%0 Journal Article %J Circ Cardiovasc Genet %D 2009 %T Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. %A Dehghan, Abbas %A Yang, Qiong %A Peters, Annette %A Basu, Saonli %A Bis, Joshua C %A Rudnicka, Alicja R %A Kavousi, Maryam %A Chen, Ming-Huei %A Baumert, Jens %A Lowe, Gordon D O %A McKnight, Barbara %A Tang, Weihong %A de Maat, Moniek %A Larson, Martin G %A Eyhermendy, Susana %A McArdle, Wendy L %A Lumley, Thomas %A Pankow, James S %A Hofman, Albert %A Massaro, Joseph M %A Rivadeneira, Fernando %A Kolz, Melanie %A Taylor, Kent D %A van Duijn, Cornelia M %A Kathiresan, Sekar %A Illig, Thomas %A Aulchenko, Yurii S %A Volcik, Kelly A %A Johnson, Andrew D %A Uitterlinden, André G %A Tofler, Geoffrey H %A Gieger, Christian %A Psaty, Bruce M %A Couper, David J %A Boerwinkle, Eric %A Koenig, Wolfgang %A O'Donnell, Christopher J %A Witteman, Jacqueline C %A Strachan, David P %A Smith, Nicholas L %A Folsom, Aaron R %K Adult %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cohort Studies %K European Continental Ancestry Group %K Female %K Fibrinogen %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Pedigree %K Polymorphism, Single Nucleotide %K Young Adult %X

BACKGROUND: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.

METHODS AND RESULTS: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)).

CONCLUSIONS: Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.

%B Circ Cardiovasc Genet %V 2 %P 125-33 %8 2009 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20031576?dopt=Abstract %R 10.1161/CIRCGENETICS.108.825224 %0 Journal Article %J J Am Soc Nephrol %D 2011 %T CUBN is a gene locus for albuminuria. %A Böger, Carsten A %A Chen, Ming-Huei %A Tin, Adrienne %A Olden, Matthias %A Köttgen, Anna %A de Boer, Ian H %A Fuchsberger, Christian %A O'Seaghdha, Conall M %A Pattaro, Cristian %A Teumer, Alexander %A Liu, Ching-Ti %A Glazer, Nicole L %A Li, Man %A O'Connell, Jeffrey R %A Tanaka, Toshiko %A Peralta, Carmen A %A Kutalik, Zoltán %A Luan, Jian'an %A Zhao, Jing Hua %A Hwang, Shih-Jen %A Akylbekova, Ermeg %A Kramer, Holly %A van der Harst, Pim %A Smith, Albert V %A Lohman, Kurt %A de Andrade, Mariza %A Hayward, Caroline %A Kollerits, Barbara %A Tönjes, Anke %A Aspelund, Thor %A Ingelsson, Erik %A Eiriksdottir, Gudny %A Launer, Lenore J %A Harris, Tamara B %A Shuldiner, Alan R %A Mitchell, Braxton D %A Arking, Dan E %A Franceschini, Nora %A Boerwinkle, Eric %A Egan, Josephine %A Hernandez, Dena %A Reilly, Muredach %A Townsend, Raymond R %A Lumley, Thomas %A Siscovick, David S %A Psaty, Bruce M %A Kestenbaum, Bryan %A Haritunians, Talin %A Bergmann, Sven %A Vollenweider, Peter %A Waeber, Gérard %A Mooser, Vincent %A Waterworth, Dawn %A Johnson, Andrew D %A Florez, Jose C %A Meigs, James B %A Lu, Xiaoning %A Turner, Stephen T %A Atkinson, Elizabeth J %A Leak, Tennille S %A Aasarød, Knut %A Skorpen, Frank %A Syvänen, Ann-Christine %A Illig, Thomas %A Baumert, Jens %A Koenig, Wolfgang %A Krämer, Bernhard K %A Devuyst, Olivier %A Mychaleckyj, Josyf C %A Minelli, Cosetta %A Bakker, Stephan J L %A Kedenko, Lyudmyla %A Paulweber, Bernhard %A Coassin, Stefan %A Endlich, Karlhans %A Kroemer, Heyo K %A Biffar, Reiner %A Stracke, Sylvia %A Völzke, Henry %A Stumvoll, Michael %A Mägi, Reedik %A Campbell, Harry %A Vitart, Veronique %A Hastie, Nicholas D %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Liu, Yongmei %A Polasek, Ozren %A Curhan, Gary %A Kronenberg, Florian %A Prokopenko, Inga %A Rudan, Igor %A Arnlöv, Johan %A Hallan, Stein %A Navis, Gerjan %A Parsa, Afshin %A Ferrucci, Luigi %A Coresh, Josef %A Shlipak, Michael G %A Bull, Shelley B %A Paterson, Nicholas J %A Wichmann, H-Erich %A Wareham, Nicholas J %A Loos, Ruth J F %A Rotter, Jerome I %A Pramstaller, Peter P %A Cupples, L Adrienne %A Beckmann, Jacques S %A Yang, Qiong %A Heid, Iris M %A Rettig, Rainer %A Dreisbach, Albert W %A Bochud, Murielle %A Fox, Caroline S %A Kao, W H L %K African Continental Ancestry Group %K Albuminuria %K European Continental Ancestry Group %K Genetic Loci %K Genetic Predisposition to Disease %K Humans %K Mutation, Missense %K Receptors, Cell Surface %X

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

%B J Am Soc Nephrol %V 22 %P 555-70 %8 2011 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21355061?dopt=Abstract %R 10.1681/ASN.2010060598 %0 Journal Article %J Circulation %D 2011 %T Genetic predictors of fibrin D-dimer levels in healthy adults. %A Smith, Nicholas L %A Huffman, Jennifer E %A Strachan, David P %A Huang, Jie %A Dehghan, Abbas %A Trompet, Stella %A Lopez, Lorna M %A Shin, So-Youn %A Baumert, Jens %A Vitart, Veronique %A Bis, Joshua C %A Wild, Sarah H %A Rumley, Ann %A Yang, Qiong %A Uitterlinden, André G %A Stott, David J %A Davies, Gail %A Carter, Angela M %A Thorand, Barbara %A Polasek, Ozren %A McKnight, Barbara %A Campbell, Harry %A Rudnicka, Alicja R %A Chen, Ming-Huei %A Buckley, Brendan M %A Harris, Sarah E %A Peters, Annette %A Pulanic, Drazen %A Lumley, Thomas %A de Craen, Anton J M %A Liewald, David C %A Gieger, Christian %A Campbell, Susan %A Ford, Ian %A Gow, Alan J %A Luciano, Michelle %A Porteous, David J %A Guo, Xiuqing %A Sattar, Naveed %A Tenesa, Albert %A Cushman, Mary %A Slagboom, P Eline %A Visscher, Peter M %A Spector, Tim D %A Illig, Thomas %A Rudan, Igor %A Bovill, Edwin G %A Wright, Alan F %A McArdle, Wendy L %A Tofler, Geoffrey %A Hofman, Albert %A Westendorp, Rudi G J %A Starr, John M %A Grant, Peter J %A Karakas, Mahir %A Hastie, Nicholas D %A Psaty, Bruce M %A Wilson, James F %A Lowe, Gordon D O %A O'Donnell, Christopher J %A Witteman, Jacqueline C M %A Jukema, J Wouter %A Deary, Ian J %A Soranzo, Nicole %A Koenig, Wolfgang %A Hayward, Caroline %K Adult %K Aged %K Blood Coagulation %K European Continental Ancestry Group %K Factor V %K Female %K Fibrin Fibrinogen Degradation Products %K Fibrinogen %K Genetic Testing %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Reference Values %K Thromboplastin %X

BACKGROUND: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.

METHODS AND RESULTS: A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.

CONCLUSIONS: Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

%B Circulation %V 123 %P 1864-72 %8 2011 May 03 %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/21502573?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.009480 %0 Journal Article %J Nat Genet %D 2011 %T Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. %A Bis, Joshua C %A Kavousi, Maryam %A Franceschini, Nora %A Isaacs, Aaron %A Abecasis, Goncalo R %A Schminke, Ulf %A Post, Wendy S %A Smith, Albert V %A Cupples, L Adrienne %A Markus, Hugh S %A Schmidt, Reinhold %A Huffman, Jennifer E %A Lehtimäki, Terho %A Baumert, Jens %A Münzel, Thomas %A Heckbert, Susan R %A Dehghan, Abbas %A North, Kari %A Oostra, Ben %A Bevan, Steve %A Stoegerer, Eva-Maria %A Hayward, Caroline %A Raitakari, Olli %A Meisinger, Christa %A Schillert, Arne %A Sanna, Serena %A Völzke, Henry %A Cheng, Yu-Ching %A Thorsson, Bolli %A Fox, Caroline S %A Rice, Kenneth %A Rivadeneira, Fernando %A Nambi, Vijay %A Halperin, Eran %A Petrovic, Katja E %A Peltonen, Leena %A Wichmann, H Erich %A Schnabel, Renate B %A Dörr, Marcus %A Parsa, Afshin %A Aspelund, Thor %A Demissie, Serkalem %A Kathiresan, Sekar %A Reilly, Muredach P %A Taylor, Kent %A Uitterlinden, Andre %A Couper, David J %A Sitzer, Matthias %A Kähönen, Mika %A Illig, Thomas %A Wild, Philipp S %A Orrù, Marco %A Lüdemann, Jan %A Shuldiner, Alan R %A Eiriksdottir, Gudny %A White, Charles C %A Rotter, Jerome I %A Hofman, Albert %A Seissler, Jochen %A Zeller, Tanja %A Usala, Gianluca %A Ernst, Florian %A Launer, Lenore J %A D'Agostino, Ralph B %A O'Leary, Daniel H %A Ballantyne, Christie %A Thiery, Joachim %A Ziegler, Andreas %A Lakatta, Edward G %A Chilukoti, Ravi Kumar %A Harris, Tamara B %A Wolf, Philip A %A Psaty, Bruce M %A Polak, Joseph F %A Li, Xia %A Rathmann, Wolfgang %A Uda, Manuela %A Boerwinkle, Eric %A Klopp, Norman %A Schmidt, Helena %A Wilson, James F %A Viikari, Jorma %A Koenig, Wolfgang %A Blankenberg, Stefan %A Newman, Anne B %A Witteman, Jacqueline %A Heiss, Gerardo %A Duijn, Cornelia van %A Scuteri, Angelo %A Homuth, Georg %A Mitchell, Braxton D %A Gudnason, Vilmundur %A O'Donnell, Christopher J %K Adult %K Aged %K Aging %K Atherosclerosis %K Carotid Intima-Media Thickness %K Cohort Studies %K Coronary Artery Disease %K European Continental Ancestry Group %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Heart %K Humans %K Middle Aged %K Phenotype %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Risk Factors %X

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 × 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.

%B Nat Genet %V 43 %P 940-7 %8 2011 Sep 11 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909108?dopt=Abstract %R 10.1038/ng.920 %0 Journal Article %J Circulation %D 2011 %T Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. %A Dehghan, Abbas %A Dupuis, Josée %A Barbalic, Maja %A Bis, Joshua C %A Eiriksdottir, Gudny %A Lu, Chen %A Pellikka, Niina %A Wallaschofski, Henri %A Kettunen, Johannes %A Henneman, Peter %A Baumert, Jens %A Strachan, David P %A Fuchsberger, Christian %A Vitart, Veronique %A Wilson, James F %A Paré, Guillaume %A Naitza, Silvia %A Rudock, Megan E %A Surakka, Ida %A de Geus, Eco J C %A Alizadeh, Behrooz Z %A Guralnik, Jack %A Shuldiner, Alan %A Tanaka, Toshiko %A Zee, Robert Y L %A Schnabel, Renate B %A Nambi, Vijay %A Kavousi, Maryam %A Ripatti, Samuli %A Nauck, Matthias %A Smith, Nicholas L %A Smith, Albert V %A Sundvall, Jouko %A Scheet, Paul %A Liu, Yongmei %A Ruokonen, Aimo %A Rose, Lynda M %A Larson, Martin G %A Hoogeveen, Ron C %A Freimer, Nelson B %A Teumer, Alexander %A Tracy, Russell P %A Launer, Lenore J %A Buring, Julie E %A Yamamoto, Jennifer F %A Folsom, Aaron R %A Sijbrands, Eric J G %A Pankow, James %A Elliott, Paul %A Keaney, John F %A Sun, Wei %A Sarin, Antti-Pekka %A Fontes, João D %A Badola, Sunita %A Astor, Brad C %A Hofman, Albert %A Pouta, Anneli %A Werdan, Karl %A Greiser, Karin H %A Kuss, Oliver %A Meyer zu Schwabedissen, Henriette E %A Thiery, Joachim %A Jamshidi, Yalda %A Nolte, Ilja M %A Soranzo, Nicole %A Spector, Timothy D %A Völzke, Henry %A Parker, Alexander N %A Aspelund, Thor %A Bates, David %A Young, Lauren %A Tsui, Kim %A Siscovick, David S %A Guo, Xiuqing %A Rotter, Jerome I %A Uda, Manuela %A Schlessinger, David %A Rudan, Igor %A Hicks, Andrew A %A Penninx, Brenda W %A Thorand, Barbara %A Gieger, Christian %A Coresh, Joe %A Willemsen, Gonneke %A Harris, Tamara B %A Uitterlinden, André G %A Jarvelin, Marjo-Riitta %A Rice, Kenneth %A Radke, Dörte %A Salomaa, Veikko %A Willems van Dijk, Ko %A Boerwinkle, Eric %A Vasan, Ramachandran S %A Ferrucci, Luigi %A Gibson, Quince D %A Bandinelli, Stefania %A Snieder, Harold %A Boomsma, Dorret I %A Xiao, Xiangjun %A Campbell, Harry %A Hayward, Caroline %A Pramstaller, Peter P %A van Duijn, Cornelia M %A Peltonen, Leena %A Psaty, Bruce M %A Gudnason, Vilmundur %A Ridker, Paul M %A Homuth, Georg %A Koenig, Wolfgang %A Ballantyne, Christie M %A Witteman, Jacqueline C M %A Benjamin, Emelia J %A Perola, Markus %A Chasman, Daniel I %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Risk Factors %K Vasculitis %X

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.

METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.

CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

%B Circulation %V 123 %P 731-8 %8 2011 Feb 22 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21300955?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.948570 %0 Journal Article %J Eur Heart J %D 2012 %T Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies. %A Grallert, Harald %A Dupuis, Josée %A Bis, Joshua C %A Dehghan, Abbas %A Barbalic, Maja %A Baumert, Jens %A Lu, Chen %A Smith, Nicholas L %A Uitterlinden, André G %A Roberts, Robert %A Khuseyinova, Natalie %A Schnabel, Renate B %A Rice, Kenneth M %A Rivadeneira, Fernando %A Hoogeveen, Ron C %A Fontes, João Daniel %A Meisinger, Christa %A Keaney, John F %A Lemaitre, Rozenn %A Aulchenko, Yurii S %A Vasan, Ramachandran S %A Ellis, Stephen %A Hazen, Stanley L %A van Duijn, Cornelia M %A Nelson, Jeanenne J %A März, Winfried %A Schunkert, Heribert %A McPherson, Ruth M %A Stirnadel-Farrant, Heide A %A Psaty, Bruce M %A Gieger, Christian %A Siscovick, David %A Hofman, Albert %A Illig, Thomas %A Cushman, Mary %A Yamamoto, Jennifer F %A Rotter, Jerome I %A Larson, Martin G %A Stewart, Alexandre F R %A Boerwinkle, Eric %A Witteman, Jacqueline C M %A Tracy, Russell P %A Koenig, Wolfgang %A Benjamin, Emelia J %A Ballantyne, Christie M %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Aged %K Coronary Artery Disease %K Coronary Disease %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Phospholipases A2 %K Polymorphism, Single Nucleotide %X

AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study.

CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.

%B Eur Heart J %V 33 %P 238-51 %8 2012 Jan %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22003152?dopt=Abstract %R 10.1093/eurheartj/ehr372 %0 Journal Article %J Blood %D 2012 %T Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. %A Huang, Jie %A Sabater-Lleal, Maria %A Asselbergs, Folkert W %A Tregouet, David %A Shin, So-Youn %A Ding, Jingzhong %A Baumert, Jens %A Oudot-Mellakh, Tiphaine %A Folkersen, Lasse %A Johnson, Andrew D %A Smith, Nicholas L %A Williams, Scott M %A Ikram, Mohammad A %A Kleber, Marcus E %A Becker, Diane M %A Truong, Vinh %A Mychaleckyj, Josyf C %A Tang, Weihong %A Yang, Qiong %A Sennblad, Bengt %A Moore, Jason H %A Williams, Frances M K %A Dehghan, Abbas %A Silbernagel, Günther %A Schrijvers, Elisabeth M C %A Smith, Shelly %A Karakas, Mahir %A Tofler, Geoffrey H %A Silveira, Angela %A Navis, Gerjan J %A Lohman, Kurt %A Chen, Ming-Huei %A Peters, Annette %A Goel, Anuj %A Hopewell, Jemma C %A Chambers, John C %A Saleheen, Danish %A Lundmark, Per %A Psaty, Bruce M %A Strawbridge, Rona J %A Boehm, Bernhard O %A Carter, Angela M %A Meisinger, Christa %A Peden, John F %A Bis, Joshua C %A McKnight, Barbara %A Ohrvik, John %A Taylor, Kent %A Franzosi, Maria Grazia %A Seedorf, Udo %A Collins, Rory %A Franco-Cereceda, Anders %A Syvänen, Ann-Christine %A Goodall, Alison H %A Yanek, Lisa R %A Cushman, Mary %A Müller-Nurasyid, Martina %A Folsom, Aaron R %A Basu, Saonli %A Matijevic, Nena %A van Gilst, Wiek H %A Kooner, Jaspal S %A Hofman, Albert %A Danesh, John %A Clarke, Robert %A Meigs, James B %A Kathiresan, Sekar %A Reilly, Muredach P %A Klopp, Norman %A Harris, Tamara B %A Winkelmann, Bernhard R %A Grant, Peter J %A Hillege, Hans L %A Watkins, Hugh %A Spector, Timothy D %A Becker, Lewis C %A Tracy, Russell P %A März, Winfried %A Uitterlinden, André G %A Eriksson, Per %A Cambien, Francois %A Morange, Pierre-Emmanuel %A Koenig, Wolfgang %A Soranzo, Nicole %A van der Harst, Pim %A Liu, Yongmei %A O'Donnell, Christopher J %A Hamsten, Anders %K Adaptor Proteins, Signal Transducing %K ARNTL Transcription Factors %K ATPases Associated with Diverse Cellular Activities %K Cell Line %K Cell Line, Tumor %K Cohort Studies %K Coronary Artery Disease %K Diabetes Mellitus, Type 2 %K Gene Expression Profiling %K Gene Expression Regulation %K Gene Frequency %K Genome-Wide Association Study %K Genotype %K Humans %K LIM Domain Proteins %K Meta-Analysis as Topic %K Monocytes %K Mucin-3 %K Plasminogen Activator Inhibitor 1 %K Polymorphism, Single Nucleotide %K PPAR gamma %K Proteasome Endopeptidase Complex %K RNA Interference %K Transcription Factors %X

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

%B Blood %V 120 %P 4873-81 %8 2012 Dec 06 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/22990020?dopt=Abstract %R 10.1182/blood-2012-06-436188 %0 Journal Article %J Hum Mol Genet %D 2013 %T Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia. %A Reiner, Alexander P %A Hartiala, Jaana %A Zeller, Tanja %A Bis, Joshua C %A Dupuis, Josée %A Fornage, Myriam %A Baumert, Jens %A Kleber, Marcus E %A Wild, Philipp S %A Baldus, Stephan %A Bielinski, Suzette J %A Fontes, João D %A Illig, Thomas %A Keating, Brendan J %A Lange, Leslie A %A Ojeda, Francisco %A Müller-Nurasyid, Martina %A Munzel, Thomas F %A Psaty, Bruce M %A Rice, Kenneth %A Rotter, Jerome I %A Schnabel, Renate B %A Tang, W H Wilson %A Thorand, Barbara %A Erdmann, Jeanette %A Jacobs, David R %A Wilson, James G %A Koenig, Wolfgang %A Tracy, Russell P %A Blankenberg, Stefan %A März, Winfried %A Gross, Myron D %A Benjamin, Emelia J %A Hazen, Stanley L %A Allayee, Hooman %K Adult %K African Americans %K Aged %K Case-Control Studies %K Complement Factor H %K Coronary Artery Disease %K European Continental Ancestry Group %K Female %K Gene Expression Regulation, Enzymologic %K Genetic Association Studies %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Peroxidase %K Polymorphism, Single Nucleotide %K Young Adult %X

Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.

%B Hum Mol Genet %V 22 %P 3381-93 %8 2013 Aug 15 %G eng %N 16 %1 http://www.ncbi.nlm.nih.gov/pubmed/23620142?dopt=Abstract %R 10.1093/hmg/ddt189 %0 Journal Article %J Biol Psychiatry %D 2013 %T A genome-wide association study of depressive symptoms. %A Hek, Karin %A Demirkan, Ayse %A Lahti, Jari %A Terracciano, Antonio %A Teumer, Alexander %A Cornelis, Marilyn C %A Amin, Najaf %A Bakshis, Erin %A Baumert, Jens %A Ding, Jingzhong %A Liu, Yongmei %A Marciante, Kristin %A Meirelles, Osorio %A Nalls, Michael A %A Sun, Yan V %A Vogelzangs, Nicole %A Yu, Lei %A Bandinelli, Stefania %A Benjamin, Emelia J %A Bennett, David A %A Boomsma, Dorret %A Cannas, Alessandra %A Coker, Laura H %A de Geus, Eco %A De Jager, Philip L %A Diez-Roux, Ana V %A Purcell, Shaun %A Hu, Frank B %A Rimma, Eric B %A Hunter, David J %A Jensen, Majken K %A Curhan, Gary %A Rice, Kenneth %A Penman, Alan D %A Rotter, Jerome I %A Sotoodehnia, Nona %A Emeny, Rebecca %A Eriksson, Johan G %A Evans, Denis A %A Ferrucci, Luigi %A Fornage, Myriam %A Gudnason, Vilmundur %A Hofman, Albert %A Illig, Thomas %A Kardia, Sharon %A Kelly-Hayes, Margaret %A Koenen, Karestan %A Kraft, Peter %A Kuningas, Maris %A Massaro, Joseph M %A Melzer, David %A Mulas, Antonella %A Mulder, Cornelis L %A Murray, Anna %A Oostra, Ben A %A Palotie, Aarno %A Penninx, Brenda %A Petersmann, Astrid %A Pilling, Luke C %A Psaty, Bruce %A Rawal, Rajesh %A Reiman, Eric M %A Schulz, Andrea %A Shulman, Joshua M %A Singleton, Andrew B %A Smith, Albert V %A Sutin, Angelina R %A Uitterlinden, André G %A Völzke, Henry %A Widen, Elisabeth %A Yaffe, Kristine %A Zonderman, Alan B %A Cucca, Francesco %A Harris, Tamara %A Ladwig, Karl-Heinz %A Llewellyn, David J %A Räikkönen, Katri %A Tanaka, Toshiko %A van Duijn, Cornelia M %A Grabe, Hans J %A Launer, Lenore J %A Lunetta, Kathryn L %A Mosley, Thomas H %A Newman, Anne B %A Tiemeier, Henning %A Murabito, Joanne %K Aged %K Aged, 80 and over %K Chromosomes, Human, Pair 5 %K Depression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.

METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.

RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258).

CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

%B Biol Psychiatry %V 73 %P 667-78 %8 2013 Apr 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23290196?dopt=Abstract %R 10.1016/j.biopsych.2012.09.033 %0 Journal Article %J Circulation %D 2013 %T 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. %A Sabater-Lleal, Maria %A Huang, Jie %A Chasman, Daniel %A Naitza, Silvia %A Dehghan, Abbas %A Johnson, Andrew D %A Teumer, Alexander %A Reiner, Alex P %A Folkersen, Lasse %A Basu, Saonli %A Rudnicka, Alicja R %A Trompet, Stella %A Mälarstig, Anders %A Baumert, Jens %A Bis, Joshua C %A Guo, Xiuqing %A Hottenga, Jouke J %A Shin, So-Youn %A Lopez, Lorna M %A Lahti, Jari %A Tanaka, Toshiko %A Yanek, Lisa R %A Oudot-Mellakh, Tiphaine %A Wilson, James F %A Navarro, Pau %A Huffman, Jennifer E %A Zemunik, Tatijana %A Redline, Susan %A Mehra, Reena %A Pulanic, Drazen %A Rudan, Igor %A Wright, Alan F %A Kolcic, Ivana %A Polasek, Ozren %A Wild, Sarah H %A Campbell, Harry %A Curb, J David %A Wallace, Robert %A Liu, Simin %A Eaton, Charles B %A Becker, Diane M %A Becker, Lewis C %A Bandinelli, Stefania %A Räikkönen, Katri %A Widen, Elisabeth %A Palotie, Aarno %A Fornage, Myriam %A Green, David %A Gross, Myron %A Davies, Gail %A Harris, Sarah E %A Liewald, David C %A Starr, John M %A Williams, Frances M K %A Grant, Peter J %A Spector, Timothy D %A Strawbridge, Rona J %A Silveira, Angela %A Sennblad, Bengt %A Rivadeneira, Fernando %A Uitterlinden, André G %A Franco, Oscar H %A Hofman, Albert %A van Dongen, Jenny %A Willemsen, Gonneke %A Boomsma, Dorret I %A Yao, Jie %A Swords Jenny, Nancy %A Haritunians, Talin %A McKnight, Barbara %A Lumley, Thomas %A Taylor, Kent D %A Rotter, Jerome I %A Psaty, Bruce M %A Peters, Annette %A Gieger, Christian %A Illig, Thomas %A Grotevendt, Anne %A Homuth, Georg %A Völzke, Henry %A Kocher, Thomas %A Goel, Anuj %A Franzosi, Maria Grazia %A Seedorf, Udo %A Clarke, Robert %A Steri, Maristella %A Tarasov, Kirill V %A Sanna, Serena %A Schlessinger, David %A Stott, David J %A Sattar, Naveed %A Buckley, Brendan M %A Rumley, Ann %A Lowe, Gordon D %A McArdle, Wendy L %A Chen, Ming-Huei %A Tofler, Geoffrey H %A Song, Jaejoon %A Boerwinkle, Eric %A Folsom, Aaron R %A Rose, Lynda M %A Franco-Cereceda, Anders %A Teichert, Martina %A Ikram, M Arfan %A Mosley, Thomas H %A Bevan, Steve %A Dichgans, Martin %A Rothwell, Peter M %A Sudlow, Cathie L M %A Hopewell, Jemma C %A Chambers, John C %A Saleheen, Danish %A Kooner, Jaspal S %A Danesh, John %A Nelson, Christopher P %A Erdmann, Jeanette %A Reilly, Muredach P %A Kathiresan, Sekar %A Schunkert, Heribert %A Morange, Pierre-Emmanuel %A Ferrucci, Luigi %A Eriksson, Johan G %A Jacobs, David %A Deary, Ian J %A Soranzo, Nicole %A Witteman, Jacqueline C M %A de Geus, Eco J C %A Tracy, Russell P %A Hayward, Caroline %A Koenig, Wolfgang %A Cucca, Francesco %A Jukema, J Wouter %A Eriksson, Per %A Seshadri, Sudha %A Markus, Hugh S %A Watkins, Hugh %A Samani, Nilesh J %A Wallaschofski, Henri %A Smith, Nicholas L %A Tregouet, David %A Ridker, Paul M %A Tang, Weihong %A Strachan, David P %A Hamsten, Anders %A O'Donnell, Christopher J %K Adolescent %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Coronary Artery Disease %K European Continental Ancestry Group %K Female %K Fibrinogen %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Hispanic Americans %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %K Venous Thromboembolism %K Young Adult %X

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.

%B Circulation %V 128 %P 1310-24 %8 2013 Sep 17 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23969696?dopt=Abstract %R 10.1161/CIRCULATIONAHA.113.002251 %0 Journal Article %J Hum Mol Genet %D 2014 %T Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations. %A Yoneyama, Sachiko %A Guo, Yiran %A Lanktree, Matthew B %A Barnes, Michael R %A Elbers, Clara C %A Karczewski, Konrad J %A Padmanabhan, Sandosh %A Bauer, Florianne %A Baumert, Jens %A Beitelshees, Amber %A Berenson, Gerald S %A Boer, Jolanda M A %A Burke, Gregory %A Cade, Brian %A Chen, Wei %A Cooper-Dehoff, Rhonda M %A Gaunt, Tom R %A Gieger, Christian %A Gong, Yan %A Gorski, Mathias %A Heard-Costa, Nancy %A Johnson, Toby %A Lamonte, Michael J %A McDonough, Caitrin %A Monda, Keri L %A Onland-Moret, N Charlotte %A Nelson, Christopher P %A O'Connell, Jeffrey R %A Ordovas, Jose %A Peter, Inga %A Peters, Annette %A Shaffer, Jonathan %A Shen, Haiqinq %A Smith, Erin %A Speilotes, Liz %A Thomas, Fridtjof %A Thorand, Barbara %A Monique Verschuren, W M %A Anand, Sonia S %A Dominiczak, Anna %A Davidson, Karina W %A Hegele, Robert A %A Heid, Iris %A Hofker, Marten H %A Huggins, Gordon S %A Illig, Thomas %A Johnson, Julie A %A Kirkland, Susan %A König, Wolfgang %A Langaee, Taimour Y %A McCaffery, Jeanne %A Melander, Olle %A Mitchell, Braxton D %A Munroe, Patricia %A Murray, Sarah S %A Papanicolaou, George %A Redline, Susan %A Reilly, Muredach %A Samani, Nilesh J %A Schork, Nicholas J %A van der Schouw, Yvonne T %A Shimbo, Daichi %A Shuldiner, Alan R %A Tobin, Martin D %A Wijmenga, Cisca %A Yusuf, Salim %A Hakonarson, Hakon %A Lange, Leslie A %A Demerath, Ellen W %A Fox, Caroline S %A North, Kari E %A Reiner, Alex P %A Keating, Brendan %A Taylor, Kira C %K Adiposity %K Adult %K Aged %K Aged, 80 and over %K Body Mass Index %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Waist Circumference %K Waist-Hip Ratio %K Young Adult %X

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

%B Hum Mol Genet %V 23 %P 2498-510 %8 2014 May 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24345515?dopt=Abstract %R 10.1093/hmg/ddt626 %0 Journal Article %J Hum Genet %D 2014 %T Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans. %A Ellis, Jaclyn %A Lange, Ethan M %A Li, Jin %A Dupuis, Josée %A Baumert, Jens %A Walston, Jeremy D %A Keating, Brendan J %A Durda, Peter %A Fox, Ervin R %A Palmer, Cameron D %A Meng, Yan A %A Young, Taylor %A Farlow, Deborah N %A Schnabel, Renate B %A Marzi, Carola S %A Larkin, Emma %A Martin, Lisa W %A Bis, Joshua C %A Auer, Paul %A Ramachandran, Vasan S %A Gabriel, Stacey B %A Willis, Monte S %A Pankow, James S %A Papanicolaou, George J %A Rotter, Jerome I %A Ballantyne, Christie M %A Gross, Myron D %A Lettre, Guillaume %A Wilson, James G %A Peters, Ulrike %A Koenig, Wolfgang %A Tracy, Russell P %A Redline, Susan %A Reiner, Alex P %A Benjamin, Emelia J %A Lange, Leslie A %K Adult %K African Americans %K Aged %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K CD36 Antigens %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10(-6)) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10(-6); CRP, p = 4.2 × 10(-71); APOE, p = 1.6 × 10(-6)). The fourth significant locus, CD36 (p = 1.6 × 10(-6)), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10(-5)) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10(-10)). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10(-6); CD36, p = 1.4 × 10(-6)). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.

%B Hum Genet %V 133 %P 985-95 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24643644?dopt=Abstract %R 10.1007/s00439-014-1439-z %0 Journal Article %J PLoS One %D 2014 %T No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects. %A Baumert, Jens %A Huang, Jie %A McKnight, Barbara %A Sabater-Lleal, Maria %A Steri, Maristella %A Chu, Audrey Y %A Trompet, Stella %A Lopez, Lorna M %A Fornage, Myriam %A Teumer, Alexander %A Tang, Weihong %A Rudnicka, Alicja R %A Mälarstig, Anders %A Hottenga, Jouke-Jan %A Kavousi, Maryam %A Lahti, Jari %A Tanaka, Toshiko %A Hayward, Caroline %A Huffman, Jennifer E %A Morange, Pierre-Emmanuel %A Rose, Lynda M %A Basu, Saonli %A Rumley, Ann %A Stott, David J %A Buckley, Brendan M %A de Craen, Anton J M %A Sanna, Serena %A Masala, Marco %A Biffar, Reiner %A Homuth, Georg %A Silveira, Angela %A Sennblad, Bengt %A Goel, Anuj %A Watkins, Hugh %A Müller-Nurasyid, Martina %A Rückerl, Regina %A Taylor, Kent %A Chen, Ming-Huei %A de Geus, Eco J C %A Hofman, Albert %A Witteman, Jacqueline C M %A de Maat, Moniek P M %A Palotie, Aarno %A Davies, Gail %A Siscovick, David S %A Kolcic, Ivana %A Wild, Sarah H %A Song, Jaejoon %A McArdle, Wendy L %A Ford, Ian %A Sattar, Naveed %A Schlessinger, David %A Grotevendt, Anne %A Franzosi, Maria Grazia %A Illig, Thomas %A Waldenberger, Melanie %A Lumley, Thomas %A Tofler, Geoffrey H %A Willemsen, Gonneke %A Uitterlinden, André G %A Rivadeneira, Fernando %A Räikkönen, Katri %A Chasman, Daniel I %A Folsom, Aaron R %A Lowe, Gordon D %A Westendorp, Rudi G J %A Slagboom, P Eline %A Cucca, Francesco %A Wallaschofski, Henri %A Strawbridge, Rona J %A Seedorf, Udo %A Koenig, Wolfgang %A Bis, Joshua C %A Mukamal, Kenneth J %A van Dongen, Jenny %A Widen, Elisabeth %A Franco, Oscar H %A Starr, John M %A Liu, Kiang %A Ferrucci, Luigi %A Polasek, Ozren %A Wilson, James F %A Oudot-Mellakh, Tiphaine %A Campbell, Harry %A Navarro, Pau %A Bandinelli, Stefania %A Eriksson, Johan %A Boomsma, Dorret I %A Dehghan, Abbas %A Clarke, Robert %A Hamsten, Anders %A Boerwinkle, Eric %A Jukema, J Wouter %A Naitza, Silvia %A Ridker, Paul M %A Völzke, Henry %A Deary, Ian J %A Reiner, Alexander P %A Trégouët, David-Alexandre %A O'Donnell, Christopher J %A Strachan, David P %A Peters, Annette %A Smith, Nicholas L %K Alcohol Drinking %K Body Mass Index %K Fibrinogen %K Gene-Environment Interaction %K Genomics %K Humans %K Smoking %X

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

%B PLoS One %V 9 %P e111156 %8 2014 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/25551457?dopt=Abstract %R 10.1371/journal.pone.0111156 %0 Journal Article %J Eur Heart J %D 2015 %T Mendelian randomization of blood lipids for coronary heart disease. %A Holmes, Michael V %A Asselbergs, Folkert W %A Palmer, Tom M %A Drenos, Fotios %A Lanktree, Matthew B %A Nelson, Christopher P %A Dale, Caroline E %A Padmanabhan, Sandosh %A Finan, Chris %A Swerdlow, Daniel I %A Tragante, Vinicius %A van Iperen, Erik P A %A Sivapalaratnam, Suthesh %A Shah, Sonia %A Elbers, Clara C %A Shah, Tina %A Engmann, Jorgen %A Giambartolomei, Claudia %A White, Jon %A Zabaneh, Delilah %A Sofat, Reecha %A McLachlan, Stela %A Doevendans, Pieter A %A Balmforth, Anthony J %A Hall, Alistair S %A North, Kari E %A Almoguera, Berta %A Hoogeveen, Ron C %A Cushman, Mary %A Fornage, Myriam %A Patel, Sanjay R %A Redline, Susan %A Siscovick, David S %A Tsai, Michael Y %A Karczewski, Konrad J %A Hofker, Marten H %A Verschuren, W Monique %A Bots, Michiel L %A van der Schouw, Yvonne T %A Melander, Olle %A Dominiczak, Anna F %A Morris, Richard %A Ben-Shlomo, Yoav %A Price, Jackie %A Kumari, Meena %A Baumert, Jens %A Peters, Annette %A Thorand, Barbara %A Koenig, Wolfgang %A Gaunt, Tom R %A Humphries, Steve E %A Clarke, Robert %A Watkins, Hugh %A Farrall, Martin %A Wilson, James G %A Rich, Stephen S %A de Bakker, Paul I W %A Lange, Leslie A %A Davey Smith, George %A Reiner, Alex P %A Talmud, Philippa J %A Kivimaki, Mika %A Lawlor, Debbie A %A Dudbridge, Frank %A Samani, Nilesh J %A Keating, Brendan J %A Hingorani, Aroon D %A Casas, Juan P %K Case-Control Studies %K Cholesterol, HDL %K Coronary Artery Disease %K Female %K Gene Frequency %K Genotype %K Genotyping Techniques %K Humans %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Assessment %K Triglycerides %X

AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.

METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).

CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

%B Eur Heart J %V 36 %P 539-50 %8 2015 Mar 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24474739?dopt=Abstract %R 10.1093/eurheartj/eht571 %0 Journal Article %J BioData Min %D 2017 %T Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals. %A Holzinger, Emily R %A Verma, Shefali S %A Moore, Carrie B %A Hall, Molly %A De, Rishika %A Gilbert-Diamond, Diane %A Lanktree, Matthew B %A Pankratz, Nathan %A Amuzu, Antoinette %A Burt, Amber %A Dale, Caroline %A Dudek, Scott %A Furlong, Clement E %A Gaunt, Tom R %A Kim, Daniel Seung %A Riess, Helene %A Sivapalaratnam, Suthesh %A Tragante, Vinicius %A van Iperen, Erik P A %A Brautbar, Ariel %A Carrell, David S %A Crosslin, David R %A Jarvik, Gail P %A Kuivaniemi, Helena %A Kullo, Iftikhar J %A Larson, Eric B %A Rasmussen-Torvik, Laura J %A Tromp, Gerard %A Baumert, Jens %A Cruickshanks, Karen J %A Farrall, Martin %A Hingorani, Aroon D %A Hovingh, G K %A Kleber, Marcus E %A Klein, Barbara E %A Klein, Ronald %A Koenig, Wolfgang %A Lange, Leslie A %A Mӓrz, Winfried %A North, Kari E %A Charlotte Onland-Moret, N %A Reiner, Alex P %A Talmud, Philippa J %A van der Schouw, Yvonne T %A Wilson, James G %A Kivimaki, Mika %A Kumari, Meena %A Moore, Jason H %A Drenos, Fotios %A Asselbergs, Folkert W %A Keating, Brendan J %A Ritchie, Marylyn D %X

BACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).

RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.

CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.

%B BioData Min %V 10 %P 25 %8 2017 %G eng %R 10.1186/s13040-017-0145-5