Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke

Stephen R. Williams, Fang Chi Hsu, Keith L. Keene, Wei Min Chen, Sarah Nelson, Andrew M. Southerland, Ebony B. Madden, Bruce M Coull, Stephanie M. Gogarten, Karen L. Furie, Godfrey Dzhivhuho, Joe L. Rowles, Prachi Mehndiratta, Rainer Malik, Josée Dupuis, Honghuang Lin, Sudha Seshadri, Stephen S. Rich, Michèle M. Sale, Bradford B. Worrall

Research output: Contribution to journalArticle

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Abstract

Objective: To investigate the genetic contributors to cerebrovascular disease and variation in biomarkers of ischemic stroke. Methods: The Vitamin Intervention for Stroke Prevention Trial (VISP) was a randomized, controlled clinical trial of B vitamin supplementation to prevent recurrent stroke, myocardial infarction, or death. VISP collected baseline measures of C-reactive protein (CRP), fibrinogen, creatinine, prothrombin fragments F 1+2, thrombin-antithrombin complex, and thrombomodulin prior to treatment initiation. Genome-wide association scans were conducted for these traits and follow-up replication analyses were performed. Results: We detected an association between CRP single nucleotide polymorphisms (SNPs) and circulating CRP levels (most associated SNP, rs2592902, p 1.14 × 10 -9) in 2,100 VISP participants. We discovered a novel association for CRP level in the AKR1D1 locus (rs2589998, p 7.3 × 10 -8, approaching genome-wide significance) that also is an expression quantitative trait locus for CRP gene expression. We replicated previously identified associations of fibrinogen with SNPs in the FGB and LEPR loci. CRP-associated SNPs and CRP levels were significantly associated with risk of ischemic stroke and recurrent stroke in VISP as well as specific stroke subtypes in METASTROKE. Fibrinogen levels but not fibrinogen-associated SNPs were also found to be associated with recurrent stroke in VISP. Conclusions: Our data identify a genetic contribution to inflammatory and hemostatic biomarkers in a stroke population. Additionally, our results suggest shared genetic contributions to circulating CRP levels measured poststroke and risk for incident and recurrent ischemic stroke. These data broaden our understanding of genetic contributors to biomarker variation and ischemic stroke risk, which should be useful in clinical risk evaluation.

Original languageEnglish (US)
Pages (from-to)351-359
Number of pages9
JournalNeurology
Volume86
Issue number4
DOIs
StatePublished - Jan 26 2016

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Genetic Predisposition to Disease
Blood Vessels
Biomarkers
Stroke
C-Reactive Protein
Vitamins
Single Nucleotide Polymorphism
Fibrinogen
Cerebrovascular Disorders
Thrombomodulin
Vitamin B Complex
Quantitative Trait Loci
Genome-Wide Association Study
Hemostatics
Creatinine
Randomized Controlled Trials
Myocardial Infarction

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Williams, S. R., Hsu, F. C., Keene, K. L., Chen, W. M., Nelson, S., Southerland, A. M., ... Worrall, B. B. (2016). Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke. Neurology, 86(4), 351-359. https://doi.org/10.1212/WNL.0000000000002319

Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke. / Williams, Stephen R.; Hsu, Fang Chi; Keene, Keith L.; Chen, Wei Min; Nelson, Sarah; Southerland, Andrew M.; Madden, Ebony B.; Coull, Bruce M; Gogarten, Stephanie M.; Furie, Karen L.; Dzhivhuho, Godfrey; Rowles, Joe L.; Mehndiratta, Prachi; Malik, Rainer; Dupuis, Josée; Lin, Honghuang; Seshadri, Sudha; Rich, Stephen S.; Sale, Michèle M.; Worrall, Bradford B.

In: Neurology, Vol. 86, No. 4, 26.01.2016, p. 351-359.

Research output: Contribution to journalArticle

Williams, SR, Hsu, FC, Keene, KL, Chen, WM, Nelson, S, Southerland, AM, Madden, EB, Coull, BM, Gogarten, SM, Furie, KL, Dzhivhuho, G, Rowles, JL, Mehndiratta, P, Malik, R, Dupuis, J, Lin, H, Seshadri, S, Rich, SS, Sale, MM & Worrall, BB 2016, 'Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke', Neurology, vol. 86, no. 4, pp. 351-359. https://doi.org/10.1212/WNL.0000000000002319
Williams SR, Hsu FC, Keene KL, Chen WM, Nelson S, Southerland AM et al. Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke. Neurology. 2016 Jan 26;86(4):351-359. https://doi.org/10.1212/WNL.0000000000002319
Williams, Stephen R. ; Hsu, Fang Chi ; Keene, Keith L. ; Chen, Wei Min ; Nelson, Sarah ; Southerland, Andrew M. ; Madden, Ebony B. ; Coull, Bruce M ; Gogarten, Stephanie M. ; Furie, Karen L. ; Dzhivhuho, Godfrey ; Rowles, Joe L. ; Mehndiratta, Prachi ; Malik, Rainer ; Dupuis, Josée ; Lin, Honghuang ; Seshadri, Sudha ; Rich, Stephen S. ; Sale, Michèle M. ; Worrall, Bradford B. / Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke. In: Neurology. 2016 ; Vol. 86, No. 4. pp. 351-359.
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abstract = "Objective: To investigate the genetic contributors to cerebrovascular disease and variation in biomarkers of ischemic stroke. Methods: The Vitamin Intervention for Stroke Prevention Trial (VISP) was a randomized, controlled clinical trial of B vitamin supplementation to prevent recurrent stroke, myocardial infarction, or death. VISP collected baseline measures of C-reactive protein (CRP), fibrinogen, creatinine, prothrombin fragments F 1+2, thrombin-antithrombin complex, and thrombomodulin prior to treatment initiation. Genome-wide association scans were conducted for these traits and follow-up replication analyses were performed. Results: We detected an association between CRP single nucleotide polymorphisms (SNPs) and circulating CRP levels (most associated SNP, rs2592902, p 1.14 × 10 -9) in 2,100 VISP participants. We discovered a novel association for CRP level in the AKR1D1 locus (rs2589998, p 7.3 × 10 -8, approaching genome-wide significance) that also is an expression quantitative trait locus for CRP gene expression. We replicated previously identified associations of fibrinogen with SNPs in the FGB and LEPR loci. CRP-associated SNPs and CRP levels were significantly associated with risk of ischemic stroke and recurrent stroke in VISP as well as specific stroke subtypes in METASTROKE. Fibrinogen levels but not fibrinogen-associated SNPs were also found to be associated with recurrent stroke in VISP. Conclusions: Our data identify a genetic contribution to inflammatory and hemostatic biomarkers in a stroke population. Additionally, our results suggest shared genetic contributions to circulating CRP levels measured poststroke and risk for incident and recurrent ischemic stroke. These data broaden our understanding of genetic contributors to biomarker variation and ischemic stroke risk, which should be useful in clinical risk evaluation.",
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AU - Williams, Stephen R.

AU - Hsu, Fang Chi

AU - Keene, Keith L.

AU - Chen, Wei Min

AU - Nelson, Sarah

AU - Southerland, Andrew M.

AU - Madden, Ebony B.

AU - Coull, Bruce M

AU - Gogarten, Stephanie M.

AU - Furie, Karen L.

AU - Dzhivhuho, Godfrey

AU - Rowles, Joe L.

AU - Mehndiratta, Prachi

AU - Malik, Rainer

AU - Dupuis, Josée

AU - Lin, Honghuang

AU - Seshadri, Sudha

AU - Rich, Stephen S.

AU - Sale, Michèle M.

AU - Worrall, Bradford B.

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N2 - Objective: To investigate the genetic contributors to cerebrovascular disease and variation in biomarkers of ischemic stroke. Methods: The Vitamin Intervention for Stroke Prevention Trial (VISP) was a randomized, controlled clinical trial of B vitamin supplementation to prevent recurrent stroke, myocardial infarction, or death. VISP collected baseline measures of C-reactive protein (CRP), fibrinogen, creatinine, prothrombin fragments F 1+2, thrombin-antithrombin complex, and thrombomodulin prior to treatment initiation. Genome-wide association scans were conducted for these traits and follow-up replication analyses were performed. Results: We detected an association between CRP single nucleotide polymorphisms (SNPs) and circulating CRP levels (most associated SNP, rs2592902, p 1.14 × 10 -9) in 2,100 VISP participants. We discovered a novel association for CRP level in the AKR1D1 locus (rs2589998, p 7.3 × 10 -8, approaching genome-wide significance) that also is an expression quantitative trait locus for CRP gene expression. We replicated previously identified associations of fibrinogen with SNPs in the FGB and LEPR loci. CRP-associated SNPs and CRP levels were significantly associated with risk of ischemic stroke and recurrent stroke in VISP as well as specific stroke subtypes in METASTROKE. Fibrinogen levels but not fibrinogen-associated SNPs were also found to be associated with recurrent stroke in VISP. Conclusions: Our data identify a genetic contribution to inflammatory and hemostatic biomarkers in a stroke population. Additionally, our results suggest shared genetic contributions to circulating CRP levels measured poststroke and risk for incident and recurrent ischemic stroke. These data broaden our understanding of genetic contributors to biomarker variation and ischemic stroke risk, which should be useful in clinical risk evaluation.

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