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 Frossard; Christian 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. Longstreth Jr.; Khalid Mahmood; Christa Meisinger; Tiina M. Metso; Thomas Mosley Jr.; Martina Muller-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; null et al.

doi:10.1371/journal.pone.0206554

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. Longstreth Jr., Khalid Mahmood, Christa Meisinger, Tiina M. Metso, Thomas Mosley Jr., Martina Muller-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, et al.

Western Sydney University

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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-tage 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 1549 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 (r(2)>= 0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-ge<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 associated with early-onset ischemic stroke in Caucasians.

Original language	English
Article number	e0206554
Number of pages	12
Journal	PLoS One
Volume	13
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0206554
Publication status	Published - 2018

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Cole, J. W., Xu, H., Ryan, K., Jaworek, T., Dueker, N., McArdle, P., Gaynor, B., Cheng, Y.-C., O'Connell, J., Bevan, S., Malik, R., Ahmed, N. U., Amouyel, P., Anjum, S., Bis, J. C., Crosslin, D., Danesh, J., Engelter, S. T., Fornage, M., ... et al. (2018). Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke. PLoS One, 13(11), Article e0206554. https://doi.org/10.1371/journal.pone.0206554

@article{e934dd6e6e6e425ab121d9c7805c4968,

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 multi-tage 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 1549 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 (r(2)>= 0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-ge<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 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 Yu-Ching Cheng 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 Anne-Katrin Giese 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 {Longstreth Jr.}, {W. T.} and Khalid Mahmood and Christa Meisinger and Metso, {Tiina M.} and {Mosley Jr.}, Thomas and Martina Muller-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 {et al.}",

year = "2018",

doi = "10.1371/journal.pone.0206554",

language = "English",

volume = "13",

journal = "PLoS One",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "11",

}

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 Jr., WT, Mahmood, K, Meisinger, C, Metso, TM, Mosley Jr., T, Muller-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 & et al. 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

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 - Longstreth Jr., W. T.

AU - Mahmood, Khalid

AU - Meisinger, Christa

AU - Metso, Tiina M.

AU - Mosley Jr., Thomas

AU - Muller-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 - et al., null

PY - 2018

Y1 - 2018

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 multi-tage 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 1549 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 (r(2)>= 0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-ge<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 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 multi-tage 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 1549 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 (r(2)>= 0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-ge<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 associated with early-onset ischemic stroke in Caucasians.

UR - http://hdl.handle.net/1959.7/uws:64707

U2 - 10.1371/journal.pone.0206554

DO - 10.1371/journal.pone.0206554

M3 - Article

SN - 1932-6203

VL - 13

JO - PLoS One

JF - PLoS One

IS - 11

M1 - e0206554

ER -

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

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