%0 Journal Article %J JAMA %D 2009 %T Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. %A Vasan, Ramachandran S %A Glazer, Nicole L %A Felix, Janine F %A Lieb, Wolfgang %A Wild, Philipp S %A Felix, Stephan B %A Watzinger, Norbert %A Larson, Martin G %A Smith, Nicholas L %A Dehghan, Abbas %A Grosshennig, Anika %A Schillert, Arne %A Teumer, Alexander %A Schmidt, Reinhold %A Kathiresan, Sekar %A Lumley, Thomas %A Aulchenko, Yurii S %A König, Inke R %A Zeller, Tanja %A Homuth, Georg %A Struchalin, Maksim %A Aragam, Jayashri %A Bis, Joshua C %A Rivadeneira, Fernando %A Erdmann, Jeanette %A Schnabel, Renate B %A Dörr, Marcus %A Zweiker, Robert %A Lind, Lars %A Rodeheffer, Richard J %A Greiser, Karin Halina %A Levy, Daniel %A Haritunians, Talin %A Deckers, Jaap W %A Stritzke, Jan %A Lackner, Karl J %A Völker, Uwe %A Ingelsson, Erik %A Kullo, Iftikhar %A Haerting, Johannes %A O'Donnell, Christopher J %A Heckbert, Susan R %A Stricker, Bruno H %A Ziegler, Andreas %A Reffelmann, Thorsten %A Redfield, Margaret M %A Werdan, Karl %A Mitchell, Gary F %A Rice, Kenneth %A Arnett, Donna K %A Hofman, Albert %A Gottdiener, John S %A Uitterlinden, André G %A Meitinger, Thomas %A Blettner, Maria %A Friedrich, Nele %A Wang, Thomas J %A Psaty, Bruce M %A van Duijn, Cornelia M %A Wichmann, H-Erich %A Munzel, Thomas F %A Kroemer, Heyo K %A Benjamin, Emelia J %A Rotter, Jerome I %A Witteman, Jacqueline C %A Schunkert, Heribert %A Schmidt, Helena %A Völzke, Henry %A Blankenberg, Stefan %K Adult %K Aged %K Aged, 80 and over %K Aorta %K Cardiovascular Diseases %K Echocardiography %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Genotype %K Heart Atria %K Heart Ventricles %K Humans %K Male %K Middle Aged %K Organ Size %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %K Ventricular Dysfunction, Left %K Ventricular Function, Left %X

CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.

OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.

DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.

MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.

RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).

CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

%B JAMA %V 302 %P 168-78 %8 2009 Jul 08 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/19584346?dopt=Abstract %R 10.1001/jama.2009.978-a %0 Journal Article %J Nat Genet %D 2009 %T Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. %A Benjamin, Emelia J %A Rice, Kenneth M %A Arking, Dan E %A Pfeufer, Arne %A van Noord, Charlotte %A Smith, Albert V %A Schnabel, Renate B %A Bis, Joshua C %A Boerwinkle, Eric %A Sinner, Moritz F %A Dehghan, Abbas %A Lubitz, Steven A %A D'Agostino, Ralph B %A Lumley, Thomas %A Ehret, Georg B %A Heeringa, Jan %A Aspelund, Thor %A Newton-Cheh, Christopher %A Larson, Martin G %A Marciante, Kristin D %A Soliman, Elsayed Z %A Rivadeneira, Fernando %A Wang, Thomas J %A Eiriksdottir, Gudny %A Levy, Daniel %A Psaty, Bruce M %A Li, Man %A Chamberlain, Alanna M %A Hofman, Albert %A Vasan, Ramachandran S %A Harris, Tamara B %A Rotter, Jerome I %A Kao, W H Linda %A Agarwal, Sunil K %A Stricker, Bruno H Ch %A Wang, Ke %A Launer, Lenore J %A Smith, Nicholas L %A Chakravarti, Aravinda %A Uitterlinden, André G %A Wolf, Philip A %A Sotoodehnia, Nona %A Köttgen, Anna %A van Duijn, Cornelia M %A Meitinger, Thomas %A Mueller, Martina %A Perz, Siegfried %A Steinbeck, Gerhard %A Wichmann, H-Erich %A Lunetta, Kathryn L %A Heckbert, Susan R %A Gudnason, Vilmundur %A Alonso, Alvaro %A Kääb, Stefan %A Ellinor, Patrick T %A Witteman, Jacqueline C M %K Atrial Fibrillation %K Chromosomes, Human, Pair 16 %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Homeodomain Proteins %K Humans %K Meta-Analysis as Topic %K Mutation %K Polymorphism, Single Nucleotide %K Reproducibility of Results %X

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).

%B Nat Genet %V 41 %P 879-81 %8 2009 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/19597492?dopt=Abstract %R 10.1038/ng.416 %0 Journal Article %J Nat Genet %D 2010 %T Common variants in KCNN3 are associated with lone atrial fibrillation. %A Ellinor, Patrick T %A Lunetta, Kathryn L %A Glazer, Nicole L %A Pfeufer, Arne %A Alonso, Alvaro %A Chung, Mina K %A Sinner, Moritz F %A de Bakker, Paul I W %A Mueller, Martina %A Lubitz, Steven A %A Fox, Ervin %A Darbar, Dawood %A Smith, Nicholas L %A Smith, Jonathan D %A Schnabel, Renate B %A Soliman, Elsayed Z %A Rice, Kenneth M %A Van Wagoner, David R %A Beckmann, Britt-M %A van Noord, Charlotte %A Wang, Ke %A Ehret, Georg B %A Rotter, Jerome I %A Hazen, Stanley L %A Steinbeck, Gerhard %A Smith, Albert V %A Launer, Lenore J %A Harris, Tamara B %A Makino, Seiko %A Nelis, Mari %A Milan, David J %A Perz, Siegfried %A Esko, Tõnu %A Köttgen, Anna %A Moebus, Susanne %A Newton-Cheh, Christopher %A Li, Man %A Möhlenkamp, Stefan %A Wang, Thomas J %A Kao, W H Linda %A Vasan, Ramachandran S %A Nöthen, Markus M %A MacRae, Calum A %A Stricker, Bruno H Ch %A Hofman, Albert %A Uitterlinden, André G %A Levy, Daniel %A Boerwinkle, Eric %A Metspalu, Andres %A Topol, Eric J %A Chakravarti, Aravinda %A Gudnason, Vilmundur %A Psaty, Bruce M %A Roden, Dan M %A Meitinger, Thomas %A Wichmann, H-Erich %A Witteman, Jacqueline C M %A Barnard, John %A Arking, Dan E %A Benjamin, Emelia J %A Heckbert, Susan R %A Kääb, Stefan %K Adolescent %K Adult %K Aged %K Atrial Fibrillation %K Case-Control Studies %K Cohort Studies %K Female %K Genome-Wide Association Study %K Humans %K Introns %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K Small-Conductance Calcium-Activated Potassium Channels %K Young Adult %X

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

%B Nat Genet %V 42 %P 240-4 %8 2010 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20173747?dopt=Abstract %R 10.1038/ng.537 %0 Journal Article %J Nat Genet %D 2010 %T Genome-wide association study of PR interval. %A Pfeufer, Arne %A van Noord, Charlotte %A Marciante, Kristin D %A Arking, Dan E %A Larson, Martin G %A Smith, Albert Vernon %A Tarasov, Kirill V %A Müller, Martina %A Sotoodehnia, Nona %A Sinner, Moritz F %A Verwoert, Germaine C %A Li, Man %A Kao, W H Linda %A Köttgen, Anna %A Coresh, Josef %A Bis, Joshua C %A Psaty, Bruce M %A Rice, Kenneth %A Rotter, Jerome I %A Rivadeneira, Fernando %A Hofman, Albert %A Kors, Jan A %A Stricker, Bruno H C %A Uitterlinden, André G %A van Duijn, Cornelia M %A Beckmann, Britt M %A Sauter, Wiebke %A Gieger, Christian %A Lubitz, Steven A %A Newton-Cheh, Christopher %A Wang, Thomas J %A Magnani, Jared W %A Schnabel, Renate B %A Chung, Mina K %A Barnard, John %A Smith, Jonathan D %A Van Wagoner, David R %A Vasan, Ramachandran S %A Aspelund, Thor %A Eiriksdottir, Gudny %A Harris, Tamara B %A Launer, Lenore J %A Najjar, Samer S %A Lakatta, Edward %A Schlessinger, David %A Uda, Manuela %A Abecasis, Goncalo R %A Müller-Myhsok, Bertram %A Ehret, Georg B %A Boerwinkle, Eric %A Chakravarti, Aravinda %A Soliman, Elsayed Z %A Lunetta, Kathryn L %A Perz, Siegfried %A Wichmann, H-Erich %A Meitinger, Thomas %A Levy, Daniel %A Gudnason, Vilmundur %A Ellinor, Patrick T %A Sanna, Serena %A Kääb, Stefan %A Witteman, Jacqueline C M %A Alonso, Alvaro %A Benjamin, Emelia J %A Heckbert, Susan R %K Aged %K Atrial Fibrillation %K Cohort Studies %K Electrocardiography %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heart Conduction System %K Humans %K Male %K Meta-Analysis as Topic %X

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

%B Nat Genet %V 42 %P 153-9 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20062060?dopt=Abstract %R 10.1038/ng.517 %0 Journal Article %J Hum Mol Genet %D 2010 %T Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. %A Barbalic, Maja %A Dupuis, Josée %A Dehghan, Abbas %A Bis, Joshua C %A Hoogeveen, Ron C %A Schnabel, Renate B %A Nambi, Vijay %A Bretler, Monique %A Smith, Nicholas L %A Peters, Annette %A Lu, Chen %A Tracy, Russell P %A Aleksic, Nena %A Heeriga, Jan %A Keaney, John F %A Rice, Kenneth %A Lip, Gregory Y H %A Vasan, Ramachandran S %A Glazer, Nicole L %A Larson, Martin G %A Uitterlinden, André G %A Yamamoto, Jennifer %A Durda, Peter %A Haritunians, Talin %A Psaty, Bruce M %A Boerwinkle, Eric %A Hofman, Albert %A Koenig, Wolfgang %A Jenny, Nancy S %A Witteman, Jacqueline C %A Ballantyne, Christie %A Benjamin, Emelia J %K ABO Blood-Group System %K Blood Platelets %K Enzyme-Linked Immunosorbent Assay %K European Continental Ancestry Group %K Fluorescence %K Genome-Wide Association Study %K Humans %K Intercellular Adhesion Molecule-1 %K P-Selectin %X

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.

%B Hum Mol Genet %V 19 %P 1863-72 %8 2010 May 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/20167578?dopt=Abstract %R 10.1093/hmg/ddq061 %0 Journal Article %J Nat Genet %D 2010 %T New loci associated with kidney function and chronic kidney disease. %A Köttgen, Anna %A Pattaro, Cristian %A Böger, Carsten A %A Fuchsberger, Christian %A Olden, Matthias %A Glazer, Nicole L %A Parsa, Afshin %A Gao, Xiaoyi %A Yang, Qiong %A Smith, Albert V %A O'Connell, Jeffrey R %A Li, Man %A Schmidt, Helena %A Tanaka, Toshiko %A Isaacs, Aaron %A Ketkar, Shamika %A Hwang, Shih-Jen %A Johnson, Andrew D %A Dehghan, Abbas %A Teumer, Alexander %A Paré, Guillaume %A Atkinson, Elizabeth J %A Zeller, Tanja %A Lohman, Kurt %A Cornelis, Marilyn C %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Tönjes, Anke %A Hayward, Caroline %A Aspelund, Thor %A Eiriksdottir, Gudny %A Launer, Lenore J %A Harris, Tamara B %A Rampersaud, Evadnie %A Mitchell, Braxton D %A Arking, Dan E %A Boerwinkle, Eric %A Struchalin, Maksim %A Cavalieri, Margherita %A Singleton, Andrew %A Giallauria, Francesco %A Metter, Jeffrey %A de Boer, Ian H %A Haritunians, Talin %A Lumley, Thomas %A Siscovick, David %A Psaty, Bruce M %A Zillikens, M Carola %A Oostra, Ben A %A Feitosa, Mary %A Province, Michael %A de Andrade, Mariza %A Turner, Stephen T %A Schillert, Arne %A Ziegler, Andreas %A Wild, Philipp S %A Schnabel, Renate B %A Wilde, Sandra %A Munzel, Thomas F %A Leak, Tennille S %A Illig, Thomas %A Klopp, Norman %A Meisinger, Christa %A Wichmann, H-Erich %A Koenig, Wolfgang %A Zgaga, Lina %A Zemunik, Tatijana %A Kolcic, Ivana %A Minelli, Cosetta %A Hu, Frank B %A Johansson, Asa %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Schreiber, Stefan %A Aulchenko, Yurii S %A Felix, Janine F %A Rivadeneira, Fernando %A Uitterlinden, André G %A Hofman, Albert %A Imboden, Medea %A Nitsch, Dorothea %A Brandstätter, Anita %A Kollerits, Barbara %A Kedenko, Lyudmyla %A Mägi, Reedik %A Stumvoll, Michael %A Kovacs, Peter %A Boban, Mladen %A Campbell, Susan %A Endlich, Karlhans %A Völzke, Henry %A Kroemer, Heyo K %A Nauck, Matthias %A Völker, Uwe %A Polasek, Ozren %A Vitart, Veronique %A Badola, Sunita %A Parker, Alexander N %A Ridker, Paul M %A Kardia, Sharon L R %A Blankenberg, Stefan %A Liu, Yongmei %A Curhan, Gary C %A Franke, Andre %A Rochat, Thierry %A Paulweber, Bernhard %A Prokopenko, Inga %A Wang, Wei %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A Shlipak, Michael G %A van Duijn, Cornelia M %A Borecki, Ingrid %A Krämer, Bernhard K %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Witteman, Jacqueline C %A Pramstaller, Peter P %A Rettig, Rainer %A Hastie, Nick %A Chasman, Daniel I %A Kao, W H %A Heid, Iris M %A Fox, Caroline S %K Cohort Studies %K Creatinine %K Cystatin C %K Diet %K Europe %K Genetic Markers %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Models, Genetic %K Risk Factors %X

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

%B Nat Genet %V 42 %P 376-84 %8 2010 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract %R 10.1038/ng.568 %0 Journal Article %J Arch Intern Med %D 2010 %T Validation of an atrial fibrillation risk algorithm in whites and African Americans. %A Schnabel, Renate B %A Aspelund, Thor %A Li, Guo %A Sullivan, Lisa M %A Suchy-Dicey, Astrid %A Harris, Tamara B %A Pencina, Michael J %A D'Agostino, Ralph B %A Levy, Daniel %A Kannel, William B %A Wang, Thomas J %A Kronmal, Richard A %A Wolf, Philip A %A Burke, Gregory L %A Launer, Lenore J %A Vasan, Ramachandran S %A Psaty, Bruce M %A Benjamin, Emelia J %A Gudnason, Vilmundur %A Heckbert, Susan R %K African Continental Ancestry Group %K Age Factors %K Aged %K Aged, 80 and over %K Algorithms %K Atrial Fibrillation %K Blood Pressure %K Body Mass Index %K Cohort Studies %K Electrocardiography %K Europe %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Hypertension %K Incidence %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Proportional Hazards Models %K Risk Factors %K Sex Factors %K Systole %K United States %X

BACKGROUND: We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups.

METHODS: We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertension treatment, and heart failure.

RESULTS: We found 1359 incident AF events in 100 074 person-years of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples: AGES, 0.67 (95% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95% CI, 0.66-0.70); and CHS African Americans, 0.66 (95% CI, 0.61-0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population-attributable risk.

CONCLUSIONS: Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% of risk.

%B Arch Intern Med %V 170 %P 1909-17 %8 2010 Nov 22 %G eng %N 21 %1 http://www.ncbi.nlm.nih.gov/pubmed/21098350?dopt=Abstract %R 10.1001/archinternmed.2010.434 %0 Journal Article %J Circ Cardiovasc Genet %D 2011 %T Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) project. %A Schnabel, Renate B %A Kerr, Kathleen F %A Lubitz, Steven A %A Alkylbekova, Ermeg L %A Marcus, Gregory M %A Sinner, Moritz F %A Magnani, Jared W %A Wolf, Philip A %A Deo, Rajat %A Lloyd-Jones, Donald M %A Lunetta, Kathryn L %A Mehra, Reena %A Levy, Daniel %A Fox, Ervin R %A Arking, Dan E %A Mosley, Thomas H %A Müller-Nurasyid, Martina %A Young, Taylor R %A Wichmann, H-Erich %A Seshadri, Sudha %A Farlow, Deborah N %A Rotter, Jerome I %A Soliman, Elsayed Z %A Glazer, Nicole L %A Wilson, James G %A Breteler, Monique M B %A Sotoodehnia, Nona %A Newton-Cheh, Christopher %A Kääb, Stefan %A Ellinor, Patrick T %A Alonso, Alvaro %A Benjamin, Emelia J %A Heckbert, Susan R %K African Americans %K Aged %K Alleles %K Atrial Fibrillation %K Chromosomes, Human, Pair 4 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Humans %K Male %K Middle Aged %K National Heart, Lung, and Blood Institute (U.S.) %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %K Risk Factors %K Stroke %K United States %X

BACKGROUND: The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.

METHODS AND RESULTS: We examined a panel of approximately 50,000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18,524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n=19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk [RR] C allele, 0.90; 95% confidence interval [CI], 0.85-0.95; P=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72-1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57-0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95% CI, 1.16-1.69; P=0.0005).

CONCLUSIONS: In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.

%B Circ Cardiovasc Genet %V 4 %P 557-64 %8 2011 Oct %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/21846873?dopt=Abstract %R 10.1161/CIRCGENETICS.110.959197 %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 Circ Cardiovasc Genet %D 2012 %T Impact of ancestry and common genetic variants on QT interval in African Americans. %A Smith, J Gustav %A Avery, Christy L %A Evans, Daniel S %A Nalls, Michael A %A Meng, Yan A %A Smith, Erin N %A Palmer, Cameron %A Tanaka, Toshiko %A Mehra, Reena %A Butler, Anne M %A Young, Taylor %A Buxbaum, Sarah G %A Kerr, Kathleen F %A Berenson, Gerald S %A Schnabel, Renate B %A Li, Guo %A Ellinor, Patrick T %A Magnani, Jared W %A Chen, Wei %A Bis, Joshua C %A Curb, J David %A Hsueh, Wen-Chi %A Rotter, Jerome I %A Liu, Yongmei %A Newman, Anne B %A Limacher, Marian C %A North, Kari E %A Reiner, Alexander P %A Quibrera, P Miguel %A Schork, Nicholas J %A Singleton, Andrew B %A Psaty, Bruce M %A Soliman, Elsayed Z %A Solomon, Allen J %A Srinivasan, Sathanur R %A Alonso, Alvaro %A Wallace, Robert %A Redline, Susan %A Zhang, Zhu-Ming %A Post, Wendy S %A Zonderman, Alan B %A Taylor, Herman A %A Murray, Sarah S %A Ferrucci, Luigi %A Arking, Dan E %A Evans, Michele K %A Fox, Ervin R %A Sotoodehnia, Nona %A Heckbert, Susan R %A Whitsel, Eric A %A Newton-Cheh, Christopher %K Adult %K African Americans %K Aged %K Electrocardiography %K European Continental Ancestry Group %K Female %K Genealogy and Heraldry %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.

METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.

CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

%B Circ Cardiovasc Genet %V 5 %P 647-55 %8 2012 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23166209?dopt=Abstract %R 10.1161/CIRCGENETICS.112.962787 %0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. %A Butler, Anne M %A Yin, Xiaoyan %A Evans, Daniel S %A Nalls, Michael A %A Smith, Erin N %A Tanaka, Toshiko %A Li, Guo %A Buxbaum, Sarah G %A Whitsel, Eric A %A Alonso, Alvaro %A Arking, Dan E %A Benjamin, Emelia J %A Berenson, Gerald S %A Bis, Josh C %A Chen, Wei %A Deo, Rajat %A Ellinor, Patrick T %A Heckbert, Susan R %A Heiss, Gerardo %A Hsueh, Wen-Chi %A Keating, Brendan J %A Kerr, Kathleen F %A Li, Yun %A Limacher, Marian C %A Liu, Yongmei %A Lubitz, Steven A %A Marciante, Kristin D %A Mehra, Reena %A Meng, Yan A %A Newman, Anne B %A Newton-Cheh, Christopher %A North, Kari E %A Palmer, Cameron D %A Psaty, Bruce M %A Quibrera, P Miguel %A Redline, Susan %A Reiner, Alex P %A Rotter, Jerome I %A Schnabel, Renate B %A Schork, Nicholas J %A Singleton, Andrew B %A Smith, J Gustav %A Soliman, Elsayed Z %A Srinivasan, Sathanur R %A Zhang, Zhu-Ming %A Zonderman, Alan B %A Ferrucci, Luigi %A Murray, Sarah S %A Evans, Michele K %A Sotoodehnia, Nona %A Magnani, Jared W %A Avery, Christy L %K Adult %K African Americans %K Cohort Studies %K Electrocardiography %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).

CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

%B Circ Cardiovasc Genet %V 5 %P 639-46 %8 2012 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23139255?dopt=Abstract %R 10.1161/CIRCGENETICS.112.963991 %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 J Am Heart Assoc %D 2013 %T Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. %A Alonso, Alvaro %A Krijthe, Bouwe P %A Aspelund, Thor %A Stepas, Katherine A %A Pencina, Michael J %A Moser, Carlee B %A Sinner, Moritz F %A Sotoodehnia, Nona %A Fontes, João D %A Janssens, A Cecile J W %A Kronmal, Richard A %A Magnani, Jared W %A Witteman, Jacqueline C %A Chamberlain, Alanna M %A Lubitz, Steven A %A Schnabel, Renate B %A Agarwal, Sunil K %A McManus, David D %A Ellinor, Patrick T %A Larson, Martin G %A Burke, Gregory L %A Launer, Lenore J %A Hofman, Albert %A Levy, Daniel %A Gottdiener, John S %A Kääb, Stefan %A Couper, David %A Harris, Tamara B %A Soliman, Elsayed Z %A Stricker, Bruno H C %A Gudnason, Vilmundur %A Heckbert, Susan R %A Benjamin, Emelia J %K African Americans %K Age Factors %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Cohort Studies %K Diabetes Mellitus %K European Continental Ancestry Group %K Female %K Heart Failure %K Humans %K Hypertension %K Iceland %K Incidence %K Male %K Middle Aged %K Myocardial Infarction %K Netherlands %K Proportional Hazards Models %K Risk Assessment %K Smoking %K United States %X

BACKGROUND: Tools for the prediction of atrial fibrillation (AF) may identify high-risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors.

METHODS AND RESULTS: Individual-level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19% African Americans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment-Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5-year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C-statistic, 0.765; 95% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C-statistic, 0.767; 95% CI, 0.750 to 0.783; categorical net reclassification improvement, -0.0032; 95% CI, -0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C-statistic, 0.664; 95% CI, 0.632 to 0.697 and RS C-statistic, 0.705; 95% CI, 0.664 to 0.747) and calibration was adequate.

CONCLUSION: A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.

%B J Am Heart Assoc %V 2 %P e000102 %8 2013 Mar 18 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23537808?dopt=Abstract %R 10.1161/JAHA.112.000102 %0 Journal Article %J Europace %D 2014 %T B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies. %A Sinner, Moritz F %A Stepas, Katherine A %A Moser, Carlee B %A Krijthe, Bouwe P %A Aspelund, Thor %A Sotoodehnia, Nona %A Fontes, João D %A Janssens, A Cecile J W %A Kronmal, Richard A %A Magnani, Jared W %A Witteman, Jacqueline C %A Chamberlain, Alanna M %A Lubitz, Steven A %A Schnabel, Renate B %A Vasan, Ramachandran S %A Wang, Thomas J %A Agarwal, Sunil K %A McManus, David D %A Franco, Oscar H %A Yin, Xiaoyan %A Larson, Martin G %A Burke, Gregory L %A Launer, Lenore J %A Hofman, Albert %A Levy, Daniel %A Gottdiener, John S %A Kääb, Stefan %A Couper, David %A Harris, Tamara B %A Astor, Brad C %A Ballantyne, Christie M %A Hoogeveen, Ron C %A Arai, Andrew E %A Soliman, Elsayed Z %A Ellinor, Patrick T %A Stricker, Bruno H C %A Gudnason, Vilmundur %A Heckbert, Susan R %A Pencina, Michael J %A Benjamin, Emelia J %A Alonso, Alvaro %K Aged %K Atrial Fibrillation %K Biomarkers %K C-Reactive Protein %K Europe %K Female %K Humans %K Incidence %K Male %K Natriuretic Peptide, Brain %K Peptide Fragments %K Predictive Value of Tests %K Risk Assessment %K Risk Factors %K United States %X

AIMS: B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.

METHODS AND RESULTS: We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.

CONCLUSION: B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.

%B Europace %V 16 %P 1426-33 %8 2014 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25037055?dopt=Abstract %R 10.1093/europace/euu175 %0 Journal Article %J J Cardiovasc Electrophysiol %D 2014 %T A common SCN5A variant is associated with PR interval and atrial fibrillation among African Americans. %A Ilkhanoff, Leonard %A Arking, Dan E %A Lemaitre, Rozenn N %A Alonso, Alvaro %A Chen, Lin Y %A Durda, Peter %A Hesselson, Stephanie E %A Kerr, Kathleen F %A Magnani, Jared W %A Marcus, Gregory M %A Schnabel, Renate B %A Smith, J Gustav %A Soliman, Elsayed Z %A Reiner, Alexander P %A Sotoodehnia, Nona %K Adult %K African Americans %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Case-Control Studies %K Cohort Studies %K Death, Sudden, Cardiac %K Female %K Genetic Variation %K Humans %K Male %K Middle Aged %K NAV1.5 Voltage-Gated Sodium Channel %K Prospective Studies %K Risk Factors %K Single-Blind Method %X

OBJECTIVE: We examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans.

BACKGROUND: The SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored.

METHODS: Using genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS).

RESULTS: Meta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration (β = -4.1 milliseconds; P = 2.2×10(-6) ), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 × 10(-4) ). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29).

CONCLUSION: The common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population.

%B J Cardiovasc Electrophysiol %V 25 %P 1150-7 %8 2014 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/25065297?dopt=Abstract %R 10.1111/jce.12483 %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 Circ Cardiovasc Genet %D 2014 %T Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A Lin, Honghuang %A Wang, Min %A Brody, Jennifer A %A Bis, Joshua C %A Dupuis, Josée %A Lumley, Thomas %A McKnight, Barbara %A Rice, Kenneth M %A Sitlani, Colleen M %A Reid, Jeffrey G %A Bressler, Jan %A Liu, Xiaoming %A Davis, Brian C %A Johnson, Andrew D %A O'Donnell, Christopher J %A Kovar, Christie L %A Dinh, Huyen %A Wu, Yuanqing %A Newsham, Irene %A Chen, Han %A Broka, Andi %A DeStefano, Anita L %A Gupta, Mayetri %A Lunetta, Kathryn L %A Liu, Ching-Ti %A White, Charles C %A Xing, Chuanhua %A Zhou, Yanhua %A Benjamin, Emelia J %A Schnabel, Renate B %A Heckbert, Susan R %A Psaty, Bruce M %A Muzny, Donna M %A Cupples, L Adrienne %A Morrison, Alanna C %A Boerwinkle, Eric %K Adult %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Heart Diseases %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Research Design %K Sequence Analysis, DNA %X

BACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.

METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.

CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.

%B Circ Cardiovasc Genet %V 7 %P 335-43 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951659?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000350 %0 Journal Article %J Lancet %D 2015 %T HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. %A Swerdlow, Daniel I %A Preiss, David %A Kuchenbaecker, Karoline B %A Holmes, Michael V %A Engmann, Jorgen E L %A Shah, Tina %A Sofat, Reecha %A Stender, Stefan %A Johnson, Paul C D %A Scott, Robert A %A Leusink, Maarten %A Verweij, Niek %A Sharp, Stephen J %A Guo, Yiran %A Giambartolomei, Claudia %A Chung, Christina %A Peasey, Anne %A Amuzu, Antoinette %A Li, KaWah %A Palmen, Jutta %A Howard, Philip %A Cooper, Jackie A %A Drenos, Fotios %A Li, Yun R %A Lowe, Gordon %A Gallacher, John %A Stewart, Marlene C W %A Tzoulaki, Ioanna %A Buxbaum, Sarah G %A van der A, Daphne L %A Forouhi, Nita G %A Onland-Moret, N Charlotte %A van der Schouw, Yvonne T %A Schnabel, Renate B %A Hubacek, Jaroslav A %A Kubinova, Ruzena %A Baceviciene, Migle %A Tamosiunas, Abdonas %A Pajak, Andrzej %A Topor-Madry, Roman %A Stepaniak, Urszula %A Malyutina, Sofia %A Baldassarre, Damiano %A Sennblad, Bengt %A Tremoli, Elena %A de Faire, Ulf %A Veglia, Fabrizio %A Ford, Ian %A Jukema, J Wouter %A Westendorp, Rudi G J %A de Borst, Gert Jan %A de Jong, Pim A %A Algra, Ale %A Spiering, Wilko %A Maitland-van der Zee, Anke H %A Klungel, Olaf H %A de Boer, Anthonius %A Doevendans, Pieter A %A Eaton, Charles B %A Robinson, Jennifer G %A Duggan, David %A Kjekshus, John %A Downs, John R %A Gotto, Antonio M %A Keech, Anthony C %A Marchioli, Roberto %A Tognoni, Gianni %A Sever, Peter S %A Poulter, Neil R %A Waters, David D %A Pedersen, Terje R %A Amarenco, Pierre %A Nakamura, Haruo %A McMurray, John J V %A Lewsey, James D %A Chasman, Daniel I %A Ridker, Paul M %A Maggioni, Aldo P %A Tavazzi, Luigi %A Ray, Kausik K %A Seshasai, Sreenivasa Rao Kondapally %A Manson, JoAnn E %A Price, Jackie F %A Whincup, Peter H %A Morris, Richard W %A Lawlor, Debbie A %A Smith, George Davey %A Ben-Shlomo, Yoav %A Schreiner, Pamela J %A Fornage, Myriam %A Siscovick, David S %A Cushman, Mary %A Kumari, Meena %A Wareham, Nick J %A Verschuren, W M Monique %A Redline, Susan %A Patel, Sanjay R %A Whittaker, John C %A Hamsten, Anders %A Delaney, Joseph A %A Dale, Caroline %A Gaunt, Tom R %A Wong, Andrew %A Kuh, Diana %A Hardy, Rebecca %A Kathiresan, Sekar %A Castillo, Berta A %A van der Harst, Pim %A Brunner, Eric J %A Tybjaerg-Hansen, Anne %A Marmot, Michael G %A Krauss, Ronald M %A Tsai, Michael %A Coresh, Josef %A Hoogeveen, Ronald C %A Psaty, Bruce M %A Lange, Leslie A %A Hakonarson, Hakon %A Dudbridge, Frank %A Humphries, Steve E %A Talmud, Philippa J %A Kivimaki, Mika %A Timpson, Nicholas J %A Langenberg, Claudia %A Asselbergs, Folkert W %A Voevoda, Mikhail %A Bobak, Martin %A Pikhart, Hynek %A Wilson, James G %A Reiner, Alex P %A Keating, Brendan J %A Hingorani, Aroon D %A Sattar, Naveed %K Aged %K Body Mass Index %K Body Weight %K Cholesterol, HDL %K Cholesterol, LDL %K Diabetes Mellitus, Type 2 %K Female %K Genetic Testing %K Humans %K Hydroxymethylglutaryl CoA Reductases %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Randomized Controlled Trials as Topic %K Risk Factors %X

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.

METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.

FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).

INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.

FUNDING: The funding sources are cited at the end of the paper.

%B Lancet %V 385 %P 351-61 %8 2015 Jan 24 %G eng %N 9965 %1 http://www.ncbi.nlm.nih.gov/pubmed/25262344?dopt=Abstract %R 10.1016/S0140-6736(14)61183-1 %0 Journal Article %J Hum Mol Genet %D 2016 %T Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans. %A Evans, Daniel S %A Avery, Christy L %A Nalls, Mike A %A Li, Guo %A Barnard, John %A Smith, Erin N %A Tanaka, Toshiko %A Butler, Anne M %A Buxbaum, Sarah G %A Alonso, Alvaro %A Arking, Dan E %A Berenson, Gerald S %A Bis, Joshua C %A Buyske, Steven %A Carty, Cara L %A Chen, Wei %A Chung, Mina K %A Cummings, Steven R %A Deo, Rajat %A Eaton, Charles B %A Fox, Ervin R %A Heckbert, Susan R %A Heiss, Gerardo %A Hindorff, Lucia A %A Hsueh, Wen-Chi %A Isaacs, Aaron %A Jamshidi, Yalda %A Kerr, Kathleen F %A Liu, Felix %A Liu, Yongmei %A Lohman, Kurt K %A Magnani, Jared W %A Maher, Joseph F %A Mehra, Reena %A Meng, Yan A %A Musani, Solomon K %A Newton-Cheh, Christopher %A North, Kari E %A Psaty, Bruce M %A Redline, Susan %A Rotter, Jerome I %A Schnabel, Renate B %A Schork, Nicholas J %A Shohet, Ralph V %A Singleton, Andrew B %A Smith, Jonathan D %A Soliman, Elsayed Z %A Srinivasan, Sathanur R %A Taylor, Herman A %A Van Wagoner, David R %A Wilson, James G %A Young, Taylor %A Zhang, Zhu-Ming %A Zonderman, Alan B %A Evans, Michele K %A Ferrucci, Luigi %A Murray, Sarah S %A Tranah, Gregory J %A Whitsel, Eric A %A Reiner, Alex P %A Sotoodehnia, Nona %X

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

%B Hum Mol Genet %8 2016 Aug 29 %G eng %R 10.1093/hmg/ddw284 %0 Journal Article %J Circ Cardiovasc Genet %D 2017 %T Fifteen Genetic Loci Associated With the Electrocardiographic P Wave. %A Christophersen, Ingrid E %A Magnani, Jared W %A Yin, Xiaoyan %A Barnard, John %A Weng, Lu-Chen %A Arking, Dan E %A Niemeijer, Maartje N %A Lubitz, Steven A %A Avery, Christy L %A Duan, Qing %A Felix, Stephan B %A Bis, Joshua C %A Kerr, Kathleen F %A Isaacs, Aaron %A Müller-Nurasyid, Martina %A Müller, Christian %A North, Kari E %A Reiner, Alex P %A Tinker, Lesley F %A Kors, Jan A %A Teumer, Alexander %A Petersmann, Astrid %A Sinner, Moritz F %A Bůzková, Petra %A Smith, Jonathan D %A Van Wagoner, David R %A Völker, Uwe %A Waldenberger, Melanie %A Peters, Annette %A Meitinger, Thomas %A Limacher, Marian C %A Wilhelmsen, Kirk C %A Psaty, Bruce M %A Hofman, Albert %A Uitterlinden, Andre %A Krijthe, Bouwe P %A Zhang, Zhu-Ming %A Schnabel, Renate B %A Kääb, Stefan %A van Duijn, Cornelia %A Rotter, Jerome I %A Sotoodehnia, Nona %A Dörr, Marcus %A Li, Yun %A Chung, Mina K %A Soliman, Elsayed Z %A Alonso, Alvaro %A Whitsel, Eric A %A Stricker, Bruno H %A Benjamin, Emelia J %A Heckbert, Susan R %A Ellinor, Patrick T %K Arrhythmias, Cardiac %K Caveolin 1 %K Caveolin 2 %K Electrocardiography %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Heart Atria %K Humans %K NAV1.5 Voltage-Gated Sodium Channel %K NAV1.8 Voltage-Gated Sodium Channel %K T-Box Domain Proteins %X

BACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.

METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.

CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

%B Circ Cardiovasc Genet %V 10 %8 2017 Aug %G eng %N 4 %R 10.1161/CIRCGENETICS.116.001667 %0 Journal Article %J Nat Genet %D 2018 %T Multi-ethnic genome-wide association study for atrial fibrillation. %A Roselli, Carolina %A Chaffin, Mark D %A Weng, Lu-Chen %A Aeschbacher, Stefanie %A Ahlberg, Gustav %A Albert, Christine M %A Almgren, Peter %A Alonso, Alvaro %A Anderson, Christopher D %A Aragam, Krishna G %A Arking, Dan E %A Barnard, John %A Bartz, Traci M %A Benjamin, Emelia J %A Bihlmeyer, Nathan A %A Bis, Joshua C %A Bloom, Heather L %A Boerwinkle, Eric %A Bottinger, Erwin B %A Brody, Jennifer A %A Calkins, Hugh %A Campbell, Archie %A Cappola, Thomas P %A Carlquist, John %A Chasman, Daniel I %A Chen, Lin Y %A Chen, Yii-Der Ida %A Choi, Eue-Keun %A Choi, Seung Hoan %A Christophersen, Ingrid E %A Chung, Mina K %A Cole, John W %A Conen, David %A Cook, James %A Crijns, Harry J %A Cutler, Michael J %A Damrauer, Scott M %A Daniels, Brian R %A Darbar, Dawood %A Delgado, Graciela %A Denny, Joshua C %A Dichgans, Martin %A Dörr, Marcus %A Dudink, Elton A %A Dudley, Samuel C %A Esa, Nada %A Esko, Tõnu %A Eskola, Markku %A Fatkin, Diane %A Felix, Stephan B %A Ford, Ian %A Franco, Oscar H %A Geelhoed, Bastiaan %A Grewal, Raji P %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gupta, Namrata %A Gustafsson, Stefan %A Gutmann, Rebecca %A Hamsten, Anders %A Harris, Tamara B %A Hayward, Caroline %A Heckbert, Susan R %A Hernesniemi, Jussi %A Hocking, Lynne J %A Hofman, Albert %A Horimoto, Andrea R V R %A Huang, Jie %A Huang, Paul L %A Huffman, Jennifer %A Ingelsson, Erik %A Ipek, Esra Gucuk %A Ito, Kaoru %A Jimenez-Conde, Jordi %A Johnson, Renee %A Jukema, J Wouter %A Kääb, Stefan %A Kähönen, Mika %A Kamatani, Yoichiro %A Kane, John P %A Kastrati, Adnan %A Kathiresan, Sekar %A Katschnig-Winter, Petra %A Kavousi, Maryam %A Kessler, Thorsten %A Kietselaer, Bas L %A Kirchhof, Paulus %A Kleber, Marcus E %A Knight, Stacey %A Krieger, Jose E %A Kubo, Michiaki %A Launer, Lenore J %A Laurikka, Jari %A Lehtimäki, Terho %A Leineweber, Kirsten %A Lemaitre, Rozenn N %A Li, Man %A Lim, Hong Euy %A Lin, Henry J %A Lin, Honghuang %A Lind, Lars %A Lindgren, Cecilia M %A Lokki, Marja-Liisa %A London, Barry %A Loos, Ruth J F %A Low, Siew-Kee %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Macfarlane, Peter W %A Magnusson, Patrik K %A Mahajan, Anubha %A Malik, Rainer %A Mansur, Alfredo J %A Marcus, Gregory M %A Margolin, Lauren %A Margulies, Kenneth B %A März, Winfried %A McManus, David D %A Melander, Olle %A Mohanty, Sanghamitra %A Montgomery, Jay A %A Morley, Michael P %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Natale, Andrea %A Nazarian, Saman %A Neumann, Benjamin %A Newton-Cheh, Christopher %A Niemeijer, Maartje N %A Nikus, Kjell %A Nilsson, Peter %A Noordam, Raymond %A Oellers, Heidi %A Olesen, Morten S %A Orho-Melander, Marju %A Padmanabhan, Sandosh %A Pak, Hui-Nam %A Paré, Guillaume %A Pedersen, Nancy L %A Pera, Joanna %A Pereira, Alexandre %A Porteous, David %A Psaty, Bruce M %A Pulit, Sara L %A Pullinger, Clive R %A Rader, Daniel J %A Refsgaard, Lena %A Ribasés, Marta %A Ridker, Paul M %A Rienstra, Michiel %A Risch, Lorenz %A Roden, Dan M %A Rosand, Jonathan %A Rosenberg, Michael A %A Rost, Natalia %A Rotter, Jerome I %A Saba, Samir %A Sandhu, Roopinder K %A Schnabel, Renate B %A Schramm, Katharina %A Schunkert, Heribert %A Schurman, Claudia %A Scott, Stuart A %A Seppälä, Ilkka %A Shaffer, Christian %A Shah, Svati %A Shalaby, Alaa A %A Shim, Jaemin %A Shoemaker, M Benjamin %A Siland, Joylene E %A Sinisalo, Juha %A Sinner, Moritz F %A Slowik, Agnieszka %A Smith, Albert V %A Smith, Blair H %A Smith, J Gustav %A Smith, Jonathan D %A Smith, Nicholas L %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Stricker, Bruno H %A Sun, Albert %A Sun, Han %A Svendsen, Jesper H %A Tanaka, Toshihiro %A Tanriverdi, Kahraman %A Taylor, Kent D %A Teder-Laving, Maris %A Teumer, Alexander %A Thériault, Sébastien %A Trompet, Stella %A Tucker, Nathan R %A Tveit, Arnljot %A Uitterlinden, André G %A van der Harst, Pim %A Van Gelder, Isabelle C %A Van Wagoner, David R %A Verweij, Niek %A Vlachopoulou, Efthymia %A Völker, Uwe %A Wang, Biqi %A Weeke, Peter E %A Weijs, Bob %A Weiss, Raul %A Weiss, Stefan %A Wells, Quinn S %A Wiggins, Kerri L %A Wong, Jorge A %A Woo, Daniel %A Worrall, Bradford B %A Yang, Pil-Sung %A Yao, Jie %A Yoneda, Zachary T %A Zeller, Tanja %A Zeng, Lingyao %A Lubitz, Steven A %A Lunetta, Kathryn L %A Ellinor, Patrick T %X

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

%B Nat Genet %V 50 %P 1225-1233 %8 2018 Sep %G eng %N 9 %R 10.1038/s41588-018-0133-9 %0 Journal Article %J Nat Commun %D 2018 %T PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. %A van Setten, Jessica %A Brody, Jennifer A %A Jamshidi, Yalda %A Swenson, Brenton R %A Butler, Anne M %A Campbell, Harry %A Del Greco, Fabiola M %A Evans, Daniel S %A Gibson, Quince %A Gudbjartsson, Daniel F %A Kerr, Kathleen F %A Krijthe, Bouwe P %A Lyytikäinen, Leo-Pekka %A Müller, Christian %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Ritchie, Marylyn D %A Robino, Antonietta %A Smith, Albert V %A Steri, Maristella %A Tanaka, Toshiko %A Teumer, Alexander %A Trompet, Stella %A Ulivi, Sheila %A Verweij, Niek %A Yin, Xiaoyan %A Arnar, David O %A Asselbergs, Folkert W %A Bader, Joel S %A Barnard, John %A Bis, Josh %A Blankenberg, Stefan %A Boerwinkle, Eric %A Bradford, Yuki %A Buckley, Brendan M %A Chung, Mina K %A Crawford, Dana %A den Hoed, Marcel %A Denny, Josh C %A Dominiczak, Anna F %A Ehret, Georg B %A Eijgelsheim, Mark %A Ellinor, Patrick T %A Felix, Stephan B %A Franco, Oscar H %A Franke, Lude %A Harris, Tamara B %A Holm, Hilma %A Ilaria, Gandin %A Iorio, Annamaria %A Kähönen, Mika %A Kolcic, Ivana %A Kors, Jan A %A Lakatta, Edward G %A Launer, Lenore J %A Lin, Honghuang %A Lin, Henry J %A Loos, Ruth J F %A Lubitz, Steven A %A Macfarlane, Peter W %A Magnani, Jared W %A Leach, Irene Mateo %A Meitinger, Thomas %A Mitchell, Braxton D %A Münzel, Thomas %A Papanicolaou, George J %A Peters, Annette %A Pfeufer, Arne %A Pramstaller, Peter P %A Raitakari, Olli T %A Rotter, Jerome I %A Rudan, Igor %A Samani, Nilesh J %A Schlessinger, David %A Silva Aldana, Claudia T %A Sinner, Moritz F %A Smith, Jonathan D %A Snieder, Harold %A Soliman, Elsayed Z %A Spector, Timothy D %A Stott, David J %A Strauch, Konstantin %A Tarasov, Kirill V %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A Van Wagoner, David R %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Jan Westra, Harm %A Wild, Philipp S %A Zeller, Tanja %A Alonso, Alvaro %A Avery, Christy L %A Bandinelli, Stefania %A Benjamin, Emelia J %A Cucca, Francesco %A Dörr, Marcus %A Ferrucci, Luigi %A Gasparini, Paolo %A Gudnason, Vilmundur %A Hayward, Caroline %A Heckbert, Susan R %A Hicks, Andrew A %A Jukema, J Wouter %A Kääb, Stefan %A Lehtimäki, Terho %A Liu, Yongmei %A Munroe, Patricia B %A Parsa, Afshin %A Polasek, Ozren %A Psaty, Bruce M %A Roden, Dan M %A Schnabel, Renate B %A Sinagra, Gianfranco %A Stefansson, Kari %A Stricker, Bruno H %A van der Harst, Pim %A van Duijn, Cornelia M %A Wilson, James F %A Gharib, Sina A %A de Bakker, Paul I W %A Isaacs, Aaron %A Arking, Dan E %A Sotoodehnia, Nona %X

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

%B Nat Commun %V 9 %P 2904 %8 2018 Jul 25 %G eng %N 1 %R 10.1038/s41467-018-04766-9 %0 Journal Article %J Circ Genom Precis Med %D 2019 %T Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation. %A Dörr, Marcus %A Hamburg, Naomi M %A Müller, Christian %A Smith, Nicholas L %A Gustafsson, Stefan %A Lehtimäki, Terho %A Teumer, Alexander %A Zeller, Tanja %A Li, Xiaohui %A Lind, Lars %A Raitakari, Olli T %A Völker, Uwe %A Blankenberg, Stefan %A McKnight, Barbara %A Morris, Andrew P %A Kähönen, Mika %A Lemaitre, Rozenn N %A Wild, Philipp S %A Nauck, Matthias %A Völzke, Henry %A Münzel, Thomas %A Mitchell, Gary F %A Psaty, Bruce M %A Lindgren, Cecilia M %A Larson, Martin G %A Felix, Stephan B %A Ingelsson, Erik %A Lyytikäinen, Leo-Pekka %A Herrington, David %A Benjamin, Emelia J %A Schnabel, Renate B %B Circ Genom Precis Med %V 12 %P e002409 %8 2019 Feb %G eng %N 2 %R 10.1161/CIRCGEN.118.002409