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1. Artery occlusion independently predicts unfavorable outcome in cervical artery dissection

Author

Traenka, C, Grond-Ginsbach, C, Goeggel Simonetti, B, Metso, T, Debette, S, Pezzini, A, Kloss, M, Majersik, J, Southerland, A, Leys, D, Baumgartner, R, Caso, V, Bejot, Y, De Marchis, G, Fischer, U, Polymeris, A, Sarikaya, H, Thijs, V, Worrall, B, Bersano, A, Brandt, T, Gensicke, H, Bonati, L, Touzee, E, Martin, J, Chabriat, H, Tatlisumak, T, Arnold, M, Engelter, S, Lyrer, P, Ferrarese, C, Traenka C., Grond-Ginsbach C., Goeggel Simonetti B., Metso T. M., Debette S., Pezzini A., Kloss M., Majersik J. J., Southerland A. M., Leys D., Baumgartner R., Caso V., Bejot Y., De Marchis G. M., Fischer U., Polymeris A., Sarikaya H., Thijs V., Worrall B. B., Bersano A., Brandt T., Gensicke H., Bonati L. H., Touzee E., Martin J. J., Chabriat H., Tatlisumak T., Arnold M., Engelter S. T., Lyrer P., Ferrarese C., Traenka, C, Grond-Ginsbach, C, Goeggel Simonetti, B, Metso, T, Debette, S, Pezzini, A, Kloss, M, Majersik, J, Southerland, A, Leys, D, Baumgartner, R, Caso, V, Bejot, Y, De Marchis, G, Fischer, U, Polymeris, A, Sarikaya, H, Thijs, V, Worrall, B, Bersano, A, Brandt, T, Gensicke, H, Bonati, L, Touzee, E, Martin, J, Chabriat, H, Tatlisumak, T, Arnold, M, Engelter, S, Lyrer, P, Ferrarese, C, Traenka C., Grond-Ginsbach C., Goeggel Simonetti B., Metso T. M., Debette S., Pezzini A., Kloss M., Majersik J. J., Southerland A. M., Leys D., Baumgartner R., Caso V., Bejot Y., De Marchis G. M., Fischer U., Polymeris A., Sarikaya H., Thijs V., Worrall B. B., Bersano A., Brandt T., Gensicke H., Bonati L. H., Touzee E., Martin J. J., Chabriat H., Tatlisumak T., Arnold M., Engelter S. T., Lyrer P., and Ferrarese C.

Abstract

OBJECTIVE: To assess the impact of dissected artery occlusion (DAO) on functional outcome and complications in patients with cervical artery dissection (CeAD). METHODS: We analyzed combined individual patient data from 3 multicenter cohorts of consecutive patients with CeAD (the Cervical Artery Dissection and Ischemic Stroke Patients [CADISP]-Plus consortium dataset). Patients with data on DAO and functional outcome were included. We compared patients with DAO to those without DAO. Primary outcome was favorable functional outcome (i.e., modified Rankin Scale [mRS] score 0-1) measured 3-6 months from baseline. Secondary outcomes included delayed cerebral ischemia, major hemorrhage, recurrent CeAD, and death. We performed univariate and multivariable binary logistic regression analyses and calculated odds ratios (OR) with 95% confidence intervals (CI), with adjustment for potential confounders. RESULTS: Of 2,148 patients (median age 45 years [interquartile range (IQR) 38-52], 43.6% women), 728 (33.9%) had DAO. Patients with DAO more frequently presented with cerebral ischemia (84.6% vs 58.5%, p < 0.001). Patients with DAO were less likely to have favorable outcome when compared to patients without DAO (mRS 0-1: 59.6% vs 80.1%, punadjusted < 0.001). After adjustment for age, sex, and initial stroke severity, DAO was independently associated with less favorable outcome (mRS 0-1: OR 0.65, CI 0.50-0.84, p = 0.001). Delayed cerebral ischemia occurred more frequently in patients with DAO than in patients without DAO (4.5% vs 2.9%, p = 0.059). CONCLUSION: DAO independently predicts less favorable functional outcome in patients with CeAD. Further research on vessel patency, collateral status and effects of revascularization therapies particularly in patients with DAO is warranted.

Published
2020

2. L’âge cérébral radiomique prédit le pronostic fonctionnel après un avc ischémique.

Author

Bretzner, M, Bonkhoff, A, Schirmer, M, Hong, S, Dalca, A, Donahue, K, Giese, A-K, Etherton, M, Rist, P, Nardin, M, Regenhardt, R, Leclerc, X, Lopes, R, Gautherot, M, Wang, C, Benavente, O, Cole, J, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Conde, JJ, Kittner, S, Lemmens, R, Levi, C, McArdle, P, McDonough, C, Meshia, J, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, R, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, T, Strbian, D, Tatlisumak, T, Thijs, V, Vagala, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, B, Maguire, J, Lindgren, A, Jern, C, Golland, P, Kuchcinski, G, Rost, N, Bretzner, M, Bonkhoff, A, Schirmer, M, Hong, S, Dalca, A, Donahue, K, Giese, A-K, Etherton, M, Rist, P, Nardin, M, Regenhardt, R, Leclerc, X, Lopes, R, Gautherot, M, Wang, C, Benavente, O, Cole, J, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Conde, JJ, Kittner, S, Lemmens, R, Levi, C, McArdle, P, McDonough, C, Meshia, J, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, R, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, T, Strbian, D, Tatlisumak, T, Thijs, V, Vagala, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, B, Maguire, J, Lindgren, A, Jern, C, Golland, P, Kuchcinski, G, and Rost, N

Published
2022

3. Artery occlusion independently predicts unfavorable outcome in cervical artery dissection

Author

Traenka C., Grond-Ginsbach C., Goeggel Simonetti B., Metso T. M., Debette S., Pezzini A., Kloss M., Majersik J. J., Southerland A. M., Leys D., Baumgartner R., Caso V., Bejot Y., De Marchis G. M., Fischer U., Polymeris A., Sarikaya H., Thijs V., Worrall B. B., Bersano A., Brandt T., Gensicke H., Bonati L. H., Touzee E., Martin J. J., Chabriat H., Tatlisumak T., Arnold M., Engelter S. T., Lyrer P., Ferrarese C., Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Traenka, C, Grond-Ginsbach, C, Goeggel Simonetti, B, Metso, T, Debette, S, Pezzini, A, Kloss, M, Majersik, J, Southerland, A, Leys, D, Baumgartner, R, Caso, V, Bejot, Y, De Marchis, G, Fischer, U, Polymeris, A, Sarikaya, H, Thijs, V, Worrall, B, Bersano, A, Brandt, T, Gensicke, H, Bonati, L, Touzee, E, Martin, J, Chabriat, H, Tatlisumak, T, Arnold, M, Engelter, S, Lyrer, P, and Ferrarese, C

Subjects
Adult, Male, medicine.medical_specialty, Cervical Artery, medicine.medical_treatment, 030204 cardiovascular system & hematology, Revascularization, Article, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Modified Rankin Scale, Aneurysm, Dissecting, Internal medicine, Humans, Medicine, Artery occlusion, Stroke, Aged, business.industry, Odds ratio, Recovery of Function, Middle Aged, medicine.disease, 3. Good health, Aortic Dissection, Cerebrovascular Disorders, Dissection, VINTAGE, Cerebrovascular Disorder, Cardiology, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cerebral Arterial Diseases, Neurology (clinical), business, Cerebral Arterial Disease, 030217 neurology & neurosurgery, Human
Abstract

ObjectiveTo assess the impact of dissected artery occlusion (DAO) on functional outcome and complications in patients with cervical artery dissection (CeAD).MethodsWe analyzed combined individual patient data from 3 multicenter cohorts of consecutive patients with CeAD (the Cervical Artery Dissection and Ischemic Stroke Patients [CADISP]–Plus consortium dataset). Patients with data on DAO and functional outcome were included. We compared patients with DAO to those without DAO. Primary outcome was favorable functional outcome (i.e., modified Rankin Scale [mRS] score 0–1) measured 3–6 months from baseline. Secondary outcomes included delayed cerebral ischemia, major hemorrhage, recurrent CeAD, and death. We performed univariate and multivariable binary logistic regression analyses and calculated odds ratios (OR) with 95% confidence intervals (CI), with adjustment for potential confounders.ResultsOf 2,148 patients (median age 45 years [interquartile range (IQR) 38–52], 43.6% women), 728 (33.9%) had DAO. Patients with DAO more frequently presented with cerebral ischemia (84.6% vs 58.5%, p < 0.001). Patients with DAO were less likely to have favorable outcome when compared to patients without DAO (mRS 0–1: 59.6% vs 80.1%, punadjusted < 0.001). After adjustment for age, sex, and initial stroke severity, DAO was independently associated with less favorable outcome (mRS 0–1: OR 0.65, CI 0.50–0.84, p = 0.001). Delayed cerebral ischemia occurred more frequently in patients with DAO than in patients without DAO (4.5% vs 2.9%, p = 0.059).ConclusionDAO independently predicts less favorable functional outcome in patients with CeAD. Further research on vessel patency, collateral status and effects of revascularization therapies particularly in patients with DAO is warranted.

Published
2020

5. 505 INTERLEUKIN-6, C-REACTIVE PROTEIN, FIBRINOGEN, AND RISK OF RECURRENCE AFTER ISCHEMIC STROKE: SYSTEMATIC REVIEW AND META-ANALYSIS

Author

McCabe, J J, primary, O’Reilly, E, additional, Coveney, S, additional, Harbison, J, additional, Collins, R, additional, Healy, L, additional, McManus, J, additional, Mulcahy, R, additional, Moynihan, B, additional, Cassidy, T, additional, Hsu, F, additional, Worrall, B, additional, Murphy, S, additional, O’Donnell, M, additional, and Kelly, P J, additional

Published
2021
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6. Genome-Wide Association Study Identifies First Locus Associated with Susceptibility to Cerebral Venous Thrombosis

Author

Ken-Dror, G, Cotlarciuc, I, Martinelli, I, Grandone, E, Hiltunen, S, Lindgren, E, Margaglione, M, Duchez, VLC, Triquenot, AB, Zedde, M, Mancuso, M, Ruigrok, YM, Marjot, T, Worrall, B, Majersik, JJ, Metso, TM, Putaala, J, Haapaniemi, E, Zuurbier, SM, Brouwer, MC, Passamonti, SM, Abbattista, M, Bucciarelli, P, Mitchell, BD, Kittner, SJ, Lemmens, R, Jern, C, Pappalardo, E, Costa, P, Colombi, M, de Sousa, DA, Rodrigues, S, Canhao, P, Tkach, A, Santacroce, R, Favuzzi, G, Arauz, A, Colaizzo, D, Spengos, K, Hodge, A, Ditta, R, Pezzini, A, Debette, S, Coutinho, JM, Thijs, V, Jood, K, Pare, G, Tatlisumak, T, Ferro, JM, Sharma, P, Ken-Dror, G, Cotlarciuc, I, Martinelli, I, Grandone, E, Hiltunen, S, Lindgren, E, Margaglione, M, Duchez, VLC, Triquenot, AB, Zedde, M, Mancuso, M, Ruigrok, YM, Marjot, T, Worrall, B, Majersik, JJ, Metso, TM, Putaala, J, Haapaniemi, E, Zuurbier, SM, Brouwer, MC, Passamonti, SM, Abbattista, M, Bucciarelli, P, Mitchell, BD, Kittner, SJ, Lemmens, R, Jern, C, Pappalardo, E, Costa, P, Colombi, M, de Sousa, DA, Rodrigues, S, Canhao, P, Tkach, A, Santacroce, R, Favuzzi, G, Arauz, A, Colaizzo, D, Spengos, K, Hodge, A, Ditta, R, Pezzini, A, Debette, S, Coutinho, JM, Thijs, V, Jood, K, Pare, G, Tatlisumak, T, Ferro, JM, and Sharma, P

Abstract

OBJECTIVE: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. METHODS: A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. RESULTS: In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 × 10-24 ; odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 × 10-16 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 × 10-16 ) increased risk of CVT compared with individuals with blood group O. INTERPRETATION: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021;90:777-788.

Published
2021

7. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Author

BAKKER, M. K., VAN DER SPEK, R. A. A., VAN RHEENEN, W., Morel, S., Bourcier, R., HOSTETTLER, I. C., ALG, V. S., VAN EIJK, K. R., KOIDO, M., Akiyama, M., TERAO, C., Matsuda, K., WALTERS, R. G., Lin, K., Li, L., MILLWOOD, I. Y., Chen, Z., Rouleau, G. A., Zhou, S., RANNIKMAE, K., SUDLOW, C. L. M., Houlden, H., VAN DEN BERG, L. H., Dina, C., Naggara, O., GENTRIC, J. C., Shotar, E., Eugene, F., DESAL, H., WINSVOLD, B. S., BORTE, S., JOHNSEN, M. B., BRUMPTON, B. M., SANDVEI, M. S., WILLER, C. J., Hveem, K., ZWART, J. A., VERSCHUREN, W. M. M., Friedrich, C. M., Hirsch, S., Schilling, S., DAUVILLIER, J., Martin, O., Jones, G. T., BOWN, M. J., KO, N. U., Kim, H., COLEMAN, J. R. I., Breen, G., ZAROFF, J. G., KLIJN, C. J. M., Malik, R., DICHGANS, M., Sargurupremraj, Muralidharan, Tatlisumak, T., Amouyel, P., Debette, Stephanie, RINKEL, G. J. E., WORRALL, B. B., Pera, J., SLOWIK, A., GAAL-PAAVOLA, E. I., NIEMELA, M., JAASKELAINEN, J. E., VON UND ZU FRAUNBERG, M., LINDGREN, A., BRODERICK, J. P., WERRING, D. J., Woo, D., REDON, R., Bijlenga, P., Kamatani, Y., VELDINK, J. H., RUIGROK, Y. M., Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, cardiovascular diseases
Abstract

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

Published
2020

10. Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study

Author

Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Frid, Petrea, Drake, Mattias, Giese, A. K., Wasselius, J., Schirmer, Markus, Donahue, K. L., Cloonan, L., Irie, R., Bouts, M. J. R. J., McIntosh, E. C., Mocking, S. J. T., Dalca, Adrian Vasile, Sridharan, Ramesh, Xu, H., Giralt-Steinhauer, E., Holmegaard, L., Jood, K., Roquer, J., Cole, J. W., McArdle, P. F., Broderick, J. P., Jimenez-Conde, J., Jern, C., Kissela, B. M., Kleindorfer, D. O., Lemmens, R., Meschia, J. F., Rundek, T., Sacco, R. L., Schmidt, R., Sharma, P., Slowik, A., Thijs, V., Woo, D., Worrall, B. B., Kittner, S. J., Mitchell, B. D., Petersson, J., Rosand, J., Golland, Polina, Wu, O., Rost, N. S., Lindgren, A., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Frid, Petrea, Drake, Mattias, Giese, A. K., Wasselius, J., Schirmer, Markus, Donahue, K. L., Cloonan, L., Irie, R., Bouts, M. J. R. J., McIntosh, E. C., Mocking, S. J. T., Dalca, Adrian Vasile, Sridharan, Ramesh, Xu, H., Giralt-Steinhauer, E., Holmegaard, L., Jood, K., Roquer, J., Cole, J. W., McArdle, P. F., Broderick, J. P., Jimenez-Conde, J., Jern, C., Kissela, B. M., Kleindorfer, D. O., Lemmens, R., Meschia, J. F., Rundek, T., Sacco, R. L., Schmidt, R., Sharma, P., Slowik, A., Thijs, V., Woo, D., Worrall, B. B., Kittner, S. J., Mitchell, B. D., Petersson, J., Rosand, J., Golland, Polina, Wu, O., Rost, N. S., and Lindgren, A.

Abstract

Objective Posterior circulation ischemic stroke (PCiS) constitutes 20–30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. Methods Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. Results PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04–1.61; male sex, OR = 1.46; 95% CI 1.21–1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. Conclusion Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS., National Institutes of Health NIBIB (Grant P41EB015902)

Published
2020

11. Interleukin-6, C-reactive protein, fibrinogen, and risk of recurrence after ischaemic stroke: Systematic review and meta-analysis

Author

McCabe, JJ, primary, O’Reilly, E, additional, Coveney, S, additional, Collins, R, additional, Healy, L, additional, McManus, J, additional, Mulcahy, R, additional, Moynihan, B, additional, Cassidy, T, additional, Hsu, F, additional, Worrall, B, additional, Murphy, S, additional, O’Donnell, M, additional, and Kelly, PJ, additional

Published
2021
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12. Gender and cervical artery dissection

Author

Metso, A. J., Metso, T. M., Debette, S., Dallongeville, J., Lyrer, P. A., Pezzini, A., Lichy, C., Kloss, M., Brandt, T., Touzé, E., Southerland, A. M., Worrall, B. B., Abboud, S., del Zotto, E., Leys, D., Engelter, S., Grond-Ginsbach, C., and Tatlisumak, T.

Published
2012
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14. Studies in the doctrine of grace in British theology : James Denny to D.M. Baillie

Author

Worrall, B. G.

Subjects
230
Abstract

The thesis aims to consider some aspects of British theology in the first half of the twentieth century through the thinking of five representative figures on the theme of grace. The first two chapters give a broad historical introduction (I) and an outline of theological thinking in Britain during the period (II). James Denney (III) is chosen as a representative of an 'orthodox' Protestant approach. Arguing chiefly from the Pauline epistles he defends a 'substitutionary' view of atonement. In contrast Hastings Rashdall (IV) working largely from a historical survey and trying to present a moral view acceptable to modern man criticised 'substitutionary' thinking and advocated an 'Abelardian' or 'moral influence' view. This chapter concludes with a discussion of the two views so far considered. John Oman (v) criticises traditional ideas of grace as omnipotent power and advances the view of grace as 'fatherly persuasion' which is always available. This rests on his view of the relation between the Natural and the Supernatural. Oliver Quick (VI) is chosen for his more Catholic approach. He understands the work of Christ under the 'sacrificial' model and has a richer view of worship and sacraments underlying this is the idea of a sacramental universe. Finally, Donald Baillie (VII) is seen as a mediating figure. Here the stress is more on the experience of grace, and the use of the 'paradox of g race' as an approach to Christology is considered. The conclusion (VIII) suggests that there have been two traditional approaches to the understanding of grace, the Protestant and the Catholic, but that a third has emerged which begins from creation rather than redemption. As far as British theology is concerned it is chiefly represented by Oman. It is widely influential but its influence is not always recognised.

Published
1973

15. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, G., Adams, H., Satizabal, C., Bis, J., Teumer, A., Sargurupremraj, M., Hofer, E., Trompet, S., Hilal, S., Smith, A., Jian, X., Malik, R., Traylor, M., Pulit, S., Amouyel, P., Mazoyer, B., Zhu, Y., Kaffashian, S., Schilling, S., Beecham, G., Montine, T., Schellenberg, G., Kjartansson, O., Guethnason, V., Knopman, D., Griswold, M., Windham, B., Gottesman, R., Mosley, T., Schmidt, R., Saba, Y., Schmidt, H., Takeuchi, F., Yamaguchi, S., Nabika, T., Kato, N., Rajan, K., Aggarwal, N., De Jager, P., Evans, D., Psaty, B., Rotter, J., Rice, K., Lopez, O., Liao, J., Chen, C., Cheng, C., Wong, T., Ikram, M., van der Lee, S., Amin, N., Chouraki, V., DeStefano, A., Aparicio, H., Romero, J., Maillard, P., DeCarli, C., Wardlaw, J., Hernandez, M., Luciano, M., Liewald, D., Deary, I., Starr, J., Bastin, M., Munoz Maniega, S., Slagboom, P., Beekman, M., Deelen, J., Uh, H., Lemmens, R., Brodaty, H., Wright, M., Ames, D., Boncoraglio, G., Hopewell, J., Beecham, A., Blanton, S., Wright, C., Sacco, R., Wen, W., Thalamuthu, A., Armstrong, N., Chong, E., Schofield, P., Kwok, J., van der Grond, J., Stott, D., Ford, I., Jukema, J., Vernooij, M., Hofman, A., Uitterlinden, A., van der Lugt, A., Wittfeld, K., Grabe, H., Hosten, N., von Sarnowski, B., Volker, U., Levi, C., Jimenez-Conde, J., Sharma, P., Sudlow, C., Rosand, J., Woo, D., Cole, J., Meschia, J., Slowik, A., Thijs, V., Lindgren, A., Melander, O., Grewal, R., Rundek, T., Rexrode, K., Rothwell, P., Arnett, D., Jern, C., Johnson, J., Benavente, O., Wasssertheil-Smoller, S., Lee, J., Wong, Q., Mitchell, B., Rich, S., McArdle, P., Geerlings, M., van der Graaf, Y., de Bakker, P., Asselbergs, F., Srikanth, V., Thomson, R., McWhirter, R., Moran, C., Callisaya, M., Phan, T., Rutten-Jacobs, L., Bevan, S., Tzourio, C., Mather, K., Sachdev, P., van Duijn, C., Worrall, B., Dichgans, M., Kittner, S., Markus, H., Fornage, M., Launer, L., Seshadri, S., Longstreth, W., Debette, S., Stroke Genetics Network, t., the Neurology Working Group of the Cohorts for, H., and Aging Research in Genomic Epidemiology, C.

Abstract

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 x 10(-8); and LINC00539/ZDHHC20, p = 5.82 x 10(-9). Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 x 10(-25); p [SSBI] = 5.23 x 10(-14) for hypertension), smoking (p [BI] = 4.4 x 10(-10); p [SSBI] = 1.2 x 10(-4)), diabetes (p [BI] = 1.7 x 10(-8); p [SSBI] = 2.8 x 10(-3)), previous cardiovascular disease (p [BI] = 1.0 x 10(-18); p [SSBI] = 2.3 x 10(-7)), stroke (p [BI] = 3.9 x 10(-69); p [SSBI] = 3.2 x 10(-24)), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 x 10(-157); p [SSBI] = 3.16 x 10(-106)), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p

Published
2019

16. Fibromuscular Dysplasia and Its Neurologic Manifestations: A Systematic Review

Author

Touze, E., SOUTHERLAND, A. M., Boulanger, M., LABEYRIE, P. E., Azizi, M., Bouatia-Naji, N., Debette, Stephanie, GORNIK, H. L., HUSSAIN, S. M., Jeunemaitre, X., Joux, J., KIRTON, A., Le Hello, C., MAJERSIK, J. J., Mocco, J., Persu, A., Sharma, A., WORRALL, B. B., OLIN, J. W., PLOUIN, P. F., Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
VINTAGE, cardiovascular system, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, cardiovascular diseases
Abstract

Importance: Data on neurologic manifestations of fibromuscular dysplasia (FMD) are rare, and current knowledge remains limited. Objectives: To present a comprehensive review of the epidemiologic characteristics, management, and prognosis of the neurologic manifestations associated with cerebrovascular FMD (ie, involving cervical or intracranial arteries) and to guide future research priorities. Evidence Review: References were identified through searches of PubMed from inception to December 2017 using both the medical subject headings and text words. Additional sources were also identified by reviewing reference lists of relevant articles and through searches of the authors' personal files. Selected articles described at least 1 clinical or radiologic feature and/or outcome of cerebrovascular FMD. Isolated case reports could be included if they described interesting or noteworthy manifestations of FMD. Findings: A total of 84 relevant references were identified. Diagnosis of cerebrovascular FMD is based on the appearance of alternating arterial dilatation and constriction ("string of beads") or of focal narrowing, with no sign of atherosclerotic or inflammatory lesions. Although the diagnosis is easily apparent on results of radiographic imaging, making a diagnosis can be challenging in children or individuals with atypical phenotypes, such as purely intracranial FMD and arterial diaphragm. Involvement of multiple arteries is common, and there is increased incidence of cervical artery dissection and intracranial aneurysms. A variant in the PHACTR1 gene has been associated with FMD as well as cervical artery dissection and migraine, although less than 5% of cases of FMD are familial. Headaches, mainly of the migraine type, are observed in up to 70% of patients with FMD. Cerebrovascular FMD is mostly asymptomatic, but the most frequent neurologic manifestations include transient ischemic attack and ischemic stroke, notably in the presence of associated cervical artery dissection. Other conditions associated with FMD include subarachnoid hemorrhage and, rarely, intracranial hemorrhage. Management relies on observational data and expert opinion. Antiplatelet therapy is considered reasonable to prevent thromboembolic complications. Endovascular therapy is typically restricted to cases with symptomatic stenosis despite optimal medical therapy or in those with rupture of an intracranial aneurysm. Conclusions and Relevance: Longitudinal cohort studies of individuals of multiple ethnicities with biosampling are needed to better understand the risk factors, pathophysiological features, and outcomes of FMD. Patient advocacy groups could assist researchers in answering patient-centered questions regarding FMD.

Published
2019

17. Brain

Author

CHUNG, J., MARINI, S., PERA, J., NORRVING, B., JIMENEZ-CONDE, J., ROQUER, J., FERNANDEZ-CADENAS, I., TIRSCHWELL, D. L., SELIM, M., BROWN, D. L., SILLIMAN, S. L., WORRALL, B. B., MESCHIA, J. F., DEMEL, S., GREENBERG, S. M., SLOWIK, A., LINDGREN, A., SCHMIDT, R., TRAYLOR, M., SARGURUPREMRAJ, Muralidharan, TIEDT, S., MALIK, R., DEBETTE, Stephanie, DICHGANS, M., LANGEFELD, C. D., WOO, D., ROSAND, J., and ANDERSON, C. D.

Published
2019

18. Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis

Author

Marini, S, Crawford, K, Morotti, A, Lee, MJ, Pezzini, A, Moomaw, CJ, Flaherty, ML, Montaner, J, Roquer, J, Jimenez-Conde, J, Giralt-Steinhauer, E, Elosua, R, Cuadrado-Godia, E, Soriano-Tarraga, C, Slowik, A, Jagiella, JM, Pera, J, Urbanik, A, Pichler, A, Hansen, BM, McCauley, JL, Tirschwell, DL, Selim, M, Brown, DL, Silliman, SL, Worrall, BB, Meschia, JF, Kidwell, CS, Testai, FD, Kittner, SJ, Schmidt, H, Enzinger, C, Deary, LJ, Rannikmae, K, Samarasekera, N, Salman, RA-S, Sudlow, CL, Klijn, CJM, van Nieuwenhuizen, KM, Fernandez-Cadenas, I, Delgado, P, Nonving, B, Lindgren, A, Goldstein, JN, Viswanathan, A, Greenberg, SM, Falcone, GJ, Biffi, A, Langefeld, CD, Woo, D, Rosand, J, Anderson, CD, Smoller, S, Sorkin, J, Wang, X, Pikula, A, Wolf, P, Debette, S, Seshadri, S, de Bakker, P, Chasman, D, Rexrode, K, Chen, I, Rotter, J, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Cotlarcius, L, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lennnnens, R, Ahmadi, K, Opherk, C, Duering, M, Dichgans, M, Malik, R, Gonik, M, Staals, J, Melander, O, Burri, P, Sadr-Nabavi, A, Romero, J, Anderson, C, Falcone, G, Brouwers, B, Rost, N, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pare, G, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jem, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Hansen, B, Norrving, B, Smith, G, Martin, JJ, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Hunter, J, Attia, J, Farrall, M, Giese, A-K, Fomage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, Sheth, K, Marini, S, Crawford, K, Morotti, A, Lee, MJ, Pezzini, A, Moomaw, CJ, Flaherty, ML, Montaner, J, Roquer, J, Jimenez-Conde, J, Giralt-Steinhauer, E, Elosua, R, Cuadrado-Godia, E, Soriano-Tarraga, C, Slowik, A, Jagiella, JM, Pera, J, Urbanik, A, Pichler, A, Hansen, BM, McCauley, JL, Tirschwell, DL, Selim, M, Brown, DL, Silliman, SL, Worrall, BB, Meschia, JF, Kidwell, CS, Testai, FD, Kittner, SJ, Schmidt, H, Enzinger, C, Deary, LJ, Rannikmae, K, Samarasekera, N, Salman, RA-S, Sudlow, CL, Klijn, CJM, van Nieuwenhuizen, KM, Fernandez-Cadenas, I, Delgado, P, Nonving, B, Lindgren, A, Goldstein, JN, Viswanathan, A, Greenberg, SM, Falcone, GJ, Biffi, A, Langefeld, CD, Woo, D, Rosand, J, Anderson, CD, Smoller, S, Sorkin, J, Wang, X, Pikula, A, Wolf, P, Debette, S, Seshadri, S, de Bakker, P, Chasman, D, Rexrode, K, Chen, I, Rotter, J, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Cotlarcius, L, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lennnnens, R, Ahmadi, K, Opherk, C, Duering, M, Dichgans, M, Malik, R, Gonik, M, Staals, J, Melander, O, Burri, P, Sadr-Nabavi, A, Romero, J, Anderson, C, Falcone, G, Brouwers, B, Rost, N, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pare, G, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jem, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Hansen, B, Norrving, B, Smith, G, Martin, JJ, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Hunter, J, Attia, J, Farrall, M, Giese, A-K, Fomage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, and Sheth, K

Published
2019

19. Cervical artery dissection in patients ≥60 years: Often painless, few mechanical triggers

Author

Traenka, C, Dougoud, D, Simonetti, B, Metso, T, Debette, S, Pezzini, A, Kloss, M, Grond Ginsbach, C, Majersik, J, Worrall, B, Leys, D, Baumgartner, R, Caso, V, Béjot, Y, Compter, A, Reiner, P, Thijs, V, Southerland, A, Bersano, A, Brandt, T, Gensicke, H, Touzé, E, Martin, J, Chabriat, H, Tatlisumak, T, Lyrer, P, Arnold, M, Engelter, ST, Abboud S, Pandolfo M, Bodenant M, Louillet F, Mas JL, Leder S, Léger A, Deltour S, Crozier S, Méresse I, Canaple S, Godefroy O, Giroud M, Decavel P, Medeiros E, Montiel P, Moulin T, Vuillier F, Amouyel P, Wiest T, Werner I, Arnold ML, Santos MD, Dichgans M, Thomas Feles C, Weber R, Del Zotto E, Giossi A, Volonghi I, Padovani A, Poli L, Morotti A, Lanfranconi S, Baron P, Beretta S, Giacolone G, Fluri F, Hatz F, Gisler D, Bonati, Amort M, Markus H, Meschia JF, Cole J, Kittner S, Buffon F, Mawet J, Heldner MR, Mattle HP, Gralla J., FERRARESE, CARLO, Neurologian yksikkö, Clinicum, Department of Neurosciences, HUS Neurocenter, Traenka, C, Dougoud, D, Simonetti, B, Metso, T, Debette, S, Pezzini, A, Kloss, M, Grond Ginsbach, C, Majersik, J, Worrall, B, Leys, D, Baumgartner, R, Caso, V, Béjot, Y, Compter, A, Reiner, P, Thijs, V, Southerland, A, Bersano, A, Brandt, T, Gensicke, H, Touzé, E, Martin, J, Chabriat, H, Tatlisumak, T, Lyrer, P, Arnold, M, Engelter, S, Abboud, S, Pandolfo, M, Bodenant, M, Louillet, F, Mas, J, Leder, S, Léger, A, Deltour, S, Crozier, S, Méresse, I, Canaple, S, Godefroy, O, Giroud, M, Decavel, P, Medeiros, E, Montiel, P, Moulin, T, Vuillier, F, Amouyel, P, Wiest, T, Werner, I, Santos, M, Dichgans, M, Thomas Feles, C, Weber, R, Del Zotto, E, Giossi, A, Volonghi, I, Padovani, A, Poli, L, Morotti, A, Lanfranconi, S, Baron, P, Beretta, S, Ferrarese, C, Giacolone, G, Fluri, F, Hatz, F, Gisler, D, Bonati, Amort, M, Markus, H, Meschia, J, Cole, J, Kittner, S, Buffon, F, Mawet, J, Heldner, M, Mattle, H, and Gralla, J

Subjects
Adult, Male, medicine.medical_specialty, Vertebral artery dissection, FEATURES, 030204 cardiovascular system & hematology, 3124 Neurology and psychiatry, Brain Ischemia, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Modified Rankin Scale, Internal medicine, YOUNG-ADULTS, CADISP, Odds Ratio, medicine, Humans, Risk factor, Young adult, 610 Medicine & health, Stroke, VASCULAR RISK-FACTORS, Aged, Vertebral Artery Dissection, Neck pain, Neck Pain, business.industry, Age Factors, Middle Aged, medicine.disease, BRAIN-SUPPLYING ARTERIES, 3. Good health, Surgery, PREVALENCE, MIGRAINE, VERTEBRAL ARTERY, Cohort, Female, Neurology (clinical), medicine.symptom, business, CAROTID-ARTERY, 030217 neurology & neurosurgery, ISCHEMIC-STROKE PATIENTS, Cohort study
Abstract

Objective:In a cohort of patients diagnosed with cervical artery dissection (CeAD), to determine the proportion of patients aged ≥60 years and compare the frequency of characteristics (presenting symptoms, risk factors, and outcome) in patients aged Methods:We combined data from 3 large cohorts of consecutive patients diagnosed with CeAD (i.e., Cervical Artery Dissection and Ischemic Stroke Patients–Plus consortium). We dichotomized cases into 2 groups, age ≥60 and Results:Among 2,391 patients diagnosed with CeAD, we identified 177 patients (7.4%) aged ≥60 years. In this age group, cervical pain (ORadjusted 0.47 [0.33–0.66]), headache (ORadjusted 0.58 [0.42–0.79]), mechanical trigger events (ORadjusted 0.53 [0.36–0.77]), and migraine (ORadjusted 0.58 [0.39–0.85]) were less frequent than in younger patients. In turn, hypercholesterolemia (ORadjusted 1.52 [1.1–2.10]) and hypertension (ORadjusted 3.08 [2.25–4.22]) were more frequent in older patients. Key differences between age groups were confirmed in secondary analyses. In multivariable, adjusted analyses, favorable outcome (i.e., modified Rankin Scale score 0–2) was less frequent in the older age group (ORadjusted 0.45 [0.25, 0.83]).Conclusion:In our study population of patients diagnosed with CeAD, 1 in 14 was aged ≥60 years. In these patients, pain and mechanical triggers might be missing, rendering the diagnosis more challenging and increasing the risk of missed CeAD diagnosis in older patients.

Published
2017
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20. Determinants and outcome of multiple and early recurrent cervical artery dissections

Author

Compter, A., Schilling, S., Vaineau, C. J., Goeggel-Simonetti, B., Metso, T. M., Southerland, A., Pezzini, A., Kloss, M., Touze, E., Worrall, B. B., Thijs, V., Bejot, Y., Reiner, P., Grond-Ginsbach, C., Bersano, A., Brandt, T., Caso, V., Lyrer, P. A., Traenka, C., Lichy, C., Martin, J. J., Leys, D., Sarikaya, H., Baumgartner, R. W., Jung, S., Fischer, U., Engelter, S. T., Dallongeville, J., Chabriat, H., Tatlisumak, T., Bousser, M. G., Arnold, M., Debette, Stéphanie, and Admin, Oskar

Subjects
VINTAGE, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

OBJECTIVE: To assess putative risk factors and outcome of multiple and early recurrent cervical artery dissection (CeAD). METHODS: We combined data from 2 multicenter cohorts and compared patients with multiple CeAD at initial diagnosis, early recurrent CeAD within 3 to 6 months, and single nonrecurrent CeAD. Putative risk factors, clinical characteristics, functional outcome, and risk of recurrent ischemic events were assessed. RESULTS: Of 1,958 patients with CeAD (mean +/- SD age 44.3 +/- 10 years, 43.9% women), 1,588 (81.1%) had single nonrecurrent CeAD, 340 (17.4%) had multiple CeAD, and 30 (1.5%) presented with single CeAD at admission and had early recurrent CeAD. Patients with multiple or early recurrent CeAD did not significantly differ with respect to putative risk factors, clinical presentation, and outcome. In multivariable analyses, patients with multiple or early recurrent CeAD more often had recent infection (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.29-2.53), vertebral artery dissection (OR 1.82, 95% CI 1.34-2.46), family history of stroke (OR 1.55, 95% CI 1.06-2.25), cervical pain (OR 1.36, 95% CI 1.01-1.84), and subarachnoid hemorrhage (OR 2.85, 95% CI 1.01-8.04) at initial presentation compared to patients with single nonrecurrent CeAD. Patients with multiple or early recurrent CeAD also had a higher incidence of cerebral ischemia (hazard ratio 2.77, 95% CI 1.49-5.14) at 3 to 6 months but no difference in functional outcome compared to patients with single nonrecurrent CeAD. CONCLUSION: Patients with multiple and early recurrent CeAD share similar risk factors, clinical characteristics, and functional outcome. Compared to patients with single nonrecurrent CeAD, they are more likely to have recurrent cerebral ischemia at 3 to 6 months, possibly reflecting an underlying transient vasculopathy.

Published
2018

21. Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke

Author

Cole, J, Xu, H, Ryan, K, Jaworek, T, Dueker, N, McArdle, P, Gaynor, B, Cheng, Y, O'Connell, J, Bevan, S, Malik, R, Ahmed, N, Amouyel, P, Anjum, S, Bis, J, Crosslin, D, Danesh, J, Engelter, S, Fornage, M, Frossard, P, Gieger, C, Giese, A, Grond-Ginsbach, C, Ho, W, Holliday, E, Hopewell, J, Hussain, M, Iqbal, W, Jabeen, S, Jannes, J, Kamal, A, Kamatani, Y, Kanse, S, Kloss, M, Lathrop, M, Leys, D, Lindgren, A, Longstreth, W, Mahmood, K, Meisinger, C, Metso, T, Mosley, T, Müller-Nurasyid, M, Norrving, B, Parati, E, Peters, A, Pezzini, A, Quereshi, I, Rasheed, A, Rauf, A, Salam, T, Shen, J, Słowik, A, Stanne, T, Strauch, K, Tatlisumak, T, Thijs, V, Tiedt, S, Traylor, M, Waldenberger, M, Walters, M, Zhao, W, Boncoraglio, G, Debette, S, Jern, C, Levi, C, Markus, H, Meschia, J, Rolfs, A, Rothwell, P, Saleheen, D, Seshadri, S, Sharma, P, Sudlow, C, Worrall, B, Isgc, Metastroke Consortium Of The, Consortium, Wtccc-2, Stine, O, Kittner, S, Mitchell, B, Cole, John W [0000-0001-9263-8930], Gaynor, Brady [0000-0002-4142-0613], Pezzini, Alessandro [0000-0001-8629-3315], Thijs, Vincent N [0000-0002-6614-8417], Apollo - University of Cambridge Repository, Faculty of Medicine, Neurologian yksikkö, Clinicum, Department of Neurosciences, HUS Neurocenter, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, Male, Thrombomodulin, Social Sciences, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular Medicine, Vascular Medicine, 3124 Neurology and psychiatry, Brain Ischemia, Brain ischemia, 0302 clinical medicine, Sociology, Consortia, YOUNG-ADULTS, Medicine and Health Sciences, Medicine, FACTOR-V-LEIDEN, Ethnicities, Age of Onset, African American people, POPULATION, education.field_of_study, Endothelial protein C receptor, Multidisciplinary, Endothelial Protein C Receptor, Genomics, Middle Aged, Population groupings, 3. Good health, Stroke, Hemorrhagic Stroke, VINTAGE, Neurology, Cardiovascular Diseases, Female, Research Article, Adult, medicine.medical_specialty, Adolescent, Science, Cerebrovascular Diseases, Population, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, CLASSIFICATION, White People, MECHANISMS, Molecular Genetics, 03 medical and health sciences, Young Adult, Internal medicine, Factor V Leiden, Genome-Wide Association Studies, Genetics, Humans, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, education, Molecular Biology, POLYMORPHISMS, METAANALYSIS, Genetic Association Studies, Ischemic Stroke, business.industry, MORTALITY, Case-control study, 3112 Neurosciences, Biology and Life Sciences, Computational Biology, Human Genetics, medicine.disease, Genome Analysis, Black or African American, MYOCARDIAL-INFARCTION, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Age of onset, People and places, business, 030217 neurology & neurosurgery
Abstract

Background and purpose Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin−protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication. Methods Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15–49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age Results Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity. Conclusion PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.

Published
2018

22. Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke

Author

Ko, S-B, Cole, JW, Xu, H, Ryan, K, Jaworek, T, Dueker, N, McArdle, P, Gaynor, B, Cheng, Y-C, O'Connell, J, Bevan, S, Malik, R, Ahmed, NU, Amouyel, P, Anjum, S, Bis, JC, Crosslin, D, Danesh, J, Engelter, ST, Fornage, M, Frossard, P, Gieger, C, Giese, A-K, Grond-Ginsbach, C, Ho, WK, Holliday, E, Hopewell, J, Hussain, M, Iqbal, W, Jabeen, S, Jannes, J, Kamal, A, Kamatani, Y, Kanse, S, Kloss, M, Lathrop, M, Leys, D, Lindgren, A, Longstreth, WT, Mahmood, K, Meisinger, C, Metso, TM, Mosley, T, Mueller-Nurasyid, M, Norrving, B, Parati, E, Peters, A, Pezzini, A, Quereshi, I, Rasheed, A, Rauf, A, Salam, T, Shen, J, Slowik, A, Stanne, T, Strauch, K, Tatlisumak, T, Thijs, VN, Tiedt, S, Traylor, M, Waldenberger, M, Walters, M, Zhao, W, Boncoraglio, G, Debette, S, Jern, C, Levi, C, Markus, H, Meschia, J, Rolfs, A, Rothwell, P, Saleheen, D, Seshadri, S, Sharma, P, Sudlow, C, Worrall, B, Stine, OC, Kittner, SJ, Mitchell, BD, Ko, S-B, Cole, JW, Xu, H, Ryan, K, Jaworek, T, Dueker, N, McArdle, P, Gaynor, B, Cheng, Y-C, O'Connell, J, Bevan, S, Malik, R, Ahmed, NU, Amouyel, P, Anjum, S, Bis, JC, Crosslin, D, Danesh, J, Engelter, ST, Fornage, M, Frossard, P, Gieger, C, Giese, A-K, Grond-Ginsbach, C, Ho, WK, Holliday, E, Hopewell, J, Hussain, M, Iqbal, W, Jabeen, S, Jannes, J, Kamal, A, Kamatani, Y, Kanse, S, Kloss, M, Lathrop, M, Leys, D, Lindgren, A, Longstreth, WT, Mahmood, K, Meisinger, C, Metso, TM, Mosley, T, Mueller-Nurasyid, M, Norrving, B, Parati, E, Peters, A, Pezzini, A, Quereshi, I, Rasheed, A, Rauf, A, Salam, T, Shen, J, Slowik, A, Stanne, T, Strauch, K, Tatlisumak, T, Thijs, VN, Tiedt, S, Traylor, M, Waldenberger, M, Walters, M, Zhao, W, Boncoraglio, G, Debette, S, Jern, C, Levi, C, Markus, H, Meschia, J, Rolfs, A, Rothwell, P, Saleheen, D, Seshadri, S, Sharma, P, Sudlow, C, Worrall, B, Stine, OC, Kittner, SJ, and Mitchell, BD

Abstract

BACKGROUND AND PURPOSE: Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin-protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication. METHODS: Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15-49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age<60 years) consisting of 3676 cases and 21118 non-stroke controls from 6 case-control studies. Lastly, we determined if the replicated SNPs also associated with older-onset ischemic stroke in the METASTROKE data-base. RESULTS: Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity. CONCLUSION: PROCR polymorphisms are as

Published
2018

23. Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

Author

Pulit, SL, Weng, L-C, McArdle, PF, Trinquart, L, Choi, SH, Mitchell, BD, Rosand, J, de Bakker, PIW, Benjamin, EJ, Ellinor, PT, Kittner, SJ, Lubitz, SA, Anderson, CD, Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J, Lin, H, Arking, DE, Smith, A, Albert, CM, Chaffin, M, Tucker, NR, Li, M, Klarin, D, Bihlmeyer, NA, Low, S-K, Weeke, PE, Mueller-Nurasyid, M, Smith, JG, Brody, JA, Niemeijer, MN, Doerr, M, Trompet, S, Huffman, J, Gustafsson, S, Schurmann, C, Kleber, ME, Lyytikainen, L-P, Seppala, I, Malik, R, Horimoto, ARVR, Perez, M, Sinisalo, J, Aeschbacher, S, Theriault, S, Yao, J, Radmanesh, F, Weiss, S, Teumer, A, Clauss, S, Deo, R, Rader, DJ, Shah, S, Sun, A, Hopewell, JC, Debette, S, Chauhan, G, Yang, Q, Worrall, BB, Pare, G, Kamatani, Y, Hagemeijer, YP, Verweij, N, Siland, JE, Kubo, M, Smith, JD, Van Wagoner, DR, Bis, JC, Perz, S, Psaty, BM, Ridker, PM, Magnani, JW, Harris, TB, Launer, LJ, Shoemaker, MB, Padmanabhan, S, Haessler, J, Bartz, TM, Waldenberger, M, Lichtner, P, Arendt, M, Krieger, JE, Kahonen, M, Risch, L, Mansur, AJ, Peters, A, Smith, BH, Lind, L, Scott, SA, Lu, Y, Bottinger, EB, Hernesniemi, J, Lindgren, CM, Wong, JA, Huang, J, Eskola, M, Morris, AP, Ford, I, Reiner, AP, Delgado, G, Chen, LY, Chen, Y-DI, Sandhu, RK, Boerwinkle, E, Eisele, L, Lannfelt, L, Rost, N, Taylor, KD, Campbell, A, Magnusson, PK, Porteous, D, Hocking, LJ, Vlachopoulou, E, Pedersen, NL, Nikus, K, Orho-Melander, M, Hamsten, A, Heeringa, J, Denny, JC, Kriebel, J, Darbar, D, Newton-Cheh, C, Shaffer, C, Macfarlane, PW, Heilmann, S, Almgren, P, Huang, PL, Sotoodehnia, N, Soliman, EZ, Uitterlinden, AG, Hofman, A, Franco, OH, Voelker, U, Joeckel, K-H, Sinner, MF, Lin, HJ, Guo, X, Dichgans, M, Ingelsson, E, Kooperberg, C, Melander, O, Loos, RJF, Laurikka, J, Conen, D, van der Harst, P, Lokki, M-L, Kathiresan, S, Pereira, A, Jukema, JW, Hayward, C, Rotter, J, Maerz, W, Lehtimaki, T, Stricker, BH, Chung, MK, Felix, SB, Gudnason, V, Alonso, A, Roden, DM, Kaeaeb, S, Chasman, D, Heckbert, SR, Tanaka, T, Lunetta, KL, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Seshadri, S, de Bakker, P, Rexrode, K, Chen, I, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez-Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lemmens, R, Ahmadi, K, Opherk, C, Duering, M, Gonik, M, Staals, J, Burri, P, Sadr-Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Jose Martin, J, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, A, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Rannikmae, K, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, A-K, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez-Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, Sheth, K, Pulit, SL, Weng, L-C, McArdle, PF, Trinquart, L, Choi, SH, Mitchell, BD, Rosand, J, de Bakker, PIW, Benjamin, EJ, Ellinor, PT, Kittner, SJ, Lubitz, SA, Anderson, CD, Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J, Lin, H, Arking, DE, Smith, A, Albert, CM, Chaffin, M, Tucker, NR, Li, M, Klarin, D, Bihlmeyer, NA, Low, S-K, Weeke, PE, Mueller-Nurasyid, M, Smith, JG, Brody, JA, Niemeijer, MN, Doerr, M, Trompet, S, Huffman, J, Gustafsson, S, Schurmann, C, Kleber, ME, Lyytikainen, L-P, Seppala, I, Malik, R, Horimoto, ARVR, Perez, M, Sinisalo, J, Aeschbacher, S, Theriault, S, Yao, J, Radmanesh, F, Weiss, S, Teumer, A, Clauss, S, Deo, R, Rader, DJ, Shah, S, Sun, A, Hopewell, JC, Debette, S, Chauhan, G, Yang, Q, Worrall, BB, Pare, G, Kamatani, Y, Hagemeijer, YP, Verweij, N, Siland, JE, Kubo, M, Smith, JD, Van Wagoner, DR, Bis, JC, Perz, S, Psaty, BM, Ridker, PM, Magnani, JW, Harris, TB, Launer, LJ, Shoemaker, MB, Padmanabhan, S, Haessler, J, Bartz, TM, Waldenberger, M, Lichtner, P, Arendt, M, Krieger, JE, Kahonen, M, Risch, L, Mansur, AJ, Peters, A, Smith, BH, Lind, L, Scott, SA, Lu, Y, Bottinger, EB, Hernesniemi, J, Lindgren, CM, Wong, JA, Huang, J, Eskola, M, Morris, AP, Ford, I, Reiner, AP, Delgado, G, Chen, LY, Chen, Y-DI, Sandhu, RK, Boerwinkle, E, Eisele, L, Lannfelt, L, Rost, N, Taylor, KD, Campbell, A, Magnusson, PK, Porteous, D, Hocking, LJ, Vlachopoulou, E, Pedersen, NL, Nikus, K, Orho-Melander, M, Hamsten, A, Heeringa, J, Denny, JC, Kriebel, J, Darbar, D, Newton-Cheh, C, Shaffer, C, Macfarlane, PW, Heilmann, S, Almgren, P, Huang, PL, Sotoodehnia, N, Soliman, EZ, Uitterlinden, AG, Hofman, A, Franco, OH, Voelker, U, Joeckel, K-H, Sinner, MF, Lin, HJ, Guo, X, Dichgans, M, Ingelsson, E, Kooperberg, C, Melander, O, Loos, RJF, Laurikka, J, Conen, D, van der Harst, P, Lokki, M-L, Kathiresan, S, Pereira, A, Jukema, JW, Hayward, C, Rotter, J, Maerz, W, Lehtimaki, T, Stricker, BH, Chung, MK, Felix, SB, Gudnason, V, Alonso, A, Roden, DM, Kaeaeb, S, Chasman, D, Heckbert, SR, Tanaka, T, Lunetta, KL, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Seshadri, S, de Bakker, P, Rexrode, K, Chen, I, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez-Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lemmens, R, Ahmadi, K, Opherk, C, Duering, M, Gonik, M, Staals, J, Burri, P, Sadr-Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Jose Martin, J, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, A, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Rannikmae, K, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, A-K, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez-Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, and Sheth, K

Abstract

OBJECTIVE: We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. METHODS: We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. RESULTS: We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 × 10-4 in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 × 10-48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07, p = 0.004), but no other primary stroke subtypes (all p > 0.1). CONCLUSIONS: Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.

Published
2018

24. Determinants and outcome of multiple and early recurrent cervical artery dissections

Author

Compter, A, Schilling, S, Vaineau, C, Goeggel-Simonetti, B, Metso, T, Southerland, A, Pezzini, A, Kloss, M, Touzé, E, Worrall, B, Thijs, V, Bejot, Y, Reiner, P, Grond-Ginsbach, C, Bersano, A, Brandt, T, Caso, V, Lyrer, P, Traenka, C, Lichy, C, Martin, J, Leys, D, Sarikaya, H, Baumgartner, R, Jung, S, Fischer, U, Engelter, S, Dallongeville, J, Chabriat, H, Tatlisumak, T, Bousser, M, Arnold, M, Debette, S, Abboud, S, Pandolfo, M, Bodenant, M, Louillet, F, Mas, J, Leder, S, Léger, A, Deltour, S, Crozier, S, Méresse, I, Canaple, S, Godefroy, O, Giroud, M, Decavel, P, Medeiros, E, Montiel, P, Moulin, T, Vuillier, F, Amouyel, P, Metso, A, Werner, I, Santos, M, Dichgans, M, Thomas-Feles, C, Weber, R, De Giuli, V, Caria, F, Poli, L, Padovani, A, Lanfranconi, S, Beretta, S, Ferrarese, C, Giacolone, G, Paolucci, S, Fluri, F, Hatz, F, Gisler, D, Bonati, L, Gensicke, H, Amort, M, Altintas, A, Markus, H, Majersik, J, Cole, J, Kittner, S, Buffon, F, Heldner, M, Mattle, H, Kurmann, R, Gralla, J, Compter, Annette, Schilling, Sabrina, Vaineau, Cloé Juliette, Goeggel-Simonetti, Barbara, Metso, Tiina M., Southerland, Andrew, Pezzini, Alessandro, Kloss, Manja, Touzé, Emmanuel, Worrall, Bradford B., Thijs, Vincent, Bejot, Yannick, Reiner, Peggy, Grond-Ginsbach, Caspar, Bersano, Anna, Brandt, Tobias, Caso, Valeria, Lyrer, Philippe A., Traenka, Christopher, Lichy, Christoph, Martin, Juan José, Leys, Didier, Sarikaya, Hakan, Baumgartner, Ralph W., Jung, Simon, Fischer, Urs, Engelter, Stefan T., Dallongeville, Jean, Chabriat, Hugues, Tatlisumak, Turgut, Bousser, Marie-Germaine, Arnold, Marcel, Debette, Stéphanie, Abboud S, Pandolfo M, Bodenant M, Louillet F, Mas JL, Leder S, Léger A, Deltour S, Crozier S, Méresse I, Canaple S, Godefroy O, Giroud M, Decavel P, Medeiros E, Montiel P, Moulin T, Vuillier F, Amouyel P, Metso AJ, Werner I, Arnold ML, Santos MD, Dichgans M, Thomas-Feles C, Weber R, De Giuli V, Caria F, Poli L, Padovani A, Lanfranconi S, Beretta S, Ferrarese C, Giacolone G, Paolucci S, Fluri F, Hatz F, Gisler D, Bonati L, Gensicke H, Amort M, Altintas A, Markus H, Majersik J, Cole J, Kittner S, Buffon F, Heldner MR, Mattle HP, Kurmann R, Gralla J., Compter, A, Schilling, S, Vaineau, C, Goeggel-Simonetti, B, Metso, T, Southerland, A, Pezzini, A, Kloss, M, Touzé, E, Worrall, B, Thijs, V, Bejot, Y, Reiner, P, Grond-Ginsbach, C, Bersano, A, Brandt, T, Caso, V, Lyrer, P, Traenka, C, Lichy, C, Martin, J, Leys, D, Sarikaya, H, Baumgartner, R, Jung, S, Fischer, U, Engelter, S, Dallongeville, J, Chabriat, H, Tatlisumak, T, Bousser, M, Arnold, M, Debette, S, Abboud, S, Pandolfo, M, Bodenant, M, Louillet, F, Mas, J, Leder, S, Léger, A, Deltour, S, Crozier, S, Méresse, I, Canaple, S, Godefroy, O, Giroud, M, Decavel, P, Medeiros, E, Montiel, P, Moulin, T, Vuillier, F, Amouyel, P, Metso, A, Werner, I, Santos, M, Dichgans, M, Thomas-Feles, C, Weber, R, De Giuli, V, Caria, F, Poli, L, Padovani, A, Lanfranconi, S, Beretta, S, Ferrarese, C, Giacolone, G, Paolucci, S, Fluri, F, Hatz, F, Gisler, D, Bonati, L, Gensicke, H, Amort, M, Altintas, A, Markus, H, Majersik, J, Cole, J, Kittner, S, Buffon, F, Heldner, M, Mattle, H, Kurmann, R, Gralla, J, Compter, Annette, Schilling, Sabrina, Vaineau, Cloé Juliette, Goeggel-Simonetti, Barbara, Metso, Tiina M., Southerland, Andrew, Pezzini, Alessandro, Kloss, Manja, Touzé, Emmanuel, Worrall, Bradford B., Thijs, Vincent, Bejot, Yannick, Reiner, Peggy, Grond-Ginsbach, Caspar, Bersano, Anna, Brandt, Tobias, Caso, Valeria, Lyrer, Philippe A., Traenka, Christopher, Lichy, Christoph, Martin, Juan José, Leys, Didier, Sarikaya, Hakan, Baumgartner, Ralph W., Jung, Simon, Fischer, Urs, Engelter, Stefan T., Dallongeville, Jean, Chabriat, Hugues, Tatlisumak, Turgut, Bousser, Marie-Germaine, Arnold, Marcel, Debette, Stéphanie, Abboud S, Pandolfo M, Bodenant M, Louillet F, Mas JL, Leder S, Léger A, Deltour S, Crozier S, Méresse I, Canaple S, Godefroy O, Giroud M, Decavel P, Medeiros E, Montiel P, Moulin T, Vuillier F, Amouyel P, Metso AJ, Werner I, Arnold ML, Santos MD, Dichgans M, Thomas-Feles C, Weber R, De Giuli V, Caria F, Poli L, Padovani A, Lanfranconi S, Beretta S, Ferrarese C, Giacolone G, Paolucci S, Fluri F, Hatz F, Gisler D, Bonati L, Gensicke H, Amort M, Altintas A, Markus H, Majersik J, Cole J, Kittner S, Buffon F, Heldner MR, Mattle HP, Kurmann R, and Gralla J.

Abstract

Objective To assess putative risk factors and outcome of multiple and early recurrent cervical artery dissection (CeAD). Methods We combined data from 2 multicenter cohorts and compared patients with multiple CeAD at initial diagnosis, early recurrent CeAD within 3 to 6 months, and single nonrecurrent CeAD. Putative risk factors, clinical characteristics, functional outcome, and risk of recurrent ischemic events were assessed. Results Of 1,958 patients with CeAD (mean ± SD age 44.3 ± 10 years, 43.9% women), 1,588 (81.1%) had single nonrecurrent CeAD, 340 (17.4%) hadmultiple CeAD, and 30 (1.5%) presented with single CeAD at admission and had early recurrent CeAD. Patients with multiple or early recurrent CeAD did not significantly differ with respect to putative risk factors, clinical presentation, and outcome. In multivariable analyses, patients with multiple or early recurrent CeAD more often had recent infection (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.29-2.53), vertebral artery dissection (OR 1.82, 95% CI 1.34-2.46), family history of stroke (OR 1.55, 95% CI 1.06-2.25), cervical pain (OR 1.36, 95% CI 1.01-1.84), and subarachnoid hemorrhage (OR 2.85, 95% CI 1.01-8.04) at initial presentation compared to patients with single nonrecurrent CeAD. Patients withmultiple or early recurrent CeAD also had a higher incidence of cerebral ischemia (hazard ratio 2.77, 95% CI 1.49-5.14) at 3 to 6 months but no difference in functional outcome compared to patients with single nonrecurrent CeAD. Conclusion Patients with multiple and early recurrent CeAD share similar risk factors, clinical characteristics, and functional outcome. Compared to patients with single nonrecurrent CeAD, they are more likely to have recurrent cerebral ischemia at 3 to 6 months, possibly reflecting an underlying transient vasculopathy.

Published
2018

25. Association between telomere length and risk of cancer and non-neoplastic diseases: A Mendelian randomization study

Author

Collaboration, Telomeres Mendelian Randomization, Haycock, P, Burgess, S, Nounu, A, Zheng, J, Okoli, G, Bowden, J, Wade, K, Timpson, N, Evans, D, Willeit, P, Aviv, A, Gaunt, T, Hemani, G, Mangino, M, Ellis, H, Kurian, K, Pooley, K, Eeles, R, Lee, J, Fang, S, Chen, W, Law, M, Bowdler, L, Iles, M, Yang, Q, Worrall, B, Markus, H, Hung, R, Amos, C, Spurdle, A, Thompson, D, O'Mara, T, Wolpin, B, Amundadottir, L, Stolzenberg-Solomon, R, Trichopoulou, A, Onland-Moret, N, Lund, E, Duell, E, Canzian, F, Severi, G, Overvad, K, Gunter, M, Tumino, R, Svenson, U, van Rij, A, Baas, A, Bown, M, Samani, N, van t'Hof, F, Tromp, G, Jones, G, Kuivaniemi, H, Elmore, J, Johansson, M, Mckay, J, Scelo, G, Carreras-Torres, R, Gaborieau, V, Brennan, P, Bracci, P, Neale, R, Olson, S, Gallinger, S, Li, D, Petersen, G, Risch, H, Klein, A, Han, J, Abnet, C, Freedman, N, Taylor, P, Maris, J, Aben, K, Kiemeney, L, Vermeulen, S, Wiencke, J, Walsh, K, Wrensch, M, Rice, T, Turnbull, C, Litchfield, K, Paternoster, L, Standl, M, Abecasis, G, SanGiovanni, J, Li, Y, Mijatovic, V, Sapkota, Y, Low, S, Zondervan, K, Montgomery, G, Nyholt, D, van Heel, D, Hunt, K, Arking, D, Ashar, F, Sotoodehnia, N, Woo, D, Rosand, J, Comeau, M, Brown, W, Silverman, E, Hokanson, J, Cho, M, Hui, J, Ferreira, M, Thompson, P, Morrison, A, Felix, J, Smith, N, Christiano, A, Petukhova, L, Betz, R, Fan, X, Zhang, X, Zhu, C, Langefeld, C, Thompson, S, Wang, F, Lin, X, Schwartz, D, Fingerlin, T, Rotter, J, Cotch, M, Jensen, R, Munz, M, Dommisch, H, Schaefer, A, Han, F, Ollila, H, Hillary, R, Albagha, O, Ralston, S, Zeng, C, Zheng, W, Shu, X, Reis, A, Uebe, S, Hüffmeier, U, Kawamura, Y, Otowa, T, Sasaki, T, Hibberd, M, Davila, S, Xie, G, Siminovitch, K, Bei, J, Zeng, Y, Försti, A, Chen, B, Landi, S, Franke, A, Fischer, A, Ellinghaus, D, Flores, C, Noth, I, Ma, S, Foo, J, Liu, J, Kim, J, Cox, D, Delattre, O, Mirabeau, O, Skibola, C, Tang, C, Garcia-Barcelo, M, Chang, K, Su, W, Chang, Y, Martin, N, Gordon, S, Wade, T, Lee, C, Kubo, M, Cha, P, Nakamura, Y, Levy, D, Kimura, M, Hwang, S, Hunt, S, Spector, T, Soranzo, N, Manichaikul, A, Barr, R, Kahali, B, Speliotes, E, Yerges-Armstrong, L, Cheng, C, Jonas, J, Wong, T, Fogh, I, Lin, K, Powell, J, Rice, K, Relton, C, Martin, R, Davey Smith, G, Erasmus MC other, Epidemiology, and Pediatrics

Subjects
0301 basic medicine, Adult, Male, Cancer Research, Single-nucleotide polymorphism, Genome-wide association study, Disease, Bioinformatics, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, Telomere Homeostasis, SDG 3 - Good Health and Well-being, Neoplasms, Mendelian randomization, Journal Article, medicine, Humans, Genetic Predisposition to Disease, Càncer, Germ-Line Mutation, Aged, Cancer, Aged, 80 and over, business.industry, Nucleotides, Odds ratio, Mendelian Randomization Analysis, Middle Aged, Telomere, medicine.disease, Nucleòtids, 030104 developmental biology, Stem cell division, Oncology, Cardiovascular Diseases, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, ICEP, business, Genome-Wide Association Study, Bristol Population Health Science Institute
Abstract

Importance The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Data Sources Genomewide association studies (GWAS) published up to January 15, 2015. Study Selection GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Data Extraction and Synthesis Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Main Outcomes and Measures Odds ratios (ORs) and 95%confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. Results Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95%CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95%CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95%CI, 0.49-0.81]), celiac disease (OR, 0.42 [95%CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95%CI, 0.05-0.15]). Conclusions and Relevance It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017

28. Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke

Author

Traylor, M, Zhang, Cr, Adib Samii, P, Devan, Wj, Parsons, Oe, Lanfranconi, S, Gregory, S, Cloonan, L, Falcone, Gj, Radmanesh, F, Fitzpatrick, K, Kanakis, A, Barrick, Tr, Moynihan, B, Lewis, Cm, Boncoraglio, Gb, Lemmens, R, Thijs, V, Sudlow, C, Wardlaw, J, Rothwell, Pm, Meschia, Jf, Worrall, Bb, Levi, C, Bevan, S, Furie, Kl, Dichgans, M, Rosand, J, Markus, Hs, Rost, N, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Debette, S, Seshadri, S, de Bakker, P, Chasman, D, Rexrode, K, Chen, I, Rotter, J, Luke, M, Sale, M, Lee, Th, Chang, Kc, Elkind, M, Goldstein, L, James, Ml, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, Kj, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Ahmadi, K, Opherk, C, Duering, M, Malik, R, Gonik, M, Staals, J, Melander, O, Burri, P, Sadr Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller Myhsok, B, Meschia, J, Brott, T, Pare, G, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Yvonne Chan, Yf, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Ke, Le, Lee, Wl, Tan, Ek, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Sheu, W, Chiou, Hy, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Martín, Jj, Klijn, K, Van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, Alessandro, Padovani, Alessandro, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Rannikmae, K, Silliman, S, Mcdonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, Mcardle, P, Chang, Yc, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, Ak, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, Jm, and Sheth, K.

Subjects
Cerebral Small Vessel Diseases, Genetic Predisposition to Disease, Genetic Testing, Humans, Polymorphism, Single Nucleotide, Risk Factors, Stroke, White Matter, Genome-Wide Association Study, Neurology (clinical), Single Nucleotide, C420 Human Genetics, Article, C431 Medical Genetics, C400 Genetics, Polymorphism, C440 Molecular Genetics
Abstract

Objective: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. Methods: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. Results: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p Conclusions: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.

Published
2016

29. Application of dynamic scheduling rules in maintenance planning and scheduling.

Author

Worrall, B. M. and Mert, B.

Subjects
PRODUCTION scheduling, MACHINE shops, FACTORY management, SIMULATION methods & models, MAINTENANCE
Abstract

A maintenance planning and scheduling system often resembles that of a 'job shop' that is, the orders are one of a kind, and is characterized by having to schedule N orders through M or less tasks. The orders are of two types, e.g., (a) emergency—have to be done now, and (b) non-emergency—can be delayed until later. In this type of 'job shop' the schedule becomes immediately out of date as soon as an emergency order is received. Consequently non-emergency orders are continually moved back in the schedule and forecasted completion dates are not met. Further if the orders entering the system exceed the normal available capacity, the backlog will continue to increase causing more disruption of schedules. The research, which is based on a large petrochemical plant, will deal with the above problems by (a) applying dynamic decision rules for day-to-day scheduling to ensure completion dates are met, (b) a method for controlling backlog, and (c) forecasting future load, and completion dates for orders. The results of the simulation experiments applied to the machine shop will be discussed. [ABSTRACT FROM AUTHOR]

Published
1980
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30. A new quantitative technique for identification of industrial and organizational problems.

Author

Swan, A. W. and Worrall, B. M.

Subjects
EXECUTIVES, SHOES, SALES, QUESTIONNAIRES, CHOICE (Psychology)
Abstract

Copyright of International Journal of Production Research is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
1974
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31. Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Author

Debette, S, Kamatani, Y, Metso, T, Kloss, M, Chauhan, G, Engelter, S, Pezzini, A, Thijs, V, Markus, H, Dichgans, M, Wolf, C, Dittrich, R, Touzé, E, Southerland, A, Samson, Y, Abboud, S, Béjot, Y, Caso, V, Bersano, A, Gschwendtner, A, Sessa, M, Cole, J, Lamy, C, Medeiros, E, Beretta, S, Bonati, L, Grau, A, Michel, P, Majersik, J, Sharma, P, Kalashnikova, L, Nazarova, M, Dobrynina, L, Bartels, E, Guillon, B, Van Den Herik, E, Fernandez Cadenas, I, Jood, K, Nalls, M, De Leeuw, F, Jern, C, Cheng, Y, Werner, I, Metso, A, Lichy, C, Lyrer, P, Brandt, T, Boncoraglio, G, Wichmann, H, Gieger, C, Johnson, A, Böttcher, T, Castellano, M, Arveiler, D, Ikram, M, Breteler, M, Padovani, A, Meschia, J, Kuhlenbäumer, G, Rolfs, A, Worrall, B, Ringelstein, E, Zelenika, D, Tatlisumak, T, Lathrop, M, Leys, D, Amouyel, P, Dallongeville, J, Lemmens R, P, Ferrarese, C, BERETTA, SIMONE, FERRARESE, CARLO, Debette, S, Kamatani, Y, Metso, T, Kloss, M, Chauhan, G, Engelter, S, Pezzini, A, Thijs, V, Markus, H, Dichgans, M, Wolf, C, Dittrich, R, Touzé, E, Southerland, A, Samson, Y, Abboud, S, Béjot, Y, Caso, V, Bersano, A, Gschwendtner, A, Sessa, M, Cole, J, Lamy, C, Medeiros, E, Beretta, S, Bonati, L, Grau, A, Michel, P, Majersik, J, Sharma, P, Kalashnikova, L, Nazarova, M, Dobrynina, L, Bartels, E, Guillon, B, Van Den Herik, E, Fernandez Cadenas, I, Jood, K, Nalls, M, De Leeuw, F, Jern, C, Cheng, Y, Werner, I, Metso, A, Lichy, C, Lyrer, P, Brandt, T, Boncoraglio, G, Wichmann, H, Gieger, C, Johnson, A, Böttcher, T, Castellano, M, Arveiler, D, Ikram, M, Breteler, M, Padovani, A, Meschia, J, Kuhlenbäumer, G, Rolfs, A, Worrall, B, Ringelstein, E, Zelenika, D, Tatlisumak, T, Lathrop, M, Leys, D, Amouyel, P, Dallongeville, J, Lemmens R, P, Ferrarese, C, BERETTA, SIMONE, and FERRARESE, CARLO

Abstract

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year)1. Minor cervical traumas, infection, migraine and hypertension are putative risk factors1-3, and inverse associations with obesity and hypercholesterolemia are described3,4. No confirmed genetic susceptibility factors have been identified using candidate gene approaches5. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10-10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10-3; combined P = 1.00 × 10-11). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction6-9. Deciphering the mechanisms underlying this pleiotropy might provide important information on the.

Published
2015

32. Message from the Editors to our Reviewers

Author

Gross, R. A., primary, Knopman, D. S., additional, Amato, A. A., additional, Cascino, G. D., additional, Ciccarelli, O., additional, Corboy, J. R., additional, Elkind, M. S. V., additional, Mink, J. W., additional, Ransohoff, R. M., additional, Uitti, R. J., additional, and Worrall, B. B., additional

Published
2014
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33. 17q25 locus is associated with white matter hyperintensity volume in ischemic stroke, but not with lacunar stroke status

Author

Adib-Samii, P, Rost, N, Traylor, M, Devan, W, Biffi, A, Lanfranconi, S, Fitzpatrick, K, Bevan, S, Kanakis, A, Valant, V, Gschwendtner, A, Malik, R, Richie, A, Gamble, D, Segal, H, Parati, EA, Ciusani, E, Holliday, EG, Maguire, J, Wardlaw, J, Worrall, B, Bis, J, Wiggins, KL, Longstreth, W, Kittner, SJ, Cheng, YC, Mosley, T, Falcone, GJ, Furie, KL, Leiva-Salinas, C, Lau, BC, Khan, MS, Sharma, P, Fornage, M, Mitchell, BD, Psaty, BM, Sudlow, C, Levi, C, Boncoraglio, GB, Rothwell, PM, Meschia, J, Dichgans, M, Rosand, J, Markus, HS, Adib-Samii, P, Rost, N, Traylor, M, Devan, W, Biffi, A, Lanfranconi, S, Fitzpatrick, K, Bevan, S, Kanakis, A, Valant, V, Gschwendtner, A, Malik, R, Richie, A, Gamble, D, Segal, H, Parati, EA, Ciusani, E, Holliday, EG, Maguire, J, Wardlaw, J, Worrall, B, Bis, J, Wiggins, KL, Longstreth, W, Kittner, SJ, Cheng, YC, Mosley, T, Falcone, GJ, Furie, KL, Leiva-Salinas, C, Lau, BC, Khan, MS, Sharma, P, Fornage, M, Mitchell, BD, Psaty, BM, Sudlow, C, Levi, C, Boncoraglio, GB, Rothwell, PM, Meschia, J, Dichgans, M, Rosand, J, and Markus, HS

Abstract

Background and Purpose-Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke. Methods-We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These singlenucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke. Results-Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke. Conclusions-This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction. © 2013 American Heart Association, Inc.

Published
2013

34. Are myocardial infarction-associated single-nucleotide polymorphisms associated with ischemic stroke?

Author

Cheng, Y.-C., Anderson, C.D., Bione, S., Keene, K., Maguire, J.M., Nalls, M., Rasheed, A., Zeginigg, M., Attia, J., Baker, R., Barlera, S., Biffi, A., Bookman, E., Brott, T.G., Brown, R. D., Chen, F., Chen, W.-M., Ciusani, E., Cole, J.W., Cortellini, L., Danesh, J., Doheny, K., Ferrucci, L., Grazia Franzosi, M., Frossard, P., Furie, K.L., Golledge, J., Hankey, G.J., Hernandez, D., Holliday, E.G., Hsu, F.-C., Jannes, J., Kamal, A., Khan, M.S., Kittner, S.J., Koblar, S.A., Lewis, M., Lincz, L., Lisa, A., Matarin, M., Moscato, P., Mychaleckyj, J.C., Parati, E.A., Parolo, S., Pugh, E., Rost, N.S., Schallert, M., Schmidt, H., Scott, R.J., Sturm, J.W., Yadav, S., Zaidi, M., Boncoraglio, G.B., Levi, C.R., Meschia, J.F., Rosand, J., Sale, M., Saleheen, D., Schmidt, R., Sharma, P., Worrall, B., Mitchell, B.D., Cheng, Y.-C., Anderson, C.D., Bione, S., Keene, K., Maguire, J.M., Nalls, M., Rasheed, A., Zeginigg, M., Attia, J., Baker, R., Barlera, S., Biffi, A., Bookman, E., Brott, T.G., Brown, R. D., Chen, F., Chen, W.-M., Ciusani, E., Cole, J.W., Cortellini, L., Danesh, J., Doheny, K., Ferrucci, L., Grazia Franzosi, M., Frossard, P., Furie, K.L., Golledge, J., Hankey, G.J., Hernandez, D., Holliday, E.G., Hsu, F.-C., Jannes, J., Kamal, A., Khan, M.S., Kittner, S.J., Koblar, S.A., Lewis, M., Lincz, L., Lisa, A., Matarin, M., Moscato, P., Mychaleckyj, J.C., Parati, E.A., Parolo, S., Pugh, E., Rost, N.S., Schallert, M., Schmidt, H., Scott, R.J., Sturm, J.W., Yadav, S., Zaidi, M., Boncoraglio, G.B., Levi, C.R., Meschia, J.F., Rosand, J., Sale, M., Saleheen, D., Schmidt, R., Sharma, P., Worrall, B., and Mitchell, B.D.

Abstract

Background and Purpose-Ischemic stroke (IS) shares many common risk factors with coronary artery disease (CAD). We hypothesized that genetic variants associated with myocardial infarction (MI) or CAD may be similarly involved in the etiology of IS. To test this hypothesis, we evaluated whether single-nucleotide polymorphisms (SNPs) at 11 different loci recently associated with MI or CAD through genome-wide association studies were associated with IS. Methods-Meta-analyses of the associations between the 11 MI-associated SNPs and IS were performed using 6865 cases and 11 395 control subjects recruited from 9 studies. SNPs were either genotyped directly or imputed; in a few cases a surrogate SNP in high linkage disequilibrium was chosen. Logistic regression was performed within each study to obtain study-specific βs and standard errors. Meta-analysis was conducted using an inverse variance weighted approach assuming a random effect model. Results-Despite having power to detect odds ratio of 1.09-1.14 for overall IS and 1.20-1.32 for major stroke subtypes, none of the SNPs were significantly associated with overall IS and/or stroke subtypes after adjusting for multiple comparisons. Conclusions-Our results suggest that the major common loci associated with MI risk do not have effects of similar magnitude on overall IS but do not preclude moderate associations restricted to specific IS subtypes. Disparate mechanisms may be critical in the development of acute ischemic coronary and cerebrovascular events.

Published
2012

35. Genome screen in familial intracranial aneurysm

Author

Foroud, T, Sauerbeck, L, Brown, R, Anderson, C, Woo, D, Kleindorfer, D, Flaherty, ML, Deka, R, Hornung, R, Meissner, I, Bailey-Wilson, JE, Langefeld, C, Rouleau, G, Connolly, ES, Lai, D, Koller, DL, Huston, J, Broderick, JP, Fisher, W, Forson, H, Mee, E, Howe, C, Vos, S, Hankey, G, Knuckey, N, Laidlaw, J, Reilly, P, Dorsch, N, Morgan, M, Besser, M, Rosenfeld, J, Athanasiadis, K, Claxton, A, Dunne, V, Griffith, J, Davidson, J, Pope, S, Froelich, A, Day, A, Brach, R, Zuccarello, M, Ringer, A, Yeh, H, Franklin, K, Ramussen, P, Andrews-Hinders, D, Wheeler, T, Sacco, R, Lamonica, D, Lewis, SB, Royster, A, Payner, T, Miracle, N, Murphy, K, Kohler, B, Ogilvy, C, Buckley, D, Manansala, J, Ferguson, G, Mayer, C, Peacock, J, Desjarlais, A, Aldrich, EF, Aldrich, C, Byard, C, Brown, RD, Jaeger, L, Morgenstern, L, Concannon, M, Qureshi, AI, Harris-Lane, P, Batjer, H, Joven, G, Thompson, S, Richard, MT, Hopper, A, Kassam, AB, Lee, K, Johnston, C, Katsura, K, Giannotta, S, Fishback, D, Steinberg, G, Luu, D, Coburn, M, Malkoff, M, Wojner, A, Kassel, N, Worrall, B, Radakovic, G, Tirschwell, D, Tanzi, P, Derdeyn, C, Catanzaro, M, Kaufmann, A, Gladish, D, Foroud, T, Sauerbeck, L, Brown, R, Anderson, C, Woo, D, Kleindorfer, D, Flaherty, ML, Deka, R, Hornung, R, Meissner, I, Bailey-Wilson, JE, Langefeld, C, Rouleau, G, Connolly, ES, Lai, D, Koller, DL, Huston, J, Broderick, JP, Fisher, W, Forson, H, Mee, E, Howe, C, Vos, S, Hankey, G, Knuckey, N, Laidlaw, J, Reilly, P, Dorsch, N, Morgan, M, Besser, M, Rosenfeld, J, Athanasiadis, K, Claxton, A, Dunne, V, Griffith, J, Davidson, J, Pope, S, Froelich, A, Day, A, Brach, R, Zuccarello, M, Ringer, A, Yeh, H, Franklin, K, Ramussen, P, Andrews-Hinders, D, Wheeler, T, Sacco, R, Lamonica, D, Lewis, SB, Royster, A, Payner, T, Miracle, N, Murphy, K, Kohler, B, Ogilvy, C, Buckley, D, Manansala, J, Ferguson, G, Mayer, C, Peacock, J, Desjarlais, A, Aldrich, EF, Aldrich, C, Byard, C, Brown, RD, Jaeger, L, Morgenstern, L, Concannon, M, Qureshi, AI, Harris-Lane, P, Batjer, H, Joven, G, Thompson, S, Richard, MT, Hopper, A, Kassam, AB, Lee, K, Johnston, C, Katsura, K, Giannotta, S, Fishback, D, Steinberg, G, Luu, D, Coburn, M, Malkoff, M, Wojner, A, Kassel, N, Worrall, B, Radakovic, G, Tirschwell, D, Tanzi, P, Derdeyn, C, Catanzaro, M, Kaufmann, A, and Gladish, D

Abstract

Background: Individuals with 1st degree relatives harboring an intracranial aneurysm (IA) are at an increased risk of IA, suggesting genetic variation is an important risk factor. Methods: Families with multiple members having ruptured or unruptured IA were recruited and all available medical records and imaging data were reviewed to classify possible IA subjects as definite, probable or possible IA or not a case. A 6 K SNP genome screen was performed in 333 families, representing the largest linkage study of IA reported to date. A 'narrow' (n = 705 definite IA cases) and 'broad' (n = 866 definite or probable IA) disease definition were used in multipoint model-free linkage analysis and parametric linkage analysis, maximizing disease parameters. Ordered subset analysis (OSA) was used to detect gene × smoking interaction. Results: Model-free linkage analyses detected modest evidence of possible linkage (all LOD < 1.5). Parametric analyses yielded an unadjusted LOD score of 2.6 on chromosome 4q (162 cM) and 3.1 on chromosome 12p (50 cM). Significant evidence for a gene × smoking interaction was detected using both disease models on chromosome 7p (60 cM; p ≤ 0.01). Our study provides modest evidence of possible linkage to several chromosomes. Conclusion: These data suggest it is unlikely that there is a single common variant with a strong effect in the majority of the IA families. Rather, it is likely that multiple genetic and environmental risk factors contribute to the susceptibility for intracranial aneurysms.

Published
2009

36. Message from the Editors to our Reviewers

Author

Gross, R. A., primary, Knopman, D. S., additional, Cascino, G. D., additional, Corboy, J. R., additional, Elkind, M. S. V., additional, Engel, A. G., additional, Mink, J. W., additional, Ransohoff, R. M., additional, Uitti, R. J., additional, and Worrall, B. B., additional

Published
2013
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37. Message from the Editors to our Reviewers

Author

Gross, R. A., primary, Knopman, D. S., additional, Cascino, G. D., additional, Corboy, J. R., additional, Elkind, M. S. V., additional, Engel, A. G., additional, Mink, J. W., additional, Ransohoff, R. M., additional, Uitti, R. J., additional, and Worrall, B. B., additional

Published
2012
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38. Genetic variation at CR1 increases risk of cerebral amyloid angiopathy

Author

Biffi, A., primary, Shulman, J. M., additional, Jagiella, J. M., additional, Cortellini, L., additional, Ayres, A. M., additional, Schwab, K., additional, Brown, D. L., additional, Silliman, S. L., additional, Selim, M., additional, Worrall, B. B., additional, Meschia, J. F., additional, Slowik, A., additional, De Jager, P. L., additional, Greenberg, S. M., additional, Schneider, J. A., additional, Bennett, D. A., additional, and Rosand, J., additional

Published
2012
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39. Message from the Editors to our Reviewers

Author

Gross, R. A., primary, Knopman, D. S., additional, Cascino, G. D., additional, Corboy, J. R., additional, Elkind, M. S. V., additional, Engel, A. G., additional, Mink, J. W., additional, Ransohoff, R. M., additional, Uitti, R. J., additional, and Worrall, B. B., additional

Published
2011
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41. White matter hyperintensity volume is increased in small vessel stroke subtypes

Author

Rost, N. S., primary, Rahman, R. M., additional, Biffi, A., additional, Smith, E. E., additional, Kanakis, A., additional, Fitzpatrick, K., additional, Lima, F., additional, Worrall, B. B., additional, Meschia, J. F., additional, Brown, R. D., additional, Brott, T. G., additional, Sorensen, A. G., additional, Greenberg, S. M., additional, Furie, K. L., additional, and Rosand, J., additional

Published
2010
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45. SEPT9 gene sequencing analysis reveals recurrent mutations in hereditary neuralgic amyotrophy

Author

Hannibal, M. C., primary, Ruzzo, E. K., additional, Miller, L. R., additional, Betz, B., additional, Buchan, J. G., additional, Knutzen, D. M., additional, Barnett, K., additional, Landsverk, M. L., additional, Brice, A., additional, LeGuern, E., additional, Bedford, H. M., additional, Worrall, B. B., additional, Lovitt, S., additional, Appel, S. H., additional, Andermann, E., additional, Bird, T. D., additional, and Chance, P. F., additional

Published
2009
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