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

Archive ouverte

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. | Frossard, P. | Gieger, C. | Giese, A. K. | Grond-Ginsbach, C. | Ho, W. K. | 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. T., Jr. | Mahmood, K. | Meisinger, C. | Metso, T. M. | Mosley, T., Jr. | 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, V. N. | Tiedt, S. | Traylor, M. | Waldenberger, M. | Walters, M. | Zhao, W. | Boncoraglio, G. | Debette, Stéphanie | Jern, C. | Levi, C. | Markus, H. | Meschia, J. | Rolfs, A. | Rothwell, P. | Saleheen, D. | Seshadri, S. | Sharma, P. | Sudlow, C. | Worrall, B. | Stine, O. C. | Kittner, S. J. | Mitchell, B. D.

Edité par CCSD ; Public Library of Science -

International audience. 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 associated with early-onset ischemic stroke in Caucasians.

• Description
• Sujet/Public
• Outil
• Outil d'anticipation
• Mémoire et thèse
• Gestion