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
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 (90 000 subjects of European ancestry, the fir...
Gespeichert in:
| Veröffentlicht in: | Circulation (New York, N.Y.) N.Y.), 2013-09, Vol.128 (12), p.1310-1324 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1324 |
|---|---|
| container_issue | 12 |
| container_start_page | 1310 |
| container_title | Circulation (New York, N.Y.) |
| container_volume | 128 |
| creator | Sabater-Lleal, Maria Huang, Jie Chasman, Daniel Naitza, Silvia Dehghan, Abbas Teumer, Alexander Folkersen, Lasse Basu, Saonli Rudnicka, Alicja R. Trompet, Stella Mälarstig, Anders Baumert, Jens Guo, Xiuqing Hottenga, Jouke J. Shin, So-Youn Lopez, Lorna M. Lahti, Jari Oudot-Mellakh, Tiphaine Wilson, James F. Navarro, Pau Huffman, Jennifer E. Zemunik, Tatijana Mehra, Reena Rudan, Igor Wright, Alan F. Campbell, Harry Wallace, Robert Liu, Simin Eaton, Charles B. Becker, Diane M. Becker, Lewis C. Räikkönen, Katri Widen, Elisabeth Palotie, Aarno Fornage, Myriam Green, David Gross, Myron Harris, Sarah E. Starr, John M. Williams, Frances M.K. Spector, Timothy D. Strawbridge, Rona J. Silveira, Angela Sennblad, Bengt Uitterlinden, Andre G. Franco, Oscar H. Hofman, Albert van Dongen, Jenny Yao, Jie Swords Jenny, Nancy Haritunians, Talin Lumley, Thomas Taylor, Kent D. Peters, Annette Illig, Thomas Kocher, Thomas Franzosi, Maria Grazia Seedorf, Udo Clarke, Robert Schlessinger, David Stott, David J. Sattar, Naveed Buckley, Brendan M. Lowe, Gordon D. Chen, Ming-Huei Tofler, Geoffrey H. Song, Jaejoon Boerwinkle, Eric Rose, Lynda M. Franco-Cereceda, Anders Teichert, Martina Mosley, Thomas H. Bevan, Steve Dichgans, Martin Sudlow, Cathie L.M. Hopewell, Jemma C. Chambers, John C. Saleheen, Danish Kooner, Jaspal S. Danesh, John Nelson, Christopher P. Reilly, Muredach P. Kathiresan, Sekar Schunkert, Heribert Morange, Pierre-Emmanuel Ferrucci, Luigi Eriksson, Johan G. Jacobs, David Deary, Ian J. Soranzo, Nicole Tracy, Russell P. Hayward, Caroline Koenig, Wolfgang Cucca, Francesco Samani, Nilesh J. Smith, Nicholas L. Ridker, Paul M Tang, Weihong Hamsten, Anders O’Donnell, Christopher J. |
| description | 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 (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 |
| doi_str_mv | 10.1161/CIRCULATIONAHA.113.002251 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1433517024</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1433517024</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3288-f78267fa740bb01afef258a293c14c0c167be29a197db4c48065e95de0e7cc123</originalsourceid><addsrcrecordid>eNpVUctO3DAUjapWMFB-oXJ33Zj6kcTJplKa8hhpAKmAuowc54YxzdjUD0Z8Lz9SRwOtkBfXPvc8LJ0s-0zJMaUl_douf7a3q-ZmeXXZnDcJ48eEMFbQd9mCFizHecHr99mCEFJjwRnbzw68v0_PkotiL9tnvC7ns8ieL-IUNIS10QpdQJC4MXJ68tojO6IzMHYD-JceADXeW6Vl0Nag6xAHDR5pg75RQlByRtexvwcVPFoOYIIe5z3j6FT3Tht7Bwa_OsCAVumC-hjQpU1mzpo7dPKYUoyCOVeiVkYvpzeh3yFsAQxqtVNxSlgS_XdH0gxJ5QZtH6WfCQ790B6kh4_Zh1FOHo5e5mF2e3py057j1dXZsm1WWHFWVXgUFSvFKEVO-p5QOcLIikqymiuaK6JoKXpgtaS1GPpc5RUpC6iLAQgIpSjjh9mXne-Ds38i-NBttFcwTdKAjb6jOecFFYTliVrvqMpZ7x2M3YPTG-meOkq6uePubccJ492u46T99BIT-w0M_5SvpSZCviNs7RTA-d9T3ILr1iCnsE4uhHBCBWaEclKn_-AZqvhfHty2oA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1433517024</pqid></control><display><type>article</type><title>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</title><source>MEDLINE</source><source>American Heart Association Journals</source><source>Journals@Ovid Complete</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Sabater-Lleal, Maria ; Huang, Jie ; Chasman, Daniel ; Naitza, Silvia ; Dehghan, Abbas ; Teumer, Alexander ; Folkersen, Lasse ; Basu, Saonli ; Rudnicka, Alicja R. ; Trompet, Stella ; Mälarstig, Anders ; Baumert, Jens ; Guo, Xiuqing ; Hottenga, Jouke J. ; Shin, So-Youn ; Lopez, Lorna M. ; Lahti, Jari ; Oudot-Mellakh, Tiphaine ; Wilson, James F. ; Navarro, Pau ; Huffman, Jennifer E. ; Zemunik, Tatijana ; Mehra, Reena ; Rudan, Igor ; Wright, Alan F. ; Campbell, Harry ; Wallace, Robert ; Liu, Simin ; Eaton, Charles B. ; Becker, Diane M. ; Becker, Lewis C. ; Räikkönen, Katri ; Widen, Elisabeth ; Palotie, Aarno ; Fornage, Myriam ; Green, David ; Gross, Myron ; Harris, Sarah E. ; Starr, John M. ; Williams, Frances M.K. ; Spector, Timothy D. ; Strawbridge, Rona J. ; Silveira, Angela ; Sennblad, Bengt ; Uitterlinden, Andre G. ; Franco, Oscar H. ; Hofman, Albert ; van Dongen, Jenny ; Yao, Jie ; Swords Jenny, Nancy ; Haritunians, Talin ; Lumley, Thomas ; Taylor, Kent D. ; Peters, Annette ; Illig, Thomas ; Kocher, Thomas ; Franzosi, Maria Grazia ; Seedorf, Udo ; Clarke, Robert ; Schlessinger, David ; Stott, David J. ; Sattar, Naveed ; Buckley, Brendan M. ; Lowe, Gordon D. ; Chen, Ming-Huei ; Tofler, Geoffrey H. ; Song, Jaejoon ; Boerwinkle, Eric ; Rose, Lynda M. ; Franco-Cereceda, Anders ; Teichert, Martina ; Mosley, Thomas H. ; Bevan, Steve ; Dichgans, Martin ; Sudlow, Cathie L.M. ; Hopewell, Jemma C. ; Chambers, John C. ; Saleheen, Danish ; Kooner, Jaspal S. ; Danesh, John ; Nelson, Christopher P. ; Reilly, Muredach P. ; Kathiresan, Sekar ; Schunkert, Heribert ; Morange, Pierre-Emmanuel ; Ferrucci, Luigi ; Eriksson, Johan G. ; Jacobs, David ; Deary, Ian J. ; Soranzo, Nicole ; Tracy, Russell P. ; Hayward, Caroline ; Koenig, Wolfgang ; Cucca, Francesco ; Samani, Nilesh J. ; Smith, Nicholas L. ; Ridker, Paul M ; Tang, Weihong ; Hamsten, Anders ; O’Donnell, Christopher J.</creator><creatorcontrib>Sabater-Lleal, Maria ; Huang, Jie ; Chasman, Daniel ; Naitza, Silvia ; Dehghan, Abbas ; Teumer, Alexander ; Folkersen, Lasse ; Basu, Saonli ; Rudnicka, Alicja R. ; Trompet, Stella ; Mälarstig, Anders ; Baumert, Jens ; Guo, Xiuqing ; Hottenga, Jouke J. ; Shin, So-Youn ; Lopez, Lorna M. ; Lahti, Jari ; Oudot-Mellakh, Tiphaine ; Wilson, James F. ; Navarro, Pau ; Huffman, Jennifer E. ; Zemunik, Tatijana ; Mehra, Reena ; Rudan, Igor ; Wright, Alan F. ; Campbell, Harry ; Wallace, Robert ; Liu, Simin ; Eaton, Charles B. ; Becker, Diane M. ; Becker, Lewis C. ; Räikkönen, Katri ; Widen, Elisabeth ; Palotie, Aarno ; Fornage, Myriam ; Green, David ; Gross, Myron ; Harris, Sarah E. ; Starr, John M. ; Williams, Frances M.K. ; Spector, Timothy D. ; Strawbridge, Rona J. ; Silveira, Angela ; Sennblad, Bengt ; Uitterlinden, Andre G. ; Franco, Oscar H. ; Hofman, Albert ; van Dongen, Jenny ; Yao, Jie ; Swords Jenny, Nancy ; Haritunians, Talin ; Lumley, Thomas ; Taylor, Kent D. ; Peters, Annette ; Illig, Thomas ; Kocher, Thomas ; Franzosi, Maria Grazia ; Seedorf, Udo ; Clarke, Robert ; Schlessinger, David ; Stott, David J. ; Sattar, Naveed ; Buckley, Brendan M. ; Lowe, Gordon D. ; Chen, Ming-Huei ; Tofler, Geoffrey H. ; Song, Jaejoon ; Boerwinkle, Eric ; Rose, Lynda M. ; Franco-Cereceda, Anders ; Teichert, Martina ; Mosley, Thomas H. ; Bevan, Steve ; Dichgans, Martin ; Sudlow, Cathie L.M. ; Hopewell, Jemma C. ; Chambers, John C. ; Saleheen, Danish ; Kooner, Jaspal S. ; Danesh, John ; Nelson, Christopher P. ; Reilly, Muredach P. ; Kathiresan, Sekar ; Schunkert, Heribert ; Morange, Pierre-Emmanuel ; Ferrucci, Luigi ; Eriksson, Johan G. ; Jacobs, David ; Deary, Ian J. ; Soranzo, Nicole ; Tracy, Russell P. ; Hayward, Caroline ; Koenig, Wolfgang ; Cucca, Francesco ; Samani, Nilesh J. ; Smith, Nicholas L. ; Ridker, Paul M ; Tang, Weihong ; Hamsten, Anders ; O’Donnell, Christopher J. ; VTE Consortium ; C4D Consortium ; STROKE Consortium ; Wellcome Trust Case Control Consortium 2 (WTCCC2) ; CARDIoGRAM Consortium</creatorcontrib><description>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) 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.</description><identifier>ISSN: 0009-7322</identifier><identifier>ISSN: 1524-4539</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/CIRCULATIONAHA.113.002251</identifier><identifier>PMID: 23969696</identifier><language>eng</language><publisher>United States: by the American College of Cardiology Foundation and the American Heart Association, Inc</publisher><subject>Adolescent ; Adult ; Aged ; Aged, 80 and over ; Black People - genetics ; Black People - statistics & numerical data ; Cardiovascular Diseases - ethnology ; Cardiovascular Diseases - genetics ; Cardiovascular Diseases - metabolism ; Coronary Artery Disease - ethnology ; Coronary Artery Disease - genetics ; Coronary Artery Disease - metabolism ; Female ; Fibrinogen - genetics ; Fibrinogen - metabolism ; Genetic Loci - genetics ; Genetic Predisposition to Disease - ethnology ; Genome-Wide Association Study ; Hispanic or Latino - genetics ; Hispanic or Latino - statistics & numerical data ; Humans ; Male ; Middle Aged ; Myocardial Infarction - ethnology ; Myocardial Infarction - genetics ; Myocardial Infarction - metabolism ; Polymorphism, Single Nucleotide - genetics ; Risk Factors ; Stroke - ethnology ; Stroke - genetics ; Stroke - metabolism ; Venous Thromboembolism - ethnology ; Venous Thromboembolism - genetics ; Venous Thromboembolism - metabolism ; White People - genetics ; White People - statistics & numerical data ; Young Adult</subject><ispartof>Circulation (New York, N.Y.), 2013-09, Vol.128 (12), p.1310-1324</ispartof><rights>2013 by the American College of Cardiology Foundation and the American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3288-f78267fa740bb01afef258a293c14c0c167be29a197db4c48065e95de0e7cc123</citedby><cites>FETCH-LOGICAL-c3288-f78267fa740bb01afef258a293c14c0c167be29a197db4c48065e95de0e7cc123</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3685,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23969696$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sabater-Lleal, Maria</creatorcontrib><creatorcontrib>Huang, Jie</creatorcontrib><creatorcontrib>Chasman, Daniel</creatorcontrib><creatorcontrib>Naitza, Silvia</creatorcontrib><creatorcontrib>Dehghan, Abbas</creatorcontrib><creatorcontrib>Teumer, Alexander</creatorcontrib><creatorcontrib>Folkersen, Lasse</creatorcontrib><creatorcontrib>Basu, Saonli</creatorcontrib><creatorcontrib>Rudnicka, Alicja R.</creatorcontrib><creatorcontrib>Trompet, Stella</creatorcontrib><creatorcontrib>Mälarstig, Anders</creatorcontrib><creatorcontrib>Baumert, Jens</creatorcontrib><creatorcontrib>Guo, Xiuqing</creatorcontrib><creatorcontrib>Hottenga, Jouke J.</creatorcontrib><creatorcontrib>Shin, So-Youn</creatorcontrib><creatorcontrib>Lopez, Lorna M.</creatorcontrib><creatorcontrib>Lahti, Jari</creatorcontrib><creatorcontrib>Oudot-Mellakh, Tiphaine</creatorcontrib><creatorcontrib>Wilson, James F.</creatorcontrib><creatorcontrib>Navarro, Pau</creatorcontrib><creatorcontrib>Huffman, Jennifer E.</creatorcontrib><creatorcontrib>Zemunik, Tatijana</creatorcontrib><creatorcontrib>Mehra, Reena</creatorcontrib><creatorcontrib>Rudan, Igor</creatorcontrib><creatorcontrib>Wright, Alan F.</creatorcontrib><creatorcontrib>Campbell, Harry</creatorcontrib><creatorcontrib>Wallace, Robert</creatorcontrib><creatorcontrib>Liu, Simin</creatorcontrib><creatorcontrib>Eaton, Charles B.</creatorcontrib><creatorcontrib>Becker, Diane M.</creatorcontrib><creatorcontrib>Becker, Lewis C.</creatorcontrib><creatorcontrib>Räikkönen, Katri</creatorcontrib><creatorcontrib>Widen, Elisabeth</creatorcontrib><creatorcontrib>Palotie, Aarno</creatorcontrib><creatorcontrib>Fornage, Myriam</creatorcontrib><creatorcontrib>Green, David</creatorcontrib><creatorcontrib>Gross, Myron</creatorcontrib><creatorcontrib>Harris, Sarah E.</creatorcontrib><creatorcontrib>Starr, John M.</creatorcontrib><creatorcontrib>Williams, Frances M.K.</creatorcontrib><creatorcontrib>Spector, Timothy D.</creatorcontrib><creatorcontrib>Strawbridge, Rona J.</creatorcontrib><creatorcontrib>Silveira, Angela</creatorcontrib><creatorcontrib>Sennblad, Bengt</creatorcontrib><creatorcontrib>Uitterlinden, Andre G.</creatorcontrib><creatorcontrib>Franco, Oscar H.</creatorcontrib><creatorcontrib>Hofman, Albert</creatorcontrib><creatorcontrib>van Dongen, Jenny</creatorcontrib><creatorcontrib>Yao, Jie</creatorcontrib><creatorcontrib>Swords Jenny, Nancy</creatorcontrib><creatorcontrib>Haritunians, Talin</creatorcontrib><creatorcontrib>Lumley, Thomas</creatorcontrib><creatorcontrib>Taylor, Kent D.</creatorcontrib><creatorcontrib>Peters, Annette</creatorcontrib><creatorcontrib>Illig, Thomas</creatorcontrib><creatorcontrib>Kocher, Thomas</creatorcontrib><creatorcontrib>Franzosi, Maria Grazia</creatorcontrib><creatorcontrib>Seedorf, Udo</creatorcontrib><creatorcontrib>Clarke, Robert</creatorcontrib><creatorcontrib>Schlessinger, David</creatorcontrib><creatorcontrib>Stott, David J.</creatorcontrib><creatorcontrib>Sattar, Naveed</creatorcontrib><creatorcontrib>Buckley, Brendan M.</creatorcontrib><creatorcontrib>Lowe, Gordon D.</creatorcontrib><creatorcontrib>Chen, Ming-Huei</creatorcontrib><creatorcontrib>Tofler, Geoffrey H.</creatorcontrib><creatorcontrib>Song, Jaejoon</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Rose, Lynda M.</creatorcontrib><creatorcontrib>Franco-Cereceda, Anders</creatorcontrib><creatorcontrib>Teichert, Martina</creatorcontrib><creatorcontrib>Mosley, Thomas H.</creatorcontrib><creatorcontrib>Bevan, Steve</creatorcontrib><creatorcontrib>Dichgans, Martin</creatorcontrib><creatorcontrib>Sudlow, Cathie L.M.</creatorcontrib><creatorcontrib>Hopewell, Jemma C.</creatorcontrib><creatorcontrib>Chambers, John C.</creatorcontrib><creatorcontrib>Saleheen, Danish</creatorcontrib><creatorcontrib>Kooner, Jaspal S.</creatorcontrib><creatorcontrib>Danesh, John</creatorcontrib><creatorcontrib>Nelson, Christopher P.</creatorcontrib><creatorcontrib>Reilly, Muredach P.</creatorcontrib><creatorcontrib>Kathiresan, Sekar</creatorcontrib><creatorcontrib>Schunkert, Heribert</creatorcontrib><creatorcontrib>Morange, Pierre-Emmanuel</creatorcontrib><creatorcontrib>Ferrucci, Luigi</creatorcontrib><creatorcontrib>Eriksson, Johan G.</creatorcontrib><creatorcontrib>Jacobs, David</creatorcontrib><creatorcontrib>Deary, Ian J.</creatorcontrib><creatorcontrib>Soranzo, Nicole</creatorcontrib><creatorcontrib>Tracy, Russell P.</creatorcontrib><creatorcontrib>Hayward, Caroline</creatorcontrib><creatorcontrib>Koenig, Wolfgang</creatorcontrib><creatorcontrib>Cucca, Francesco</creatorcontrib><creatorcontrib>Samani, Nilesh J.</creatorcontrib><creatorcontrib>Smith, Nicholas L.</creatorcontrib><creatorcontrib>Ridker, Paul M</creatorcontrib><creatorcontrib>Tang, Weihong</creatorcontrib><creatorcontrib>Hamsten, Anders</creatorcontrib><creatorcontrib>O’Donnell, Christopher J.</creatorcontrib><creatorcontrib>VTE Consortium</creatorcontrib><creatorcontrib>C4D Consortium</creatorcontrib><creatorcontrib>STROKE Consortium</creatorcontrib><creatorcontrib>Wellcome Trust Case Control Consortium 2 (WTCCC2)</creatorcontrib><creatorcontrib>CARDIoGRAM Consortium</creatorcontrib><title>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</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>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) 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.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Black People - genetics</subject><subject>Black People - statistics & numerical data</subject><subject>Cardiovascular Diseases - ethnology</subject><subject>Cardiovascular Diseases - genetics</subject><subject>Cardiovascular Diseases - metabolism</subject><subject>Coronary Artery Disease - ethnology</subject><subject>Coronary Artery Disease - genetics</subject><subject>Coronary Artery Disease - metabolism</subject><subject>Female</subject><subject>Fibrinogen - genetics</subject><subject>Fibrinogen - metabolism</subject><subject>Genetic Loci - genetics</subject><subject>Genetic Predisposition to Disease - ethnology</subject><subject>Genome-Wide Association Study</subject><subject>Hispanic or Latino - genetics</subject><subject>Hispanic or Latino - statistics & numerical data</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Myocardial Infarction - ethnology</subject><subject>Myocardial Infarction - genetics</subject><subject>Myocardial Infarction - metabolism</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Risk Factors</subject><subject>Stroke - ethnology</subject><subject>Stroke - genetics</subject><subject>Stroke - metabolism</subject><subject>Venous Thromboembolism - ethnology</subject><subject>Venous Thromboembolism - genetics</subject><subject>Venous Thromboembolism - metabolism</subject><subject>White People - genetics</subject><subject>White People - statistics & numerical data</subject><subject>Young Adult</subject><issn>0009-7322</issn><issn>1524-4539</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUctO3DAUjapWMFB-oXJ33Zj6kcTJplKa8hhpAKmAuowc54YxzdjUD0Z8Lz9SRwOtkBfXPvc8LJ0s-0zJMaUl_douf7a3q-ZmeXXZnDcJ48eEMFbQd9mCFizHecHr99mCEFJjwRnbzw68v0_PkotiL9tnvC7ns8ieL-IUNIS10QpdQJC4MXJ68tojO6IzMHYD-JceADXeW6Vl0Nag6xAHDR5pg75RQlByRtexvwcVPFoOYIIe5z3j6FT3Tht7Bwa_OsCAVumC-hjQpU1mzpo7dPKYUoyCOVeiVkYvpzeh3yFsAQxqtVNxSlgS_XdH0gxJ5QZtH6WfCQ790B6kh4_Zh1FOHo5e5mF2e3py057j1dXZsm1WWHFWVXgUFSvFKEVO-p5QOcLIikqymiuaK6JoKXpgtaS1GPpc5RUpC6iLAQgIpSjjh9mXne-Ds38i-NBttFcwTdKAjb6jOecFFYTliVrvqMpZ7x2M3YPTG-meOkq6uePubccJ492u46T99BIT-w0M_5SvpSZCviNs7RTA-d9T3ILr1iCnsE4uhHBCBWaEclKn_-AZqvhfHty2oA</recordid><startdate>20130917</startdate><enddate>20130917</enddate><creator>Sabater-Lleal, Maria</creator><creator>Huang, Jie</creator><creator>Chasman, Daniel</creator><creator>Naitza, Silvia</creator><creator>Dehghan, Abbas</creator><creator>Teumer, Alexander</creator><creator>Folkersen, Lasse</creator><creator>Basu, Saonli</creator><creator>Rudnicka, Alicja R.</creator><creator>Trompet, Stella</creator><creator>Mälarstig, Anders</creator><creator>Baumert, Jens</creator><creator>Guo, Xiuqing</creator><creator>Hottenga, Jouke J.</creator><creator>Shin, So-Youn</creator><creator>Lopez, Lorna M.</creator><creator>Lahti, Jari</creator><creator>Oudot-Mellakh, Tiphaine</creator><creator>Wilson, James F.</creator><creator>Navarro, Pau</creator><creator>Huffman, Jennifer E.</creator><creator>Zemunik, Tatijana</creator><creator>Mehra, Reena</creator><creator>Rudan, Igor</creator><creator>Wright, Alan F.</creator><creator>Campbell, Harry</creator><creator>Wallace, Robert</creator><creator>Liu, Simin</creator><creator>Eaton, Charles B.</creator><creator>Becker, Diane M.</creator><creator>Becker, Lewis C.</creator><creator>Räikkönen, Katri</creator><creator>Widen, Elisabeth</creator><creator>Palotie, Aarno</creator><creator>Fornage, Myriam</creator><creator>Green, David</creator><creator>Gross, Myron</creator><creator>Harris, Sarah E.</creator><creator>Starr, John M.</creator><creator>Williams, Frances M.K.</creator><creator>Spector, Timothy D.</creator><creator>Strawbridge, Rona J.</creator><creator>Silveira, Angela</creator><creator>Sennblad, Bengt</creator><creator>Uitterlinden, Andre G.</creator><creator>Franco, Oscar H.</creator><creator>Hofman, Albert</creator><creator>van Dongen, Jenny</creator><creator>Yao, Jie</creator><creator>Swords Jenny, Nancy</creator><creator>Haritunians, Talin</creator><creator>Lumley, Thomas</creator><creator>Taylor, Kent D.</creator><creator>Peters, Annette</creator><creator>Illig, Thomas</creator><creator>Kocher, Thomas</creator><creator>Franzosi, Maria Grazia</creator><creator>Seedorf, Udo</creator><creator>Clarke, Robert</creator><creator>Schlessinger, David</creator><creator>Stott, David J.</creator><creator>Sattar, Naveed</creator><creator>Buckley, Brendan M.</creator><creator>Lowe, Gordon D.</creator><creator>Chen, Ming-Huei</creator><creator>Tofler, Geoffrey H.</creator><creator>Song, Jaejoon</creator><creator>Boerwinkle, Eric</creator><creator>Rose, Lynda M.</creator><creator>Franco-Cereceda, Anders</creator><creator>Teichert, Martina</creator><creator>Mosley, Thomas H.</creator><creator>Bevan, Steve</creator><creator>Dichgans, Martin</creator><creator>Sudlow, Cathie L.M.</creator><creator>Hopewell, Jemma C.</creator><creator>Chambers, John C.</creator><creator>Saleheen, Danish</creator><creator>Kooner, Jaspal S.</creator><creator>Danesh, John</creator><creator>Nelson, Christopher P.</creator><creator>Reilly, Muredach P.</creator><creator>Kathiresan, Sekar</creator><creator>Schunkert, Heribert</creator><creator>Morange, Pierre-Emmanuel</creator><creator>Ferrucci, Luigi</creator><creator>Eriksson, Johan G.</creator><creator>Jacobs, David</creator><creator>Deary, Ian J.</creator><creator>Soranzo, Nicole</creator><creator>Tracy, Russell P.</creator><creator>Hayward, Caroline</creator><creator>Koenig, Wolfgang</creator><creator>Cucca, Francesco</creator><creator>Samani, Nilesh J.</creator><creator>Smith, Nicholas L.</creator><creator>Ridker, Paul M</creator><creator>Tang, Weihong</creator><creator>Hamsten, Anders</creator><creator>O’Donnell, Christopher J.</creator><general>by the American College of Cardiology Foundation and the American Heart Association, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20130917</creationdate><title>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</title><author>Sabater-Lleal, Maria ; Huang, Jie ; Chasman, Daniel ; Naitza, Silvia ; Dehghan, Abbas ; Teumer, Alexander ; Folkersen, Lasse ; Basu, Saonli ; Rudnicka, Alicja R. ; Trompet, Stella ; Mälarstig, Anders ; Baumert, Jens ; Guo, Xiuqing ; Hottenga, Jouke J. ; Shin, So-Youn ; Lopez, Lorna M. ; Lahti, Jari ; Oudot-Mellakh, Tiphaine ; Wilson, James F. ; Navarro, Pau ; Huffman, Jennifer E. ; Zemunik, Tatijana ; Mehra, Reena ; Rudan, Igor ; Wright, Alan F. ; Campbell, Harry ; Wallace, Robert ; Liu, Simin ; Eaton, Charles B. ; Becker, Diane M. ; Becker, Lewis C. ; Räikkönen, Katri ; Widen, Elisabeth ; Palotie, Aarno ; Fornage, Myriam ; Green, David ; Gross, Myron ; Harris, Sarah E. ; Starr, John M. ; Williams, Frances M.K. ; Spector, Timothy D. ; Strawbridge, Rona J. ; Silveira, Angela ; Sennblad, Bengt ; Uitterlinden, Andre G. ; Franco, Oscar H. ; Hofman, Albert ; van Dongen, Jenny ; Yao, Jie ; Swords Jenny, Nancy ; Haritunians, Talin ; Lumley, Thomas ; Taylor, Kent D. ; Peters, Annette ; Illig, Thomas ; Kocher, Thomas ; Franzosi, Maria Grazia ; Seedorf, Udo ; Clarke, Robert ; Schlessinger, David ; Stott, David J. ; Sattar, Naveed ; Buckley, Brendan M. ; Lowe, Gordon D. ; Chen, Ming-Huei ; Tofler, Geoffrey H. ; Song, Jaejoon ; Boerwinkle, Eric ; Rose, Lynda M. ; Franco-Cereceda, Anders ; Teichert, Martina ; Mosley, Thomas H. ; Bevan, Steve ; Dichgans, Martin ; Sudlow, Cathie L.M. ; Hopewell, Jemma C. ; Chambers, John C. ; Saleheen, Danish ; Kooner, Jaspal S. ; Danesh, John ; Nelson, Christopher P. ; Reilly, Muredach P. ; Kathiresan, Sekar ; Schunkert, Heribert ; Morange, Pierre-Emmanuel ; Ferrucci, Luigi ; Eriksson, Johan G. ; Jacobs, David ; Deary, Ian J. ; Soranzo, Nicole ; Tracy, Russell P. ; Hayward, Caroline ; Koenig, Wolfgang ; Cucca, Francesco ; Samani, Nilesh J. ; Smith, Nicholas L. ; Ridker, Paul M ; Tang, Weihong ; Hamsten, Anders ; O’Donnell, Christopher J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3288-f78267fa740bb01afef258a293c14c0c167be29a197db4c48065e95de0e7cc123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Black People - genetics</topic><topic>Black People - statistics & numerical data</topic><topic>Cardiovascular Diseases - ethnology</topic><topic>Cardiovascular Diseases - genetics</topic><topic>Cardiovascular Diseases - metabolism</topic><topic>Coronary Artery Disease - ethnology</topic><topic>Coronary Artery Disease - genetics</topic><topic>Coronary Artery Disease - metabolism</topic><topic>Female</topic><topic>Fibrinogen - genetics</topic><topic>Fibrinogen - metabolism</topic><topic>Genetic Loci - genetics</topic><topic>Genetic Predisposition to Disease - ethnology</topic><topic>Genome-Wide Association Study</topic><topic>Hispanic or Latino - genetics</topic><topic>Hispanic or Latino - statistics & numerical data</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Myocardial Infarction - ethnology</topic><topic>Myocardial Infarction - genetics</topic><topic>Myocardial Infarction - metabolism</topic><topic>Polymorphism, Single Nucleotide - genetics</topic><topic>Risk Factors</topic><topic>Stroke - ethnology</topic><topic>Stroke - genetics</topic><topic>Stroke - metabolism</topic><topic>Venous Thromboembolism - ethnology</topic><topic>Venous Thromboembolism - genetics</topic><topic>Venous Thromboembolism - metabolism</topic><topic>White People - genetics</topic><topic>White People - statistics & numerical data</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sabater-Lleal, Maria</creatorcontrib><creatorcontrib>Huang, Jie</creatorcontrib><creatorcontrib>Chasman, Daniel</creatorcontrib><creatorcontrib>Naitza, Silvia</creatorcontrib><creatorcontrib>Dehghan, Abbas</creatorcontrib><creatorcontrib>Teumer, Alexander</creatorcontrib><creatorcontrib>Folkersen, Lasse</creatorcontrib><creatorcontrib>Basu, Saonli</creatorcontrib><creatorcontrib>Rudnicka, Alicja R.</creatorcontrib><creatorcontrib>Trompet, Stella</creatorcontrib><creatorcontrib>Mälarstig, Anders</creatorcontrib><creatorcontrib>Baumert, Jens</creatorcontrib><creatorcontrib>Guo, Xiuqing</creatorcontrib><creatorcontrib>Hottenga, Jouke J.</creatorcontrib><creatorcontrib>Shin, So-Youn</creatorcontrib><creatorcontrib>Lopez, Lorna M.</creatorcontrib><creatorcontrib>Lahti, Jari</creatorcontrib><creatorcontrib>Oudot-Mellakh, Tiphaine</creatorcontrib><creatorcontrib>Wilson, James F.</creatorcontrib><creatorcontrib>Navarro, Pau</creatorcontrib><creatorcontrib>Huffman, Jennifer E.</creatorcontrib><creatorcontrib>Zemunik, Tatijana</creatorcontrib><creatorcontrib>Mehra, Reena</creatorcontrib><creatorcontrib>Rudan, Igor</creatorcontrib><creatorcontrib>Wright, Alan F.</creatorcontrib><creatorcontrib>Campbell, Harry</creatorcontrib><creatorcontrib>Wallace, Robert</creatorcontrib><creatorcontrib>Liu, Simin</creatorcontrib><creatorcontrib>Eaton, Charles B.</creatorcontrib><creatorcontrib>Becker, Diane M.</creatorcontrib><creatorcontrib>Becker, Lewis C.</creatorcontrib><creatorcontrib>Räikkönen, Katri</creatorcontrib><creatorcontrib>Widen, Elisabeth</creatorcontrib><creatorcontrib>Palotie, Aarno</creatorcontrib><creatorcontrib>Fornage, Myriam</creatorcontrib><creatorcontrib>Green, David</creatorcontrib><creatorcontrib>Gross, Myron</creatorcontrib><creatorcontrib>Harris, Sarah E.</creatorcontrib><creatorcontrib>Starr, John M.</creatorcontrib><creatorcontrib>Williams, Frances M.K.</creatorcontrib><creatorcontrib>Spector, Timothy D.</creatorcontrib><creatorcontrib>Strawbridge, Rona J.</creatorcontrib><creatorcontrib>Silveira, Angela</creatorcontrib><creatorcontrib>Sennblad, Bengt</creatorcontrib><creatorcontrib>Uitterlinden, Andre G.</creatorcontrib><creatorcontrib>Franco, Oscar H.</creatorcontrib><creatorcontrib>Hofman, Albert</creatorcontrib><creatorcontrib>van Dongen, Jenny</creatorcontrib><creatorcontrib>Yao, Jie</creatorcontrib><creatorcontrib>Swords Jenny, Nancy</creatorcontrib><creatorcontrib>Haritunians, Talin</creatorcontrib><creatorcontrib>Lumley, Thomas</creatorcontrib><creatorcontrib>Taylor, Kent D.</creatorcontrib><creatorcontrib>Peters, Annette</creatorcontrib><creatorcontrib>Illig, Thomas</creatorcontrib><creatorcontrib>Kocher, Thomas</creatorcontrib><creatorcontrib>Franzosi, Maria Grazia</creatorcontrib><creatorcontrib>Seedorf, Udo</creatorcontrib><creatorcontrib>Clarke, Robert</creatorcontrib><creatorcontrib>Schlessinger, David</creatorcontrib><creatorcontrib>Stott, David J.</creatorcontrib><creatorcontrib>Sattar, Naveed</creatorcontrib><creatorcontrib>Buckley, Brendan M.</creatorcontrib><creatorcontrib>Lowe, Gordon D.</creatorcontrib><creatorcontrib>Chen, Ming-Huei</creatorcontrib><creatorcontrib>Tofler, Geoffrey H.</creatorcontrib><creatorcontrib>Song, Jaejoon</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Rose, Lynda M.</creatorcontrib><creatorcontrib>Franco-Cereceda, Anders</creatorcontrib><creatorcontrib>Teichert, Martina</creatorcontrib><creatorcontrib>Mosley, Thomas H.</creatorcontrib><creatorcontrib>Bevan, Steve</creatorcontrib><creatorcontrib>Dichgans, Martin</creatorcontrib><creatorcontrib>Sudlow, Cathie L.M.</creatorcontrib><creatorcontrib>Hopewell, Jemma C.</creatorcontrib><creatorcontrib>Chambers, John C.</creatorcontrib><creatorcontrib>Saleheen, Danish</creatorcontrib><creatorcontrib>Kooner, Jaspal S.</creatorcontrib><creatorcontrib>Danesh, John</creatorcontrib><creatorcontrib>Nelson, Christopher P.</creatorcontrib><creatorcontrib>Reilly, Muredach P.</creatorcontrib><creatorcontrib>Kathiresan, Sekar</creatorcontrib><creatorcontrib>Schunkert, Heribert</creatorcontrib><creatorcontrib>Morange, Pierre-Emmanuel</creatorcontrib><creatorcontrib>Ferrucci, Luigi</creatorcontrib><creatorcontrib>Eriksson, Johan G.</creatorcontrib><creatorcontrib>Jacobs, David</creatorcontrib><creatorcontrib>Deary, Ian J.</creatorcontrib><creatorcontrib>Soranzo, Nicole</creatorcontrib><creatorcontrib>Tracy, Russell P.</creatorcontrib><creatorcontrib>Hayward, Caroline</creatorcontrib><creatorcontrib>Koenig, Wolfgang</creatorcontrib><creatorcontrib>Cucca, Francesco</creatorcontrib><creatorcontrib>Samani, Nilesh J.</creatorcontrib><creatorcontrib>Smith, Nicholas L.</creatorcontrib><creatorcontrib>Ridker, Paul M</creatorcontrib><creatorcontrib>Tang, Weihong</creatorcontrib><creatorcontrib>Hamsten, Anders</creatorcontrib><creatorcontrib>O’Donnell, Christopher J.</creatorcontrib><creatorcontrib>VTE Consortium</creatorcontrib><creatorcontrib>C4D Consortium</creatorcontrib><creatorcontrib>STROKE Consortium</creatorcontrib><creatorcontrib>Wellcome Trust Case Control Consortium 2 (WTCCC2)</creatorcontrib><creatorcontrib>CARDIoGRAM Consortium</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sabater-Lleal, Maria</au><au>Huang, Jie</au><au>Chasman, Daniel</au><au>Naitza, Silvia</au><au>Dehghan, Abbas</au><au>Teumer, Alexander</au><au>Folkersen, Lasse</au><au>Basu, Saonli</au><au>Rudnicka, Alicja R.</au><au>Trompet, Stella</au><au>Mälarstig, Anders</au><au>Baumert, Jens</au><au>Guo, Xiuqing</au><au>Hottenga, Jouke J.</au><au>Shin, So-Youn</au><au>Lopez, Lorna M.</au><au>Lahti, Jari</au><au>Oudot-Mellakh, Tiphaine</au><au>Wilson, James F.</au><au>Navarro, Pau</au><au>Huffman, Jennifer E.</au><au>Zemunik, Tatijana</au><au>Mehra, Reena</au><au>Rudan, Igor</au><au>Wright, Alan F.</au><au>Campbell, Harry</au><au>Wallace, Robert</au><au>Liu, Simin</au><au>Eaton, Charles B.</au><au>Becker, Diane M.</au><au>Becker, Lewis C.</au><au>Räikkönen, Katri</au><au>Widen, Elisabeth</au><au>Palotie, Aarno</au><au>Fornage, Myriam</au><au>Green, David</au><au>Gross, Myron</au><au>Harris, Sarah E.</au><au>Starr, John M.</au><au>Williams, Frances M.K.</au><au>Spector, Timothy D.</au><au>Strawbridge, Rona J.</au><au>Silveira, Angela</au><au>Sennblad, Bengt</au><au>Uitterlinden, Andre G.</au><au>Franco, Oscar H.</au><au>Hofman, Albert</au><au>van Dongen, Jenny</au><au>Yao, Jie</au><au>Swords Jenny, Nancy</au><au>Haritunians, Talin</au><au>Lumley, Thomas</au><au>Taylor, Kent D.</au><au>Peters, Annette</au><au>Illig, Thomas</au><au>Kocher, Thomas</au><au>Franzosi, Maria Grazia</au><au>Seedorf, Udo</au><au>Clarke, Robert</au><au>Schlessinger, David</au><au>Stott, David J.</au><au>Sattar, Naveed</au><au>Buckley, Brendan M.</au><au>Lowe, Gordon D.</au><au>Chen, Ming-Huei</au><au>Tofler, Geoffrey H.</au><au>Song, Jaejoon</au><au>Boerwinkle, Eric</au><au>Rose, Lynda M.</au><au>Franco-Cereceda, Anders</au><au>Teichert, Martina</au><au>Mosley, Thomas H.</au><au>Bevan, Steve</au><au>Dichgans, Martin</au><au>Sudlow, Cathie L.M.</au><au>Hopewell, Jemma C.</au><au>Chambers, John C.</au><au>Saleheen, Danish</au><au>Kooner, Jaspal S.</au><au>Danesh, John</au><au>Nelson, Christopher P.</au><au>Reilly, Muredach P.</au><au>Kathiresan, Sekar</au><au>Schunkert, Heribert</au><au>Morange, Pierre-Emmanuel</au><au>Ferrucci, Luigi</au><au>Eriksson, Johan G.</au><au>Jacobs, David</au><au>Deary, Ian J.</au><au>Soranzo, Nicole</au><au>Tracy, Russell P.</au><au>Hayward, Caroline</au><au>Koenig, Wolfgang</au><au>Cucca, Francesco</au><au>Samani, Nilesh J.</au><au>Smith, Nicholas L.</au><au>Ridker, Paul M</au><au>Tang, Weihong</au><au>Hamsten, Anders</au><au>O’Donnell, Christopher J.</au><aucorp>VTE Consortium</aucorp><aucorp>C4D Consortium</aucorp><aucorp>STROKE Consortium</aucorp><aucorp>Wellcome Trust Case Control Consortium 2 (WTCCC2)</aucorp><aucorp>CARDIoGRAM Consortium</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2013-09-17</date><risdate>2013</risdate><volume>128</volume><issue>12</issue><spage>1310</spage><epage>1324</epage><pages>1310-1324</pages><issn>0009-7322</issn><issn>1524-4539</issn><eissn>1524-4539</eissn><abstract>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) 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.</abstract><cop>United States</cop><pub>by the American College of Cardiology Foundation and the American Heart Association, Inc</pub><pmid>23969696</pmid><doi>10.1161/CIRCULATIONAHA.113.002251</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0009-7322 |
| ispartof | Circulation (New York, N.Y.), 2013-09, Vol.128 (12), p.1310-1324 |
| issn | 0009-7322 1524-4539 1524-4539 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1433517024 |
| source | MEDLINE; American Heart Association Journals; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals |
| subjects | Adolescent Adult Aged Aged, 80 and over Black People - genetics Black People - statistics & numerical data Cardiovascular Diseases - ethnology Cardiovascular Diseases - genetics Cardiovascular Diseases - metabolism Coronary Artery Disease - ethnology Coronary Artery Disease - genetics Coronary Artery Disease - metabolism Female Fibrinogen - genetics Fibrinogen - metabolism Genetic Loci - genetics Genetic Predisposition to Disease - ethnology Genome-Wide Association Study Hispanic or Latino - genetics Hispanic or Latino - statistics & numerical data Humans Male Middle Aged Myocardial Infarction - ethnology Myocardial Infarction - genetics Myocardial Infarction - metabolism Polymorphism, Single Nucleotide - genetics Risk Factors Stroke - ethnology Stroke - genetics Stroke - metabolism Venous Thromboembolism - ethnology Venous Thromboembolism - genetics Venous Thromboembolism - metabolism White People - genetics White People - statistics & numerical data Young Adult |
| title | 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 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-10T22%3A57%3A36IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Multiethnic%20Meta-Analysis%20of%20Genome-Wide%20Association%20Studies%20in%20%3E100%20000%20Subjects%20Identifies%2023%20Fibrinogen-Associated%20Loci%20but%20No%20Strong%20Evidence%20of%20a%20Causal%20Association%20Between%20Circulating%20Fibrinogen%20and%20Cardiovascular%20Disease&rft.jtitle=Circulation%20(New%20York,%20N.Y.)&rft.au=Sabater-Lleal,%20Maria&rft.aucorp=VTE%20Consortium&rft.date=2013-09-17&rft.volume=128&rft.issue=12&rft.spage=1310&rft.epage=1324&rft.pages=1310-1324&rft.issn=0009-7322&rft.eissn=1524-4539&rft_id=info:doi/10.1161/CIRCULATIONAHA.113.002251&rft_dat=%3Cproquest_cross%3E1433517024%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1433517024&rft_id=info:pmid/23969696&rfr_iscdi=true |