TY - JOUR
T1 - Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke
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
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.
N1 - Funding Information:
The authors thank all the individuals who volunteered and participated in the VISP studies; the physicians involved in VISP; Daniel Gallo and Emily Farber at the University of Virginia''s Genome Sciences Laboratory for technical support; and Fang Chen at the University of Virginia. Study recruitment and collection of datasets for the VISP trial were supported by a grant (R01 NS34447; PI James Toole) from the National Institute of Neurological Disorders and Stroke (NINDS). GWAS genotyping performed at the Center for Inherited Disease Research (CIDR) (U01 HG004438l; PI David Valle) was funded by the National Human Genome Research Institute and the Genomics and Randomized Trials (GARNET) Network (U01HG00516-03; co-PI Michèle M. Sale and Bradford B. Worrall) and genetic data cleaning was provided by the GARNET Coordinating Center (U01HG005157; PI Bruce S. Weir). Given that all VISP participants were stroke cases, we obtained GWAS data (dbGAP) for external controls from the High Density SNP Association Analysis of Melanoma: Case-Control and Outcomes Investigation (study accession: phs000187.v1.p1); they were also genotyped on the Illumina Human-Omni1-Quad by CIDR. The Framingham Heart Study is funded by the National Heart, Lung and Blood Institute (NHLBI) (contract no. N01-HC-25195; http://www.framinghamheartstudy.org/) and by grants from NINDS (NS17950, www.ninds.nih.gov/), the NHLBI (U01HL 096917; www.nhlbi.nih.gov), and the National Institute on Aging (NIA) (AG08122, AG033193; www.nia.nih.gov). All links are current as of August 4, 2015. METASTROKE is an unfunded consortium of large case-control and cohort GWAS studies of stroke.
Publisher Copyright:
© 2015 American Academy of Neurology.
PY - 2016/1/26
Y1 - 2016/1/26
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.
AB - 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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U2 - 10.1212/WNL.0000000000002319
DO - 10.1212/WNL.0000000000002319
M3 - Article
C2 - 26718567
AN - SCOPUS:84956818056
SN - 0028-3878
VL - 86
SP - 351
EP - 359
JO - Neurology
JF - Neurology
IS - 4
ER -