@article {1323, title = {Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Sep 11}, pages = {940-7}, abstract = {

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 {\texttimes} 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

}, keywords = {Adult, Aged, Aging, Atherosclerosis, Carotid Intima-Media Thickness, Cohort Studies, Coronary Artery Disease, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genotype, Heart, Humans, Middle Aged, Phenotype, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.920}, author = {Bis, Joshua C and Kavousi, Maryam and Franceschini, Nora and Isaacs, Aaron and Abecasis, Goncalo R and Schminke, Ulf and Post, Wendy S and Smith, Albert V and Cupples, L Adrienne and Markus, Hugh S and Schmidt, Reinhold and Huffman, Jennifer E and Lehtim{\"a}ki, Terho and Baumert, Jens and M{\"u}nzel, Thomas and Heckbert, Susan R and Dehghan, Abbas and North, Kari and Oostra, Ben and Bevan, Steve and Stoegerer, Eva-Maria and Hayward, Caroline and Raitakari, Olli and Meisinger, Christa and Schillert, Arne and Sanna, Serena and V{\"o}lzke, Henry and Cheng, Yu-Ching and Thorsson, Bolli and Fox, Caroline S and Rice, Kenneth and Rivadeneira, Fernando and Nambi, Vijay and Halperin, Eran and Petrovic, Katja E and Peltonen, Leena and Wichmann, H Erich and Schnabel, Renate B and D{\"o}rr, Marcus and Parsa, Afshin and Aspelund, Thor and Demissie, Serkalem and Kathiresan, Sekar and Reilly, Muredach P and Taylor, Kent and Uitterlinden, Andre and Couper, David J and Sitzer, Matthias and K{\"a}h{\"o}nen, Mika and Illig, Thomas and Wild, Philipp S and Orr{\`u}, Marco and L{\"u}demann, Jan and Shuldiner, Alan R and Eiriksdottir, Gudny and White, Charles C and Rotter, Jerome I and Hofman, Albert and Seissler, Jochen and Zeller, Tanja and Usala, Gianluca and Ernst, Florian and Launer, Lenore J and D{\textquoteright}Agostino, Ralph B and O{\textquoteright}Leary, Daniel H and Ballantyne, Christie and Thiery, Joachim and Ziegler, Andreas and Lakatta, Edward G and Chilukoti, Ravi Kumar and Harris, Tamara B and Wolf, Philip A and Psaty, Bruce M and Polak, Joseph F and Li, Xia and Rathmann, Wolfgang and Uda, Manuela and Boerwinkle, Eric and Klopp, Norman and Schmidt, Helena and Wilson, James F and Viikari, Jorma and Koenig, Wolfgang and Blankenberg, Stefan and Newman, Anne B and Witteman, Jacqueline and Heiss, Gerardo and Duijn, Cornelia van and Scuteri, Angelo and Homuth, Georg and Mitchell, Braxton D and Gudnason, Vilmundur and O{\textquoteright}Donnell, Christopher J} } @article {6108, title = {Ischemic stroke is associated with the ABO locus: the EuroCLOT study.}, journal = {Ann Neurol}, volume = {73}, year = {2013}, month = {2013 Jan}, pages = {16-31}, abstract = {

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.

METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).

RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 {\texttimes} 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 {\texttimes} 10(-186)), rs10665 with FVII (p = 2.4 {\texttimes} 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 {\texttimes} 10(-57)) and factor VIII (p = 1.2 {\texttimes} 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95\% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).

INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

}, keywords = {ABO Blood-Group System, Adolescent, Adult, Aged, Aged, 80 and over, Blood Coagulation, Brain Ischemia, Cohort Studies, Europe, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Stroke, Young Adult}, issn = {1531-8249}, doi = {10.1002/ana.23838}, author = {Williams, Frances M K and Carter, Angela M and Hysi, Pirro G and Surdulescu, Gabriela and Hodgkiss, Dylan and Soranzo, Nicole and Traylor, Matthew and Bevan, Steve and Dichgans, Martin and Rothwell, Peter M W and Sudlow, Cathie and Farrall, Martin and Silander, Kaisa and Kaunisto, Mari and Wagner, Peter and Saarela, Olli and Kuulasmaa, Kari and Virtamo, Jarmo and Salomaa, Veikko and Amouyel, Philippe and Arveiler, Dominique and Ferrieres, Jean and Wiklund, Per-Gunnar and Ikram, M Arfan and Hofman, Albert and Boncoraglio, Giorgio B and Parati, Eugenio A and Helgadottir, Anna and Gretarsdottir, Solveig and Thorsteinsdottir, Unnur and Thorleifsson, Gudmar and Stefansson, Kari and Seshadri, Sudha and DeStefano, Anita and Gschwendtner, Andreas and Psaty, Bruce and Longstreth, Will and Mitchell, Braxton D and Cheng, Yu-Ching and Clarke, Robert and Ferrario, Marco and Bis, Joshua C and Levi, Christopher and Attia, John and Holliday, Elizabeth G and Scott, Rodney J and Fornage, Myriam and Sharma, Pankaj and Furie, Karen L and Rosand, Jonathan and Nalls, Mike and Meschia, James and Mosely, Thomas H and Evans, Alun and Palotie, Aarno and Markus, Hugh S and Grant, Peter J and Spector, Tim D} } @article {6155, 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.}, journal = {Circulation}, volume = {128}, year = {2013}, month = {2013 Sep 17}, pages = {1310-24}, 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{\texttimes}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.

}, keywords = {Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Cardiovascular Diseases, Coronary Artery Disease, European Continental Ancestry Group, Female, Fibrinogen, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic Americans, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Risk Factors, Stroke, Venous Thromboembolism, Young Adult}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.113.002251}, author = {Sabater-Lleal, Maria and Huang, Jie and Chasman, Daniel and Naitza, Silvia and Dehghan, Abbas and Johnson, Andrew D and Teumer, Alexander and Reiner, Alex P and Folkersen, Lasse and Basu, Saonli and Rudnicka, Alicja R and Trompet, Stella and M{\"a}larstig, Anders and Baumert, Jens and Bis, Joshua C and Guo, Xiuqing and Hottenga, Jouke J and Shin, So-Youn and Lopez, Lorna M and Lahti, Jari and Tanaka, Toshiko and Yanek, Lisa R and Oudot-Mellakh, Tiphaine and Wilson, James F and Navarro, Pau and Huffman, Jennifer E and Zemunik, Tatijana and Redline, Susan and Mehra, Reena and Pulanic, Drazen and Rudan, Igor and Wright, Alan F and Kolcic, Ivana and Polasek, Ozren and Wild, Sarah H and Campbell, Harry and Curb, J David and Wallace, Robert and Liu, Simin and Eaton, Charles B and Becker, Diane M and Becker, Lewis C and Bandinelli, Stefania and R{\"a}ikk{\"o}nen, Katri and Widen, Elisabeth and Palotie, Aarno and Fornage, Myriam and Green, David and Gross, Myron and Davies, Gail and Harris, Sarah E and Liewald, David C and Starr, John M and Williams, Frances M K and Grant, Peter J and Spector, Timothy D and Strawbridge, Rona J and Silveira, Angela and Sennblad, Bengt and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Hofman, Albert and van Dongen, Jenny and Willemsen, Gonneke and Boomsma, Dorret I and Yao, Jie and Swords Jenny, Nancy and Haritunians, Talin and McKnight, Barbara and Lumley, Thomas and Taylor, Kent D and Rotter, Jerome I and Psaty, Bruce M and Peters, Annette and Gieger, Christian and Illig, Thomas and Grotevendt, Anne and Homuth, Georg and V{\"o}lzke, Henry and Kocher, Thomas and Goel, Anuj and Franzosi, Maria Grazia and Seedorf, Udo and Clarke, Robert and Steri, Maristella and Tarasov, Kirill V and Sanna, Serena and Schlessinger, David and Stott, David J and Sattar, Naveed and Buckley, Brendan M and Rumley, Ann and Lowe, Gordon D and McArdle, Wendy L and Chen, Ming-Huei and Tofler, Geoffrey H and Song, Jaejoon and Boerwinkle, Eric and Folsom, Aaron R and Rose, Lynda M and Franco-Cereceda, Anders and Teichert, Martina and Ikram, M Arfan and Mosley, Thomas H and Bevan, Steve and Dichgans, Martin and Rothwell, Peter M and Sudlow, Cathie L M and Hopewell, Jemma C and Chambers, John C and Saleheen, Danish and Kooner, Jaspal S and Danesh, John and Nelson, Christopher P and Erdmann, Jeanette and Reilly, Muredach P and Kathiresan, Sekar and Schunkert, Heribert and Morange, Pierre-Emmanuel and Ferrucci, Luigi and Eriksson, Johan G and Jacobs, David and Deary, Ian J and Soranzo, Nicole and Witteman, Jacqueline C M and de Geus, Eco J C and Tracy, Russell P and Hayward, Caroline and Koenig, Wolfgang and Cucca, Francesco and Jukema, J Wouter and Eriksson, Per and Seshadri, Sudha and Markus, Hugh S and Watkins, Hugh and Samani, Nilesh J and Wallaschofski, Henri and Smith, Nicholas L and Tregouet, David and Ridker, Paul M and Tang, Weihong and Strachan, David P and Hamsten, Anders and O{\textquoteright}Donnell, Christopher J} }