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Low dehydroepiandrosterone sulfate is associated with increased risk of ischemic stroke among women.

ABSTRACT: Previous research suggests greater risk of coronary heart disease with lower levels of the adrenal steroid dehydroepiandrosterone sulfate (DHEAS). No studies have examined the association between DHEAS and risk of ischemic stroke. DHEAS may influence ischemic stroke risk through atherosclerotic-related mechanisms (endothelial function and smooth muscle cell proliferation) or insulin resistance.Between 1989 and 1990, 32 826 women without prior stroke in the Nurses' Health Study, an observational cohort, provided blood samples and were followed up for cardiovascular events. Among this sample, using a nested case-control design, 461 ischemic strokes were confirmed by medical records by 2006. Cases were matched to controls free of stroke at the time of the index case and by age, race, menopausal status, postmenopausal hormone use, smoking status, and date of sample collection. Multivariable conditional logistic regression was used.Median DHEAS levels did not differ between cases (median=58.7) and controls (median=66.0; P=0.10). Conditional on matching factors, the lowest DHEAS quartile exhibited a relative risk of 1.30 for ischemic stroke (95% confidence interval, 0.88-1.94), compared with the highest quartile and marginally unchanged when adjusted for confounders (relative risk=1.33; 95% confidence interval, 0.87-2.02). When modeled as a binary variable dichotomized at the lowest quartile, women with low DHEAS (?the lowest quartile) had a significantly increased multivariable adjusted risk of ischemic stroke compared with those with higher levels (relative risk=1.41; 95% confidence interval, 1.03-1.92).Lower DHEAS levels were associated with a greater risk of ischemic stroke, even after adjustment for potential confounders. These novel observations warrant confirmation in other populations.

SUBMITTER: Jimenez MC

PROVIDER: S-EPMC3811081 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Low dehydroepiandrosterone sulfate is associated with increased risk of ischemic stroke among women.

Jiménez Monik C MC Sun Qi Q Schürks Markus M Chiuve Stephanie S Hu Frank B FB Manson Joann E JE Rexrode Kathryn M KM

Stroke 20130523 7

<h4>Background and purpose</h4>Previous research suggests greater risk of coronary heart disease with lower levels of the adrenal steroid dehydroepiandrosterone sulfate (DHEAS). No studies have examined the association between DHEAS and risk of ischemic stroke. DHEAS may influence ischemic stroke risk through atherosclerotic-related mechanisms (endothelial function and smooth muscle cell proliferation) or insulin resistance.<h4>Methods</h4>Between 1989 and 1990, 32 826 women without prior stroke ...[more]

PMID: 23704104

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Project description:Ischemic stroke causes a high mortality and morbidity worldwide. It results from a complex interplay of incompletely known environmental and genetic risk factors. We investigated the ABCC6 gene as a candidate risk factor for ischemic stroke because of the increased ischemic stroke incidence in the autosomal recessive disorder pseudoxanthoma elasticum, caused by biallelic pathogenic ABCC6 variants, the higher cardiovascular risk in heterozygous carriers and the established role of ABCC6 dysfunction in myocardial ischemia. We established segregation of a known pathogenic ABCC6 variant (p.[Arg1314Gln]) in 11/19 family members of an ischemic stroke patient in a large multigenerational family suffering from ischemic stroke and/or cardiovascular disease at a relatively young age. In an independent case-control study in 424 ischemic stroke patients and 250 healthy controls, pathogenic ABCC6 variants were 4.9 times more frequent (P = 0.036; 95% CI 1.11-21.33) in the ischemic stroke patient cohort. To study cellular consequences of ABCC6 deficiency in the brain, immunostaining of brain sections in Abcc6-deficient mice and wild-type controls were performed. An upregulation of Bmp4 and Eng and a downregulation of Alk2 was identified in Abcc6-/- mice, suggesting an increase in apoptosis and angiogenesis. As both of these processes are induced in ischemia, we propose that a pro-ischemic state may explain the higher risk to suffer from ischemic stroke in patients carrying a pathogenic ABCC6 variant, as this may lower the threshold to develop acute ischemic events in these patients. In conclusion, this study identified heterozygous ABCC6 variants as a risk factor for ischemic stroke. Further, dysregulation of Bmp (Bmp4, Alk2) and Tgfβ (Eng) signaling in the brain of Abcc6-/- mice could lead to a pro-ischemic state, lowering the threshold to develop acute ischemic events. These data demonstrate the importance of a molecular analysis of the ABCC6 gene in patients diagnosed with cryptogenic ischemic stroke.

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Low dehydroepiandrosterone sulfate is associated with increased risk of ischemic stroke among women.

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Low dehydroepiandrosterone sulfate is associated with increased risk of ischemic stroke among women.

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