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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 and Cheng, Yu Ching, et al. (2018) In PLoS ONE 13(11).
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).... (More)

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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PLoS ONE
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11
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Public Library of Science
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  • scopus:85055915276
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1932-6203
DOI
10.1371/journal.pone.0206554
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English
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59f0fec0-2003-4030-9fc8-2df4f8ac5257
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2018-12-14 16:23:55
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2019-02-20 11:39:58
@article{59f0fec0-2003-4030-9fc8-2df4f8ac5257,
  abstract     = {<p>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&lt; 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.</p>},
  articleno    = {e0206554},
  author       = {,  and ,  and Cole, John W. and Xu, Huichun and Ryan, Kathleen and Jaworek, Thomas and Dueker, Nicole and McArdle, Patrick and Gaynor, Brady and Cheng, Yu Ching and O'Connell, Jeffrey and Bevan, Steve and Malik, Rainer and Ahmed, Naveed Uddin and Amouyel, Philippe and Anjum, Sheraz and Bis, Joshua C. and Crosslin, David and Danesh, John and Engelter, Stefan T. and Fornage, Myriam and Frossard, Philippe and Gieger, Christian and Giese, Anne Katrin and Grond-Ginsbach, Caspar and Ho, Weang Kee and Holliday, Elizabeth and Hopewell, Jemma and Hussain, M. and Iqbal, W. and Jabeen, S. and Jannes, Jim and Kamal, Ayeesha and Kamatani, Yoichiro and Kanse, Sandip and Kloss, Manja and Lathrop, Mark and Leys, Didier and Lindgren, Arne and LongstrethJr, W. T. and Mahmood, Khalid and Meisinger, Christa and Metso, Tiina M. and Mosley, Thomas and Müller-Nurasyid, Martina and Norrving, Bo and Parati, Eugenio and Peters, Annette and Pezzini, Alessandro and Quereshi, I. and Rasheed, Asif and Rauf, A. and Salam, T. and Shen, J. and Slowik, A. and Stanne, T. and Strauch, K. and Tatlisumak, T. and Thijs, V. N. and Tiedt, S. and Traylor, M. and Waldenberger, M. and Walters, M. and Zhao, W. and Boncoraglio, G. and Debette, S. and Jern, S. and Levi, C. and Markus, H. and Meschia, J. and Rolfs, A. and Rothwell, P. and Saleheen, D. and Seshadri, S. and Sharma, P. and Sudlow, C. and Worrall, B. and Colin Stine, O. and Kittner, S. J. and Mitchell, B. D.},
  issn         = {1932-6203},
  language     = {eng},
  month        = {11},
  number       = {11},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke},
  url          = {http://dx.doi.org/10.1371/journal.pone.0206554},
  volume       = {13},
  year         = {2018},
}