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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.* ; 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.* ; 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.N.* ; 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, O.C.* ; Kittner, S.J.* ; Mitchell, B.D.*

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

PLoS ONE 13:e0206554 (2018)

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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.

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