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

John W. Cole, Huichun Xu, Kathleen Ryan, Thomas Jaworek, Nicole Dueker, Patrick McArdle, Brady Gaynor, Yu Ching Cheng, Jeffrey O'Connell, Steve Bevan, Rainer Malik, Naveed Uddin Ahmed, Philippe Amouyel, Sheraz Anjum, Joshua C. Bis, David Crosslin, John Danesh, Stefan T. Engelter, Myriam Fornage, Philippe FrossardChristian Gieger, Anne Katrin Giese, Caspar Grond-Ginsbach, Weang Kee Ho, Elizabeth Holliday, Jemma Hopewell, M. Hussain, W. Iqbal, S. Jabeen, Jim Jannes, Ayeesha Kamal, Yoichiro Kamatani, Sandip Kanse, Manja Kloss, Mark Lathrop, Didier Leys, Arne Lindgren, W. T. LongstrethJr, Khalid Mahmood, Christa Meisinger, Tiina M. Metso, Thomas Mosley, Martina Müller-Nurasyid, Bo Norrving, Eugenio Parati, Annette Peters, Alessandro Pezzini, I. Quereshi, Asif Rasheed, A. Rauf, T. Salam, Jess Shen, Agnieszka Slowik, Tara Stanne, Konstantin Strauch, Turgut Tatlisumak, Vincent N. Thijs, Steffen Tiedt, Matthew Traylor, Melanie Waldenberger, Matthew Walters, Wei Zhao, Giorgio Boncoraglio, Stephanie Debette, Christina Jern, Christopher Levi, Hugh Markus, James Meschia, Arndt Rolfs, Peter Rothwell, Danish Saleheen, Sudha Seshadri, Pankaj Sharma, Cathie Sudlow, Bradford Worrall, O. Colin Stine, Steven J. Kittner, Braxton D. Mitchell

Research output: Contribution to journalArticle

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 multistage 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 (onsetage< 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 additivemodel 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.

Original languageEnglish (US)
Article numbere0206554
JournalPLoS One
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2018
Externally publishedYes

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Thrombomodulin
Polymorphism
stroke
endothelial cells
Stroke
receptors
Nucleotides
single nucleotide polymorphism
Single Nucleotide Polymorphism
proteins
African Americans
case-control studies
activated protein C receptor
Genetics
Case-Control Studies
risk factors
Protein C
Coagulation
genetic polymorphism
Population

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Cole, J. W., Xu, H., Ryan, K., Jaworek, T., Dueker, N., McArdle, P., ... Mitchell, B. D. (2018). Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke. PLoS One, 13(11), [e0206554]. https://doi.org/10.1371/journal.pone.0206554

Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke. / Cole, John W.; Xu, Huichun; Ryan, Kathleen; Jaworek, Thomas; Dueker, Nicole; McArdle, Patrick; Gaynor, Brady; Cheng, Yu Ching; O'Connell, Jeffrey; Bevan, Steve; Malik, Rainer; Ahmed, Naveed Uddin; Amouyel, Philippe; Anjum, Sheraz; Bis, Joshua C.; Crosslin, David; Danesh, John; Engelter, Stefan T.; Fornage, Myriam; Frossard, Philippe; Gieger, Christian; Giese, Anne Katrin; Grond-Ginsbach, Caspar; Ho, Weang Kee; Holliday, Elizabeth; Hopewell, Jemma; Hussain, M.; Iqbal, W.; Jabeen, S.; Jannes, Jim; Kamal, Ayeesha; Kamatani, Yoichiro; Kanse, Sandip; Kloss, Manja; Lathrop, Mark; Leys, Didier; Lindgren, Arne; LongstrethJr, W. T.; Mahmood, Khalid; Meisinger, Christa; Metso, Tiina M.; Mosley, Thomas; Müller-Nurasyid, Martina; Norrving, Bo; Parati, Eugenio; Peters, Annette; Pezzini, Alessandro; Quereshi, I.; Rasheed, Asif; Rauf, A.; Salam, T.; Shen, Jess; Slowik, Agnieszka; Stanne, Tara; Strauch, Konstantin; Tatlisumak, Turgut; Thijs, Vincent N.; Tiedt, Steffen; Traylor, Matthew; Waldenberger, Melanie; Walters, Matthew; Zhao, Wei; Boncoraglio, Giorgio; Debette, Stephanie; Jern, Christina; Levi, Christopher; Markus, Hugh; Meschia, James; Rolfs, Arndt; Rothwell, Peter; Saleheen, Danish; Seshadri, Sudha; Sharma, Pankaj; Sudlow, Cathie; Worrall, Bradford; Stine, O. Colin; Kittner, Steven J.; Mitchell, Braxton D.

In: PLoS One, Vol. 13, No. 11, e0206554, 01.11.2018.

Research output: Contribution to journalArticle

Cole, JW, Xu, H, Ryan, K, Jaworek, T, Dueker, N, McArdle, P, Gaynor, B, Cheng, YC, 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, AK, 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, LongstrethJr, WT, Mahmood, K, Meisinger, C, Metso, TM, Mosley, T, Müller-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 2018, 'Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke', PLoS One, vol. 13, no. 11, e0206554. https://doi.org/10.1371/journal.pone.0206554
Cole, John W. ; Xu, Huichun ; Ryan, Kathleen ; Jaworek, Thomas ; Dueker, Nicole ; McArdle, Patrick ; Gaynor, Brady ; Cheng, Yu Ching ; O'Connell, Jeffrey ; Bevan, Steve ; Malik, Rainer ; Ahmed, Naveed Uddin ; Amouyel, Philippe ; Anjum, Sheraz ; Bis, Joshua C. ; Crosslin, David ; Danesh, John ; Engelter, Stefan T. ; Fornage, Myriam ; Frossard, Philippe ; Gieger, Christian ; Giese, Anne Katrin ; Grond-Ginsbach, Caspar ; Ho, Weang Kee ; Holliday, Elizabeth ; Hopewell, Jemma ; Hussain, M. ; Iqbal, W. ; Jabeen, S. ; Jannes, Jim ; Kamal, Ayeesha ; Kamatani, Yoichiro ; Kanse, Sandip ; Kloss, Manja ; Lathrop, Mark ; Leys, Didier ; Lindgren, Arne ; LongstrethJr, W. T. ; Mahmood, Khalid ; Meisinger, Christa ; Metso, Tiina M. ; Mosley, Thomas ; Müller-Nurasyid, Martina ; Norrving, Bo ; Parati, Eugenio ; Peters, Annette ; Pezzini, Alessandro ; Quereshi, I. ; Rasheed, Asif ; Rauf, A. ; Salam, T. ; Shen, Jess ; Slowik, Agnieszka ; Stanne, Tara ; Strauch, Konstantin ; Tatlisumak, Turgut ; Thijs, Vincent N. ; Tiedt, Steffen ; Traylor, Matthew ; Waldenberger, Melanie ; Walters, Matthew ; Zhao, Wei ; Boncoraglio, Giorgio ; Debette, Stephanie ; Jern, Christina ; Levi, Christopher ; Markus, Hugh ; Meschia, James ; Rolfs, Arndt ; Rothwell, Peter ; Saleheen, Danish ; Seshadri, Sudha ; Sharma, Pankaj ; Sudlow, Cathie ; Worrall, Bradford ; Stine, O. Colin ; Kittner, Steven J. ; Mitchell, Braxton D. / Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke. In: PLoS One. 2018 ; Vol. 13, No. 11.
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title = "Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke",
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 multistage 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 (onsetage< 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 additivemodel 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.",
author = "Cole, {John W.} and Huichun Xu and Kathleen Ryan and Thomas Jaworek and Nicole Dueker and Patrick McArdle and Brady Gaynor and Cheng, {Yu Ching} and Jeffrey O'Connell and Steve Bevan and Rainer Malik and Ahmed, {Naveed Uddin} and Philippe Amouyel and Sheraz Anjum and Bis, {Joshua C.} and David Crosslin and John Danesh and Engelter, {Stefan T.} and Myriam Fornage and Philippe Frossard and Christian Gieger and Giese, {Anne Katrin} and Caspar Grond-Ginsbach and Ho, {Weang Kee} and Elizabeth Holliday and Jemma Hopewell and M. Hussain and W. Iqbal and S. Jabeen and Jim Jannes and Ayeesha Kamal and Yoichiro Kamatani and Sandip Kanse and Manja Kloss and Mark Lathrop and Didier Leys and Arne Lindgren and LongstrethJr, {W. T.} and Khalid Mahmood and Christa Meisinger and Metso, {Tiina M.} and Thomas Mosley and Martina M{\"u}ller-Nurasyid and Bo Norrving and Eugenio Parati and Annette Peters and Alessandro Pezzini and I. Quereshi and Asif Rasheed and A. Rauf and T. Salam and Jess Shen and Agnieszka Slowik and Tara Stanne and Konstantin Strauch and Turgut Tatlisumak and Thijs, {Vincent N.} and Steffen Tiedt and Matthew Traylor and Melanie Waldenberger and Matthew Walters and Wei Zhao and Giorgio Boncoraglio and Stephanie Debette and Christina Jern and Christopher Levi and Hugh Markus and James Meschia and Arndt Rolfs and Peter Rothwell and Danish Saleheen and Sudha Seshadri and Pankaj Sharma and Cathie Sudlow and Bradford Worrall and Stine, {O. Colin} and Kittner, {Steven J.} and Mitchell, {Braxton D.}",
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TY - JOUR

T1 - Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke

AU - Cole, John W.

AU - Xu, Huichun

AU - Ryan, Kathleen

AU - Jaworek, Thomas

AU - Dueker, Nicole

AU - McArdle, Patrick

AU - Gaynor, Brady

AU - Cheng, Yu Ching

AU - O'Connell, Jeffrey

AU - Bevan, Steve

AU - Malik, Rainer

AU - Ahmed, Naveed Uddin

AU - Amouyel, Philippe

AU - Anjum, Sheraz

AU - Bis, Joshua C.

AU - Crosslin, David

AU - Danesh, John

AU - Engelter, Stefan T.

AU - Fornage, Myriam

AU - Frossard, Philippe

AU - Gieger, Christian

AU - Giese, Anne Katrin

AU - Grond-Ginsbach, Caspar

AU - Ho, Weang Kee

AU - Holliday, Elizabeth

AU - Hopewell, Jemma

AU - Hussain, M.

AU - Iqbal, W.

AU - Jabeen, S.

AU - Jannes, Jim

AU - Kamal, Ayeesha

AU - Kamatani, Yoichiro

AU - Kanse, Sandip

AU - Kloss, Manja

AU - Lathrop, Mark

AU - Leys, Didier

AU - Lindgren, Arne

AU - LongstrethJr, W. T.

AU - Mahmood, Khalid

AU - Meisinger, Christa

AU - Metso, Tiina M.

AU - Mosley, Thomas

AU - Müller-Nurasyid, Martina

AU - Norrving, Bo

AU - Parati, Eugenio

AU - Peters, Annette

AU - Pezzini, Alessandro

AU - Quereshi, I.

AU - Rasheed, Asif

AU - Rauf, A.

AU - Salam, T.

AU - Shen, Jess

AU - Slowik, Agnieszka

AU - Stanne, Tara

AU - Strauch, Konstantin

AU - Tatlisumak, Turgut

AU - Thijs, Vincent N.

AU - Tiedt, Steffen

AU - Traylor, Matthew

AU - Waldenberger, Melanie

AU - Walters, Matthew

AU - Zhao, Wei

AU - Boncoraglio, Giorgio

AU - Debette, Stephanie

AU - Jern, Christina

AU - Levi, Christopher

AU - Markus, Hugh

AU - Meschia, James

AU - Rolfs, Arndt

AU - Rothwell, Peter

AU - Saleheen, Danish

AU - Seshadri, Sudha

AU - Sharma, Pankaj

AU - Sudlow, Cathie

AU - Worrall, Bradford

AU - Stine, O. Colin

AU - Kittner, Steven J.

AU - Mitchell, Braxton D.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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 multistage 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 (onsetage< 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 additivemodel 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.

AB - 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 multistage 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 (onsetage< 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 additivemodel 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.

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