.

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            Pregnancy and the risk of stroke.

            It is widely believed that pregnancy increases the risk of stroke, but there are few data available to quantify that risk. We identified all female patients 15 through 44 years of age in central Maryland and Washington, D.C., who were discharged from any of 46 hospitals in the study area in 1988 or 1991. Two neurologists reviewed each case, using data from the women's medical records. We determined whether the women had been pregnant at the time of the stroke or up to six weeks before it occurred. For purposes of this analysis, the six-week period after pregnancy could begin with an induced or spontaneous abortion or with the delivery of a live or stillborn child. Seventeen cerebral infarctions and 14 intracerebral hemorrhages occurred in women who were or had recently been pregnant (pregnancy-related strokes), and there were 175 cerebral infarctions and 48 intracerebral hemorrhages that were not related to pregnancy. For cerebral infarction, the relative risk during pregnancy, adjusted age and race, was 0.7 (95 percent confidence interval, 0.3 to 1.6), but it increased to 8.7 for the postpartum period (after a live birth or stillbirth) (95 percent confidence interval, 4.6 to 16.7). For intracerebral hemorrhage, the adjusted relative risk was 2.5 during pregnancy (95 percent confidence interval, 1.0 to 6.4) but 28.3 for the postpartum period (95 percent confidence interval, 13.0 to 61.4). Overall, for either type of stroke during or within six weeks after pregnancy, the adjusted relative risk was 2.4 (95 percent confidence interval, 1.6 to 3.6), and the attributable, or excess, risk was 8.1 strokes per 100,000 pregnancies (95 percent confidence interval, 6.4 to 9.7). The risks of both cerebral infarction and intracerebral hemorrhage are increased in the six weeks after delivery but not during pregnancy itself.
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              Point: population stratification: a problem for case-control studies of candidate-gene associations?

               John Witte,  C Thomas (2002)

                Author and article information

                BMC Neurol
                BMC Neurology
                BioMed Central (London )
                1 December 2004
                : 4
                : 21
                [1 ]Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA
                [2 ]Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
                [3 ]Department of Medicine University of Maryland School of Medicine, Baltimore, Maryland, USA
                [4 ]Geriatrics Research, Education, and Clinical Center, Department of Veterans Affairs Medical Center, Baltimore, Maryland, USA
                [5 ]Molecular Biology Branch, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
                [6 ]Division of Adult and Community Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
                [7 ]Coordinating Center for Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
                Copyright © 2004 Cole et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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