Genetic associations with pulmonary embolism among those with a deep vein thrombosis: the International Network Against Venous Thrombosis Consortium.
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Lozano-Esparza Susana, Shakt Gabrielle E, Brody Jennifer A, Martinez-Perez Angel, Conomos Matthew P, Germain Marine, Clapham Katharine R, Teder-Laving Maris, van Hylckama Vlieg Astrid, Kauko Anni, Thibord Florian, Bezerra Ohanna C L, Nadkarni Girish N, Munsch Gaëlle, Nøst Therese Haugdahl, Goode Ellen L, Ji Yuekai, Chasman Daniel I, Reiner Alexander P, Turman Constance, Wiggins Kerri L, Sitlani Colleen M, Souto Juan Carlos, Lutsey Pamela L, Bellomo Tiffany, Biobank Estonian, Program Million Veteran, Li-Gao Ruifang, Winstén Aleksi Kristian, Chen Ming-Huei, Do Ron, Gourhant Lénaick, Hveem Kristian, Armasu Sebastian M, Saut Noémie, Pankratz Nathan, Giulianini Franco, Haessler Jeffrey, Song Mingyang, Olaso Robert, Boerwinkle Eric, Dochtermann Daniel, Soria Jose Manuel, Rich Stephen S, Smadja David, Koyama Satoshi, Rosendaal Frits R, Niiranen Teemu, Gagnon France, Vy Ha My T, Zakai Neil, Lemarie Catherine, Skogholt Anne Heidi, Deleuze Jean-François, Pankow James S, Ridker Paul M, Liu Yuxi, Rice Kenneth M, Pyarajan Saiju, Cushman Mary, Emmerich Jospeh, Psaty Bruce M, Natarajan Pradeep, Johnson Andrew D, Rodger Marc A, Suchon Pierre, Couturaud Francis, Morange Pierre-Emmanuel, Tang Weihong, Kooperberg Charles, Kabrhel Christopher, Sabater-Lleal Maria, Trégouët David-Alexandre, Wolberg Alisa S, Damrauer Scott M, Smith Nicholas L
Аннотация
OBJECTIVES: The aim of this study was to identify causal genetic factors that alter risk of PE among those with a presumed DVT.
METHODS: Using a case-only design of VTE, we conducted meta-analyses of genome-wide association studies (GWASs) in the International Network Against Venous Thrombosis Consortium. Among participants diagnosed with VTE, each study identified those who had a clinically reported PE, with or without a clinically reported DVT; those remaining had isolated DVT. Logistic regression models (PE as outcome compared with isolated DVT) were used for variant discovery and replication analyses. A polygenic risk score was created from the GWAS findings. Transcriptome-wide association study analyses were conducted using the GWAS discovery estimates.
RESULTS: Our discovery and replication analyses included 126 316 individuals with a VTE across 29 studies: 54 389 who had a PE and the remaining 71 927 who had an isolated DVT. Five variants reached genome-wide significance (P < 5 × 10-8) in discovery, 4 of which replicated: F5 rs6025 (factor V Leiden), odds ratio (OR) 0.66; FGG rs2066864, OR 1.08; F11 rs4253417, OR 1.07; and SLC12A2-DT rs3749748, OR 0.92. Each 1 SD increase in the polygenic risk score was associated with risk (OR: 1.05; 95% CI: 1.003-1.094). Transcriptome-wide association study analysis identified genetic associations with FGG, SLC12A2-DT, and CDHR4 transcripts.
CONCLUSION: Although the overall risk for VTE is strongly heritable, our findings support the hypothesis that PE in the setting of a presumed DVT is regulated by genetics, although the overall effect appears modest.