Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease
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Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. / Sabater-Lleal, Maria; Huang, Jie; Chasman, Daniel; Naitza, Silvia; Dehghan, Abbas; Johnson, Andrew D; Teumer, Alexander; Reiner, Alex P; Folkersen, Lasse; Basu, Saonli; Rudnicka, Alicja R; Trompet, Stella; Mälarstig, Anders; Baumert, Jens; Bis, Joshua C; Guo, Xiuqing; Hottenga, Jouke J; Shin, So-Youn; Lopez, Lorna M; Lahti, Jari; Tanaka, Toshiko; Yanek, Lisa R; Oudot-Mellakh, Tiphaine; Wilson, James F; Navarro, Pau; Huffman, Jennifer E; Zemunik, Tatijana; Redline, Susan; Mehra, Reena; Pulanic, Drazen; Rudan, Igor; Wright, Alan F; Kolcic, Ivana; Polasek, Ozren; Wild, Sarah H; Campbell, Harry; Curb, J David; Wallace, Robert; Liu, Simin; Eaton, Charles B; Becker, Diane M; Becker, Lewis C; Bandinelli, Stefania; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Fornage, Myriam; Green, David; Gross, Myron; Davies, Gail; Harris, Sarah E; Liewald, David C; Starr, John M; Williams, Frances M K; Grant, Peter J; Spector, Timothy D; Strawbridge, Rona J; Silveira, Angela; Sennblad, Bengt; Rivadeneira, Fernando; Uitterlinden, Andre G; Franco, Oscar H; Hofman, Albert; van Dongen, Jenny; Willemsen, Gonneke; Boomsma, Dorret I; Yao, Jie; Swords Jenny, Nancy; Haritunians, Talin; McKnight, Barbara; Lumley, Thomas; Taylor, Kent D; Rotter, Jerome I; Psaty, Bruce M; Peters, Annette; Gieger, Christian; Illig, Thomas; Grotevendt, Anne; Homuth, Georg; Völzke, Henry; Kocher, Thomas; Goel, Anuj; Franzosi, Maria Grazia; Seedorf, Udo; Clarke, Robert; Steri, Maristella; Tarasov, Kirill V; Sanna, Serena; Schlessinger, David; Stott, David J; Sattar, Naveed; Buckley, Brendan M; Rumley, Ann; Lowe, Gordon D; McArdle, Wendy L; Chen, Ming-Huei; Tofler, Geoffrey H; Song, Jaejoon; Boerwinkle, Eric; Folsom, Aaron R; Rose, Lynda M; Franco-Cereceda, Anders; Teichert, Martina; Ikram, M Arfan; Mosley, Thomas H; Bevan, Steve; Dichgans, Martin; Rothwell, Peter M; Sudlow, Cathie L M; Hopewell, Jemma C; Chambers, John C; Saleheen, Danish; Kooner, Jaspal S; Danesh, John; Nelson, Christopher P; Erdmann, Jeanette; Reilly, Muredach P; Kathiresan, Sekar; Schunkert, Heribert; Morange, Pierre-Emmanuel; Ferrucci, Luigi; Eriksson, Johan G; Jacobs, David; Deary, Ian J; Soranzo, Nicole; Witteman, Jacqueline C M; de Geus, Eco J C; Tracy, Russell P; Hayward, Caroline; Koenig, Wolfgang; Cucca, Francesco; Jukema, J Wouter; Eriksson, Per; Seshadri, Sudha; Markus, Hugh S; Watkins, Hugh; Samani, Nilesh J; Wallaschofski, Henri; Smith, Nicholas L; Tregouet, David; Ridker, Paul M; Tang, Weihong; Strachan, David P; Hamsten, Anders; O'Donnell, Christopher J; VTE Consortium.
in: CIRCULATION, Jahrgang 128, Nr. 12, 17.09.2013, S. 1310-1324.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease
AU - Sabater-Lleal, Maria
AU - Huang, Jie
AU - Chasman, Daniel
AU - Naitza, Silvia
AU - Dehghan, Abbas
AU - Johnson, Andrew D
AU - Teumer, Alexander
AU - Reiner, Alex P
AU - Folkersen, Lasse
AU - Basu, Saonli
AU - Rudnicka, Alicja R
AU - Trompet, Stella
AU - Mälarstig, Anders
AU - Baumert, Jens
AU - Bis, Joshua C
AU - Guo, Xiuqing
AU - Hottenga, Jouke J
AU - Shin, So-Youn
AU - Lopez, Lorna M
AU - Lahti, Jari
AU - Tanaka, Toshiko
AU - Yanek, Lisa R
AU - Oudot-Mellakh, Tiphaine
AU - Wilson, James F
AU - Navarro, Pau
AU - Huffman, Jennifer E
AU - Zemunik, Tatijana
AU - Redline, Susan
AU - Mehra, Reena
AU - Pulanic, Drazen
AU - Rudan, Igor
AU - Wright, Alan F
AU - Kolcic, Ivana
AU - Polasek, Ozren
AU - Wild, Sarah H
AU - Campbell, Harry
AU - Curb, J David
AU - Wallace, Robert
AU - Liu, Simin
AU - Eaton, Charles B
AU - Becker, Diane M
AU - Becker, Lewis C
AU - Bandinelli, Stefania
AU - Räikkönen, Katri
AU - Widen, Elisabeth
AU - Palotie, Aarno
AU - Fornage, Myriam
AU - Green, David
AU - Gross, Myron
AU - Davies, Gail
AU - Harris, Sarah E
AU - Liewald, David C
AU - Starr, John M
AU - Williams, Frances M K
AU - Grant, Peter J
AU - Spector, Timothy D
AU - Strawbridge, Rona J
AU - Silveira, Angela
AU - Sennblad, Bengt
AU - Rivadeneira, Fernando
AU - Uitterlinden, Andre G
AU - Franco, Oscar H
AU - Hofman, Albert
AU - van Dongen, Jenny
AU - Willemsen, Gonneke
AU - Boomsma, Dorret I
AU - Yao, Jie
AU - Swords Jenny, Nancy
AU - Haritunians, Talin
AU - McKnight, Barbara
AU - Lumley, Thomas
AU - Taylor, Kent D
AU - Rotter, Jerome I
AU - Psaty, Bruce M
AU - Peters, Annette
AU - Gieger, Christian
AU - Illig, Thomas
AU - Grotevendt, Anne
AU - Homuth, Georg
AU - Völzke, Henry
AU - Kocher, Thomas
AU - Goel, Anuj
AU - Franzosi, Maria Grazia
AU - Seedorf, Udo
AU - Clarke, Robert
AU - Steri, Maristella
AU - Tarasov, Kirill V
AU - Sanna, Serena
AU - Schlessinger, David
AU - Stott, David J
AU - Sattar, Naveed
AU - Buckley, Brendan M
AU - Rumley, Ann
AU - Lowe, Gordon D
AU - McArdle, Wendy L
AU - Chen, Ming-Huei
AU - Tofler, Geoffrey H
AU - Song, Jaejoon
AU - Boerwinkle, Eric
AU - Folsom, Aaron R
AU - Rose, Lynda M
AU - Franco-Cereceda, Anders
AU - Teichert, Martina
AU - Ikram, M Arfan
AU - Mosley, Thomas H
AU - Bevan, Steve
AU - Dichgans, Martin
AU - Rothwell, Peter M
AU - Sudlow, Cathie L M
AU - Hopewell, Jemma C
AU - Chambers, John C
AU - Saleheen, Danish
AU - Kooner, Jaspal S
AU - Danesh, John
AU - Nelson, Christopher P
AU - Erdmann, Jeanette
AU - Reilly, Muredach P
AU - Kathiresan, Sekar
AU - Schunkert, Heribert
AU - Morange, Pierre-Emmanuel
AU - Ferrucci, Luigi
AU - Eriksson, Johan G
AU - Jacobs, David
AU - Deary, Ian J
AU - Soranzo, Nicole
AU - Witteman, Jacqueline C M
AU - de Geus, Eco J C
AU - Tracy, Russell P
AU - Hayward, Caroline
AU - Koenig, Wolfgang
AU - Cucca, Francesco
AU - Jukema, J Wouter
AU - Eriksson, Per
AU - Seshadri, Sudha
AU - Markus, Hugh S
AU - Watkins, Hugh
AU - Samani, Nilesh J
AU - Wallaschofski, Henri
AU - Smith, Nicholas L
AU - Tregouet, David
AU - Ridker, Paul M
AU - Tang, Weihong
AU - Strachan, David P
AU - Hamsten, Anders
AU - O'Donnell, Christopher J
AU - VTE Consortium
AU - Zeller, Tanja
AU - Blankenberg, Stefan
PY - 2013/9/17
Y1 - 2013/9/17
N2 - BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
AB - BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
KW - Adolescent
KW - Adult
KW - African Continental Ancestry Group/genetics
KW - Aged
KW - Aged, 80 and over
KW - Cardiovascular Diseases/ethnology
KW - Coronary Artery Disease/ethnology
KW - European Continental Ancestry Group/genetics
KW - Female
KW - Fibrinogen/genetics
KW - Genetic Loci/genetics
KW - Genetic Predisposition to Disease/ethnology
KW - Genome-Wide Association Study
KW - Hispanic Americans/genetics
KW - Humans
KW - Male
KW - Middle Aged
KW - Myocardial Infarction/ethnology
KW - Polymorphism, Single Nucleotide/genetics
KW - Risk Factors
KW - Stroke/ethnology
KW - Venous Thromboembolism/ethnology
KW - Young Adult
U2 - 10.1161/CIRCULATIONAHA.113.002251
DO - 10.1161/CIRCULATIONAHA.113.002251
M3 - SCORING: Journal article
C2 - 23969696
VL - 128
SP - 1310
EP - 1324
JO - CIRCULATION
JF - CIRCULATION
SN - 0009-7322
IS - 12
ER -