@article {733, title = {Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly.}, journal = {Circulation}, volume = {107}, year = {2003}, month = {2003 Apr 22}, pages = {2021-4}, abstract = {

BACKGROUND: Genetic polymorphisms at codons 16 and 27 of the beta2-adrenergic receptor have been associated with altered response to sympathetic stimulation. We examined these polymorphisms in relation to cardiovascular event risk in the Cardiovascular Health Study.

METHODS AND RESULTS: A total of 808 black and 4441 white participants (mean age, 73 years) were genotyped for the Arg16Gly and Gln27Glu polymorphisms of the beta2-adrenergic receptor. There were 702 incident coronary events, 438 ischemic strokes, and 1136 combined cardiovascular events during 7 to 10 years of follow-up. Allele frequencies differed by race but not by age or hypertension status. Glu27 carriers had a lower risk of coronary events than Gln27 homozygotes (hazard ratio, 0.82; 95\% CI, 0.70 to 0.95), and there was a suggestion of decreased risk among Gly16 carriers compared with Arg16 homozygotes (hazard ratio, 0.88; 95\% CI, 0.72 to 1.07). There was no association of beta2-adrenergic receptor genotype with ischemic stroke or combined cardiovascular events.

CONCLUSIONS: The Glu27 allele of the beta2-adrenergic receptor was associated with a lower risk of incident coronary events in this elderly population.

}, keywords = {African Continental Ancestry Group, Aged, Alleles, Brain Ischemia, Cardiovascular Diseases, Cohort Studies, Comorbidity, Coronary Disease, European Continental Ancestry Group, Follow-Up Studies, Gene Frequency, Humans, Incidence, Linkage Disequilibrium, Polymorphism, Genetic, Receptors, Adrenergic, beta-2, Risk Assessment, Stroke, United States}, issn = {1524-4539}, doi = {10.1161/01.CIR.0000065231.07729.92}, author = {Heckbert, Susan R and Hindorff, Lucia A and Edwards, Karen L and Psaty, Bruce M and Lumley, Thomas and Siscovick, David S and Tang, Zhonghua and Durda, J Peter and Kronmal, Richard A and Tracy, Russell P} } @article {825, title = {beta(2)-Adrenergic receptor polymorphisms and determinants of cardiovascular risk: the Cardiovascular Health Study.}, journal = {Am J Hypertens}, volume = {18}, year = {2005}, month = {2005 Mar}, pages = {392-7}, abstract = {

BACKGROUND: Common Arg16Gly and Gln27Glu polymorphisms of the beta(2)-adrenergic receptor (beta(2)AR) have been associated with hypertension and coronary disease. This analysis of older adults in the Cardiovascular Health Study examined whether these polymorphisms were associated with blood pressure (BP), subclinical atherosclerosis, and, among treated hypertensive individuals, differences in coronary disease risk according to antihypertensive drug class.

METHODS: Altogether, 5249 participants (4441 white and 808 African American, median follow-up time 10.2 years) were genotyped for both polymorphisms. Ankle-arm index (AAI), carotid intima-media thickness (IMT), and brachial flow-mediated dilation were measured cross-sectionally. All estimates were adjusted for ethnicity.

RESULTS: Relative to Gln27 homozygotes, carrying the Glu27 allele was not associated with new-onset hypertension (hazard ratio [HR] = 1.01, 95\% confidence interval [CI] = 0.87 to 1.16), BP control (odds ratio [OR] = 0.97, 95\% CI = 0.89 to 1.06), AAI (mean difference 0.0042 +/- 0.0052), carotid IMT (mean difference 0.0044 +/- 0.02 mm), or brachial flow-mediated dilation (mean difference in baseline diameter -0.028 +/- 0.036 mm; the most marked of three measures). Among treated hypertensive individuals, coronary disease risk was similar in Glu27 carriers relative to Gln27 homozygotes in subgroups defined by use of beta-blockers (HR = 1.09, 95\% CI = 0.64 to 1.87) or other antihypertensive medications (HR = 1.00, 95\% CI = 0.78 to 1.28). Results were similar for the Arg16Gly polymorphism.

CONCLUSIONS: The association of beta(2)AR genotype with coronary disease previously reported in this older adult population is not likely to be explained by BP levels, subclinical atherosclerosis, or antihypertensive treatment. Other measures of vascular response, gene-gene or gene-environment interactions, or characteristics developing earlier in life may mediate the association between beta(2)AR genotype and coronary disease and merit further research.

}, keywords = {African Americans, Antihypertensive Agents, Arteriosclerosis, Coronary Artery Disease, European Continental Ancestry Group, Female, Genotype, Homozygote, Humans, Hypertension, Incidence, Male, Middle Aged, Polymorphism, Genetic, Receptors, Adrenergic, beta-2, Risk Factors}, issn = {0895-7061}, doi = {10.1016/j.amjhyper.2004.10.014}, author = {Hindorff, Lucia A and Heckbert, Susan R and Psaty, Bruce M and Lumley, Thomas and Siscovick, David S and Herrington, David M and Edwards, Karen L and Tracy, Russell P} } @article {995, title = {Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {28}, year = {2008}, month = {2008 Jan}, pages = {173-9}, abstract = {

OBJECTIVE: We asked whether single nucleotide polymorphisms (SNPs) that had been nominally associated with cardiovascular disease in antecedent studies were also associated with cardiovascular disease in a population-based prospective study of 4522 individuals aged 65 or older.

METHODS AND RESULTS: Based on antecedent studies, we prespecified a risk allele and an inheritance model for each of 74 SNPs. We then tested the association of these SNPs with myocardial infarction (MI) in the Cardiovascular Health Study (CHS). The prespecified risk alleles of 8 SNPs were nominally associated (1-sided P<0.05) with increased risk of MI in White CHS participants. The false discovery rate for these 8 was 0.43, suggesting that about 4 of these 8 are likely to be true positives. The 4 of these 8 SNPs that had the strongest evidence for association with cardiovascular disease before testing in CHS (association in 3 antecedent studies) were in KIF6 (CHS HR=1.29; 90\%CI 1.1 to 1.52), VAMP8 (HR=1.2; 90\%CI 1.02 to 1.41), TAS2R50 (HR=1.13; 90\%CI 1 to 1.27), and LPA (HR=1.62; 90\%CI 1.09 to 2.42).

CONCLUSIONS: Although most of the SNPs investigated were not associated with MI in CHS, evidence from this investigation combined with previous studies suggests that 4 of these SNPs are likely associated with MI.

}, keywords = {African Americans, Aged, Aged, 80 and over, Coronary Disease, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Humans, Longitudinal Studies, Male, Myocardial Infarction, National Heart, Lung, and Blood Institute (U.S.), Polymorphism, Single Nucleotide, Proportional Hazards Models, United States}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.107.153981}, author = {Shiffman, Dov and O{\textquoteright}Meara, Ellen S and Bare, Lance A and Rowland, Charles M and Louie, Judy Z and Arellano, Andre R and Lumley, Thomas and Rice, Kenneth and Iakoubova, Olga and Luke, May M and Young, Bradford A and Malloy, Mary J and Kane, John P and Ellis, Stephen G and Tracy, Russell P and Devlin, James J and Psaty, Bruce M} } @article {1153, title = {Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts.}, journal = {Circ Cardiovasc Genet}, volume = {2}, year = {2009}, month = {2009 Apr}, pages = {125-33}, abstract = {

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.

}, keywords = {Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Female, Fibrinogen, Genetic Loci, Genome-Wide Association Study, Humans, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, Young Adult}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.108.825224}, author = {Dehghan, Abbas and Yang, Qiong and Peters, Annette and Basu, Saonli and Bis, Joshua C and Rudnicka, Alicja R and Kavousi, Maryam and Chen, Ming-Huei and Baumert, Jens and Lowe, Gordon D O and McKnight, Barbara and Tang, Weihong and de Maat, Moniek and Larson, Martin G and Eyhermendy, Susana and McArdle, Wendy L and Lumley, Thomas and Pankow, James S and Hofman, Albert and Massaro, Joseph M and Rivadeneira, Fernando and Kolz, Melanie and Taylor, Kent D and van Duijn, Cornelia M and Kathiresan, Sekar and Illig, Thomas and Aulchenko, Yurii S and Volcik, Kelly A and Johnson, Andrew D and Uitterlinden, Andr{\'e} G and Tofler, Geoffrey H and Gieger, Christian and Psaty, Bruce M and Couper, David J and Boerwinkle, Eric and Koenig, Wolfgang and O{\textquoteright}Donnell, Christopher J and Witteman, Jacqueline C and Strachan, David P and Smith, Nicholas L and Folsom, Aaron R} } @article {1087, title = {Common variants at ten loci influence QT interval duration in the QTGEN Study.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Apr}, pages = {399-406}, abstract = {

QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 x 10(-8) with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5\% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, Aged, Arrhythmias, Cardiac, Chromosome Mapping, Death, Sudden, Cardiac, Electroencephalography, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels, European Continental Ancestry Group, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, KCNQ1 Potassium Channel, Meta-Analysis as Topic, Muscle Proteins, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Potassium Channels, Voltage-Gated, Risk Factors, Sodium Channels}, issn = {1546-1718}, doi = {10.1038/ng.364}, author = {Newton-Cheh, Christopher and Eijgelsheim, Mark and Rice, Kenneth M and de Bakker, Paul I W and Yin, Xiaoyan and Estrada, Karol and Bis, Joshua C and Marciante, Kristin and Rivadeneira, Fernando and Noseworthy, Peter A and Sotoodehnia, Nona and Smith, Nicholas L and Rotter, Jerome I and Kors, Jan A and Witteman, Jacqueline C M and Hofman, Albert and Heckbert, Susan R and O{\textquoteright}Donnell, Christopher J and Uitterlinden, Andr{\'e} G and Psaty, Bruce M and Lumley, Thomas and Larson, Martin G and Stricker, Bruno H Ch} } @article {1064, title = {Gene variants associated with ischemic stroke: the cardiovascular health study.}, journal = {Stroke}, volume = {40}, year = {2009}, month = {2009 Feb}, pages = {363-8}, abstract = {

BACKGROUND AND PURPOSE: The purpose of this study was to determine whether 74 single nucleotide polymorphisms (SNPs), which had been associated with coronary heart disease, are associated with incident ischemic stroke.

METHODS: Based on antecedent studies of coronary heart disease, we prespecified the risk allele for each of the 74 SNPs. We used Cox proportional hazards models that adjusted for traditional risk factors to estimate the associations of these SNPs with incident ischemic stroke during 14 years of follow-up in a population-based study of older adults: the Cardiovascular Health Study (CHS).

RESULTS: In white CHS participants, the prespecified risk alleles of 7 of the 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) were nominally associated with increased risk of stroke (one-sided P<0.05, false discovery rate=0.42). In black participants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were nominally associated with stroke (one-sided P<0.05, false discovery rate=0.55). The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90\% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90\% CI, 1.11 to 11.6) participants of CHS. Kaplan-Meier estimates of the 10-year cumulative incidence of stroke were greater among Val allele homozygotes than among Met allele carriers in both white (10\% versus 6\%) and black (12\% versus 3\%) participants of CHS.

CONCLUSIONS: The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS.

}, keywords = {African Continental Ancestry Group, Aged, Alleles, Brain Ischemia, Cardiovascular Diseases, Coronary Disease, Ethnic Groups, European Continental Ancestry Group, Female, Gene Frequency, Genetic Variation, Humans, Kaplan-Meier Estimate, Male, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Stroke, United States}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.108.521328}, author = {Luke, May M and O{\textquoteright}Meara, Ellen S and Rowland, Charles M and Shiffman, Dov and Bare, Lance A and Arellano, Andre R and Longstreth, W T and Lumley, Thomas and Rice, Kenneth and Tracy, Russell P and Devlin, James J and Psaty, Bruce M} } @article {1108, title = {Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.}, journal = {JAMA}, volume = {302}, year = {2009}, month = {2009 Jul 08}, pages = {168-78}, abstract = {

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.

}, keywords = {Adult, Aged, Aged, 80 and over, Aorta, Cardiovascular Diseases, Echocardiography, European Continental Ancestry Group, Female, Genome-Wide Association Study, Genotype, Heart Atria, Heart Ventricles, Humans, Male, Middle Aged, Organ Size, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Ventricular Dysfunction, Left, Ventricular Function, Left}, issn = {1538-3598}, doi = {10.1001/jama.2009.978-a}, author = {Vasan, Ramachandran S and Glazer, Nicole L and Felix, Janine F and Lieb, Wolfgang and Wild, Philipp S and Felix, Stephan B and Watzinger, Norbert and Larson, Martin G and Smith, Nicholas L and Dehghan, Abbas and Grosshennig, Anika and Schillert, Arne and Teumer, Alexander and Schmidt, Reinhold and Kathiresan, Sekar and Lumley, Thomas and Aulchenko, Yurii S and K{\"o}nig, Inke R and Zeller, Tanja and Homuth, Georg and Struchalin, Maksim and Aragam, Jayashri and Bis, Joshua C and Rivadeneira, Fernando and Erdmann, Jeanette and Schnabel, Renate B and D{\"o}rr, Marcus and Zweiker, Robert and Lind, Lars and Rodeheffer, Richard J and Greiser, Karin Halina and Levy, Daniel and Haritunians, Talin and Deckers, Jaap W and Stritzke, Jan and Lackner, Karl J and V{\"o}lker, Uwe and Ingelsson, Erik and Kullo, Iftikhar and Haerting, Johannes and O{\textquoteright}Donnell, Christopher J and Heckbert, Susan R and Stricker, Bruno H and Ziegler, Andreas and Reffelmann, Thorsten and Redfield, Margaret M and Werdan, Karl and Mitchell, Gary F and Rice, Kenneth and Arnett, Donna K and Hofman, Albert and Gottdiener, John S and Uitterlinden, Andr{\'e} G and Meitinger, Thomas and Blettner, Maria and Friedrich, Nele and Wang, Thomas J and Psaty, Bruce M and van Duijn, Cornelia M and Wichmann, H-Erich and Munzel, Thomas F and Kroemer, Heyo K and Benjamin, Emelia J and Rotter, Jerome I and Witteman, Jacqueline C and Schunkert, Heribert and Schmidt, Helena and V{\"o}lzke, Henry and Blankenberg, Stefan} } @article {1092, title = {Genomewide association studies of stroke.}, journal = {N Engl J Med}, volume = {360}, year = {2009}, month = {2009 Apr 23}, pages = {1718-28}, abstract = {

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.

METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.

RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95\% confidence interval [CI], 1.19 to 1.42) and 1.33 (95\% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11\% and 12\% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95\% CI, 1.01 to 1.79; P=0.04) and 1.42 (95\% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95\% CI, 1.01 to 1.37; P=0.03) and 1.19 (95\% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.

CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

}, keywords = {African Continental Ancestry Group, Aged, Chromosomes, Human, Pair 12, Cohort Studies, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk Factors, Stroke}, issn = {1533-4406}, doi = {10.1056/NEJMoa0900094}, author = {Ikram, M Arfan and Seshadri, Sudha and Bis, Joshua C and Fornage, Myriam and DeStefano, Anita L and Aulchenko, Yurii S and Debette, Stephanie and Lumley, Thomas and Folsom, Aaron R and van den Herik, Evita G and Bos, Michiel J and Beiser, Alexa and Cushman, Mary and Launer, Lenore J and Shahar, Eyal and Struchalin, Maksim and Du, Yangchun and Glazer, Nicole L and Rosamond, Wayne D and Rivadeneira, Fernando and Kelly-Hayes, Margaret and Lopez, Oscar L and Coresh, Josef and Hofman, Albert and DeCarli, Charles and Heckbert, Susan R and Koudstaal, Peter J and Yang, Qiong and Smith, Nicholas L and Kase, Carlos S and Rice, Kenneth and Haritunians, Talin and Roks, Gerwin and de Kort, Paul L M and Taylor, Kent D and de Lau, Lonneke M and Oostra, Ben A and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Boerwinkle, Eric and Psaty, Bruce M and Mosley, Thomas H and van Duijn, Cornelia M and Breteler, Monique M B and Longstreth, W T and Wolf, Philip A} } @article {1114, title = {Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Aug}, pages = {879-81}, abstract = {

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)).

}, keywords = {Atrial Fibrillation, Chromosomes, Human, Pair 16, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeodomain Proteins, Humans, Meta-Analysis as Topic, Mutation, Polymorphism, Single Nucleotide, Reproducibility of Results}, issn = {1546-1718}, doi = {10.1038/ng.416}, author = {Benjamin, Emelia J and Rice, Kenneth M and Arking, Dan E and Pfeufer, Arne and van Noord, Charlotte and Smith, Albert V and Schnabel, Renate B and Bis, Joshua C and Boerwinkle, Eric and Sinner, Moritz F and Dehghan, Abbas and Lubitz, Steven A and D{\textquoteright}Agostino, Ralph B and Lumley, Thomas and Ehret, Georg B and Heeringa, Jan and Aspelund, Thor and Newton-Cheh, Christopher and Larson, Martin G and Marciante, Kristin D and Soliman, Elsayed Z and Rivadeneira, Fernando and Wang, Thomas J and Eiriksdottir, Gudny and Levy, Daniel and Psaty, Bruce M and Li, Man and Chamberlain, Alanna M and Hofman, Albert and Vasan, Ramachandran S and Harris, Tamara B and Rotter, Jerome I and Kao, W H Linda and Agarwal, Sunil K and Stricker, Bruno H Ch and Wang, Ke and Launer, Lenore J and Smith, Nicholas L and Chakravarti, Aravinda and Uitterlinden, Andr{\'e} G and Wolf, Philip A and Sotoodehnia, Nona and K{\"o}ttgen, Anna and van Duijn, Cornelia M and Meitinger, Thomas and Mueller, Martina and Perz, Siegfried and Steinbeck, Gerhard and Wichmann, H-Erich and Lunetta, Kathryn L and Heckbert, Susan R and Gudnason, Vilmundur and Alonso, Alvaro and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T and Witteman, Jacqueline C M} } @article {1197, title = {Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.}, journal = {Circ Cardiovasc Genet}, volume = {3}, year = {2010}, month = {2010 Jun}, pages = {256-66}, abstract = {

BACKGROUND: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12\%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16\%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3.

CONCLUSIONS: We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

}, keywords = {African Americans, Aged, Aged, 80 and over, Cohort Studies, Endopeptidases, European Continental Ancestry Group, Female, Genome-Wide Association Study, Heart Failure, Humans, Incidence, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk, Ubiquitin-Specific Proteases}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.109.895763}, author = {Smith, Nicholas L and Felix, Janine F and Morrison, Alanna C and Demissie, Serkalem and Glazer, Nicole L and Loehr, Laura R and Cupples, L Adrienne and Dehghan, Abbas and Lumley, Thomas and Rosamond, Wayne D and Lieb, Wolfgang and Rivadeneira, Fernando and Bis, Joshua C and Folsom, Aaron R and Benjamin, Emelia and Aulchenko, Yurii S and Haritunians, Talin and Couper, David and Murabito, Joanne and Wang, Ying A and Stricker, Bruno H and Gottdiener, John S and Chang, Patricia P and Wang, Thomas J and Rice, Kenneth M and Hofman, Albert and Heckbert, Susan R and Fox, Ervin R and O{\textquoteright}Donnell, Christopher J and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Willerson, James T and Levy, Daniel and van Duijn, Cornelia M and Psaty, Bruce M and Witteman, Jacqueline C M and Boerwinkle, Eric and Vasan, Ramachandran S} } @article {1243, title = {Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.}, journal = {PLoS Genet}, volume = {6}, year = {2010}, month = {2010 Oct 28}, pages = {e1001184}, abstract = {

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0{\texttimes}10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0\%-3.2\% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61{\texttimes}10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25{\texttimes}10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15{\texttimes}10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32{\texttimes}10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Child, Child, Preschool, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Cohort Studies, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Microcirculation, Middle Aged, Polymorphism, Single Nucleotide, Retinal Vessels, Young Adult}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1001184}, author = {Ikram, M Kamran and Sim, Xueling and Xueling, Sim and Jensen, Richard A and Cotch, Mary Frances and Hewitt, Alex W and Ikram, M Arfan and Wang, Jie Jin and Klein, Ronald and Klein, Barbara E K and Breteler, Monique M B and Cheung, Ning and Liew, Gerald and Mitchell, Paul and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Hofman, Albert and de Jong, Paulus T V M and van Duijn, Cornelia M and Kao, Linda and Cheng, Ching-Yu and Smith, Albert Vernon and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and Jonasson, Fridbert and Eiriksdottir, Gudny and Aspelund, Thor and Harris, Tamara B and Launer, Lenore J and Taylor, Kent D and Li, Xiaohui and Iyengar, Sudha K and Xi, Quansheng and Sivakumaran, Theru A and Mackey, David A and Macgregor, Stuart and Martin, Nicholas G and Young, Terri L and Bis, Josh C and Wiggins, Kerri L and Heckbert, Susan R and Hammond, Christopher J and Andrew, Toby and Fahy, Samantha and Attia, John and Holliday, Elizabeth G and Scott, Rodney J and Islam, F M Amirul and Rotter, Jerome I and McAuley, Annie K and Boerwinkle, Eric and Tai, E Shyong and Gudnason, Vilmundur and Siscovick, David S and Vingerling, Johannes R and Wong, Tien Y} } @article {1187, title = {Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium.}, journal = {Circ Cardiovasc Genet}, volume = {3}, year = {2010}, month = {2010 Jun}, pages = {248-55}, abstract = {

BACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance.

CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.

}, keywords = {African Americans, Aged, Aged, 80 and over, Chemokines, Cohort Studies, European Continental Ancestry Group, Female, Genome-Wide Association Study, Genotype, Heart Failure, Humans, Introns, Male, MARVEL Domain-Containing Proteins, Membrane Proteins, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.109.895995}, author = {Morrison, Alanna C and Felix, Janine F and Cupples, L Adrienne and Glazer, Nicole L and Loehr, Laura R and Dehghan, Abbas and Demissie, Serkalem and Bis, Joshua C and Rosamond, Wayne D and Aulchenko, Yurii S and Wang, Ying A and Haritunians, Talin and Folsom, Aaron R and Rivadeneira, Fernando and Benjamin, Emelia J and Lumley, Thomas and Couper, David and Stricker, Bruno H and O{\textquoteright}Donnell, Christopher J and Rice, Kenneth M and Chang, Patricia P and Hofman, Albert and Levy, Daniel and Rotter, Jerome I and Fox, Ervin R and Uitterlinden, Andr{\'e} G and Wang, Thomas J and Psaty, Bruce M and Willerson, James T and van Duijn, Cornelia M and Boerwinkle, Eric and Witteman, Jacqueline C M and Vasan, Ramachandran S and Smith, Nicholas L} } @article {1271, title = {CUBN is a gene locus for albuminuria.}, journal = {J Am Soc Nephrol}, volume = {22}, year = {2011}, month = {2011 Mar}, pages = {555-70}, abstract = {

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 {\texttimes} 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.

}, keywords = {African Continental Ancestry Group, Albuminuria, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Humans, Mutation, Missense, Receptors, Cell Surface}, issn = {1533-3450}, doi = {10.1681/ASN.2010060598}, author = {B{\"o}ger, Carsten A and Chen, Ming-Huei and Tin, Adrienne and Olden, Matthias and K{\"o}ttgen, Anna and de Boer, Ian H and Fuchsberger, Christian and O{\textquoteright}Seaghdha, Conall M and Pattaro, Cristian and Teumer, Alexander and Liu, Ching-Ti and Glazer, Nicole L and Li, Man and O{\textquoteright}Connell, Jeffrey R and Tanaka, Toshiko and Peralta, Carmen A and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Zhao, Jing Hua and Hwang, Shih-Jen and Akylbekova, Ermeg and Kramer, Holly and van der Harst, Pim and Smith, Albert V and Lohman, Kurt and de Andrade, Mariza and Hayward, Caroline and Kollerits, Barbara and T{\"o}njes, Anke and Aspelund, Thor and Ingelsson, Erik and Eiriksdottir, Gudny and Launer, Lenore J and Harris, Tamara B and Shuldiner, Alan R and Mitchell, Braxton D and Arking, Dan E and Franceschini, Nora and Boerwinkle, Eric and Egan, Josephine and Hernandez, Dena and Reilly, Muredach and Townsend, Raymond R and Lumley, Thomas and Siscovick, David S and Psaty, Bruce M and Kestenbaum, Bryan and Haritunians, Talin and Bergmann, Sven and Vollenweider, Peter and Waeber, G{\'e}rard and Mooser, Vincent and Waterworth, Dawn and Johnson, Andrew D and Florez, Jose C and Meigs, James B and Lu, Xiaoning and Turner, Stephen T and Atkinson, Elizabeth J and Leak, Tennille S and Aasar{\o}d, Knut and Skorpen, Frank and Syv{\"a}nen, Ann-Christine and Illig, Thomas and Baumert, Jens and Koenig, Wolfgang and Kr{\"a}mer, Bernhard K and Devuyst, Olivier and Mychaleckyj, Josyf C and Minelli, Cosetta and Bakker, Stephan J L and Kedenko, Lyudmyla and Paulweber, Bernhard and Coassin, Stefan and Endlich, Karlhans and Kroemer, Heyo K and Biffar, Reiner and Stracke, Sylvia and V{\"o}lzke, Henry and Stumvoll, Michael and M{\"a}gi, Reedik and Campbell, Harry and Vitart, Veronique and Hastie, Nicholas D and Gudnason, Vilmundur and Kardia, Sharon L R and Liu, Yongmei and Polasek, Ozren and Curhan, Gary and Kronenberg, Florian and Prokopenko, Inga and Rudan, Igor and Arnl{\"o}v, Johan and Hallan, Stein and Navis, Gerjan and Parsa, Afshin and Ferrucci, Luigi and Coresh, Josef and Shlipak, Michael G and Bull, Shelley B and Paterson, Nicholas J and Wichmann, H-Erich and Wareham, Nicholas J and Loos, Ruth J F and Rotter, Jerome I and Pramstaller, Peter P and Cupples, L Adrienne and Beckmann, Jacques S and Yang, Qiong and Heid, Iris M and Rettig, Rainer and Dreisbach, Albert W and Bochud, Murielle and Fox, Caroline S and Kao, W H L} } @article {1284, title = {Genetic predictors of fibrin D-dimer levels in healthy adults.}, journal = {Circulation}, volume = {123}, year = {2011}, month = {2011 May 03}, pages = {1864-72}, abstract = {

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{\textendash}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{\texttimes}10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4{\texttimes}10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9{\texttimes}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{\textendash}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.

}, keywords = {Adult, Aged, Blood Coagulation, European Continental Ancestry Group, Factor V, Female, Fibrin Fibrinogen Degradation Products, Fibrinogen, Genetic Testing, Genome-Wide Association Study, Humans, Male, Middle Aged, Reference Values, Thromboplastin}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.110.009480}, author = {Smith, Nicholas L and Huffman, Jennifer E and Strachan, David P and Huang, Jie and Dehghan, Abbas and Trompet, Stella and Lopez, Lorna M and Shin, So-Youn and Baumert, Jens and Vitart, Veronique and Bis, Joshua C and Wild, Sarah H and Rumley, Ann and Yang, Qiong and Uitterlinden, Andr{\'e} G and Stott, David J and Davies, Gail and Carter, Angela M and Thorand, Barbara and Polasek, Ozren and McKnight, Barbara and Campbell, Harry and Rudnicka, Alicja R and Chen, Ming-Huei and Buckley, Brendan M and Harris, Sarah E and Peters, Annette and Pulanic, Drazen and Lumley, Thomas and de Craen, Anton J M and Liewald, David C and Gieger, Christian and Campbell, Susan and Ford, Ian and Gow, Alan J and Luciano, Michelle and Porteous, David J and Guo, Xiuqing and Sattar, Naveed and Tenesa, Albert and Cushman, Mary and Slagboom, P Eline and Visscher, Peter M and Spector, Tim D and Illig, Thomas and Rudan, Igor and Bovill, Edwin G and Wright, Alan F and McArdle, Wendy L and Tofler, Geoffrey and Hofman, Albert and Westendorp, Rudi G J and Starr, John M and Grant, Peter J and Karakas, Mahir and Hastie, Nicholas D and Psaty, Bruce M and Wilson, James F and Lowe, Gordon D O and O{\textquoteright}Donnell, Christopher J and Witteman, Jacqueline C M and Jukema, J Wouter and Deary, Ian J and Soranzo, Nicole and Koenig, Wolfgang and Hayward, Caroline} } @article {6096, title = {Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Sep 25}, pages = {1082-90}, abstract = {

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 {\texttimes} 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

}, keywords = {Child, European Continental Ancestry Group, Genome-Wide Association Study, Humans, Pulmonary Disease, Chronic Obstructive, Respiratory Function Tests}, issn = {1546-1718}, doi = {10.1038/ng.941}, author = {Soler Artigas, Maria and Loth, Daan W and Wain, Louise V and Gharib, Sina A and Obeidat, Ma{\textquoteright}en and Tang, Wenbo and Zhai, Guangju and Zhao, Jing Hua and Smith, Albert Vernon and Huffman, Jennifer E and Albrecht, Eva and Jackson, Catherine M and Evans, David M and Cadby, Gemma and Fornage, Myriam and Manichaikul, Ani and Lopez, Lorna M and Johnson, Toby and Aldrich, Melinda C and Aspelund, Thor and Barroso, In{\^e}s and Campbell, Harry and Cassano, Patricia A and Couper, David J and Eiriksdottir, Gudny and Franceschini, Nora and Garcia, Melissa and Gieger, Christian and Gislason, Gauti Kjartan and Grkovic, Ivica and Hammond, Christopher J and Hancock, Dana B and Harris, Tamara B and Ramasamy, Adaikalavan and Heckbert, Susan R and Heli{\"o}vaara, Markku and Homuth, Georg and Hysi, Pirro G and James, Alan L and Jankovic, Stipan and Joubert, Bonnie R and Karrasch, Stefan and Klopp, Norman and Koch, Beate and Kritchevsky, Stephen B and Launer, Lenore J and Liu, Yongmei and Loehr, Laura R and Lohman, Kurt and Loos, Ruth J F and Lumley, Thomas and Al Balushi, Khalid A and Ang, Wei Q and Barr, R Graham and Beilby, John and Blakey, John D and Boban, Mladen and Boraska, Vesna and Brisman, Jonas and Britton, John R and Brusselle, Guy G and Cooper, Cyrus and Curjuric, Ivan and Dahgam, Santosh and Deary, Ian J and Ebrahim, Shah and Eijgelsheim, Mark and Francks, Clyde and Gaysina, Darya and Granell, Raquel and Gu, Xiangjun and Hankinson, John L and Hardy, Rebecca and Harris, Sarah E and Henderson, John and Henry, Amanda and Hingorani, Aroon D and Hofman, Albert and Holt, Patrick G and Hui, Jennie and Hunter, Michael L and Imboden, Medea and Jameson, Karen A and Kerr, Shona M and Kolcic, Ivana and Kronenberg, Florian and Liu, Jason Z and Marchini, Jonathan and McKeever, Tricia and Morris, Andrew D and Olin, Anna-Carin and Porteous, David J and Postma, Dirkje S and Rich, Stephen S and Ring, Susan M and Rivadeneira, Fernando and Rochat, Thierry and Sayer, Avan Aihie and Sayers, Ian and Sly, Peter D and Smith, George Davey and Sood, Akshay and Starr, John M and Uitterlinden, Andr{\'e} G and Vonk, Judith M and Wannamethee, S Goya and Whincup, Peter H and Wijmenga, Cisca and Williams, O Dale and Wong, Andrew and Mangino, Massimo and Marciante, Kristin D and McArdle, Wendy L and Meibohm, Bernd and Morrison, Alanna C and North, Kari E and Omenaas, Ernst and Palmer, Lyle J and Pietil{\"a}inen, Kirsi H and Pin, Isabelle and Pola Sbreve Ek, Ozren and Pouta, Anneli and Psaty, Bruce M and Hartikainen, Anna-Liisa and Rantanen, Taina and Ripatti, Samuli and Rotter, Jerome I and Rudan, Igor and Rudnicka, Alicja R and Schulz, Holger and Shin, So-Youn and Spector, Tim D and Surakka, Ida and Vitart, Veronique and V{\"o}lzke, Henry and Wareham, Nicholas J and Warrington, Nicole M and Wichmann, H-Erich and Wild, Sarah H and Wilk, Jemma B and Wjst, Matthias and Wright, Alan F and Zgaga, Lina and Zemunik, Tatijana and Pennell, Craig E and Nyberg, Fredrik and Kuh, Diana and Holloway, John W and Boezen, H Marike and Lawlor, Debbie A and Morris, Richard W and Probst-Hensch, Nicole and Kaprio, Jaakko and Wilson, James F and Hayward, Caroline and K{\"a}h{\"o}nen, Mika and Heinrich, Joachim and Musk, Arthur W and Jarvis, Deborah L and Gl{\"a}ser, Sven and Jarvelin, Marjo-Riitta and Ch Stricker, Bruno H and Elliott, Paul and O{\textquoteright}Connor, George T and Strachan, David P and London, Stephanie J and Hall, Ian P and Gudnason, Vilmundur and Tobin, Martin D} } @article {1298, title = {Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.}, journal = {Ann Neurol}, volume = {69}, year = {2011}, month = {2011 Jun}, pages = {928-39}, abstract = {

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 {\texttimes} 10(-9) ; p(replication) = 1.3 {\texttimes} 10(-7) ; p(combined) = 4.0 {\texttimes} 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 {\texttimes} 10(-9) ), rs11869977 (p = 5.7 {\texttimes} 10(-9) ), rs936393 (p = 6.8 {\texttimes} 10(-9) ), rs3744017 (p = 7.3 {\texttimes} 10(-9) ), and rs1055129 (p = 4.1 {\texttimes} 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8\% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

}, keywords = {Aged, Aged, 80 and over, Cerebral Cortex, Chromosomes, Human, Pair 17, Cognition Disorders, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Middle Aged, Movement Disorders, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Residence Characteristics, RNA, Messenger}, issn = {1531-8249}, doi = {10.1002/ana.22403}, author = {Fornage, Myriam and Debette, Stephanie and Bis, Joshua C and Schmidt, Helena and Ikram, M Arfan and Dufouil, Carole and Sigurdsson, Sigurdur and Lumley, Thomas and DeStefano, Anita L and Fazekas, Franz and Vrooman, Henri A and Shibata, Dean K and Maillard, Pauline and Zijdenbos, Alex and Smith, Albert V and Gudnason, Haukur and de Boer, Renske and Cushman, Mary and Mazoyer, Bernard and Heiss, Gerardo and Vernooij, Meike W and Enzinger, Christian and Glazer, Nicole L and Beiser, Alexa and Knopman, David S and Cavalieri, Margherita and Niessen, Wiro J and Harris, Tamara B and Petrovic, Katja and Lopez, Oscar L and Au, Rhoda and Lambert, Jean-Charles and Hofman, Albert and Gottesman, Rebecca F and Garcia, Melissa and Heckbert, Susan R and Atwood, Larry D and Catellier, Diane J and Uitterlinden, Andr{\'e} G and Yang, Qiong and Smith, Nicholas L and Aspelund, Thor and Romero, Jose R and Rice, Kenneth and Taylor, Kent D and Nalls, Michael A and Rotter, Jerome I and Sharrett, Richey and van Duijn, Cornelia M and Amouyel, Philippe and Wolf, Philip A and Gudnason, Vilmundur and van der Lugt, Aad and Boerwinkle, Eric and Psaty, Bruce M and Seshadri, Sudha and Tzourio, Christophe and Breteler, Monique M B and Mosley, Thomas H and Schmidt, Reinhold and Longstreth, W T and DeCarli, Charles and Launer, Lenore J} } @article {6027, title = {Genetic loci for retinal arteriolar microcirculation.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e65804}, abstract = {

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5{\texttimes}10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11{\texttimes}10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

}, keywords = {Aged, Aged, 80 and over, Arterioles, Chromosomes, Human, Pair 5, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Male, MEF2 Transcription Factors, Microcirculation, Middle Aged, Models, Genetic, Retinal Vessels}, issn = {1932-6203}, doi = {10.1371/journal.pone.0065804}, author = {Sim, Xueling and Jensen, Richard A and Ikram, M Kamran and Cotch, Mary Frances and Li, Xiaohui and Macgregor, Stuart and Xie, Jing and Smith, Albert Vernon and Boerwinkle, Eric and Mitchell, Paul and Klein, Ronald and Klein, Barbara E K and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and de Jong, Paulus T V M and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Jonasson, Fridbert and Launer, Lenore J and Attia, John and Baird, Paul N and Harrap, Stephen and Holliday, Elizabeth G and Inouye, Michael and Rochtchina, Elena and Scott, Rodney J and Viswanathan, Ananth and Li, Guo and Smith, Nicholas L and Wiggins, Kerri L and Kuo, Jane Z and Taylor, Kent D and Hewitt, Alex W and Martin, Nicholas G and Montgomery, Grant W and Sun, Cong and Young, Terri L and Mackey, David A and van Zuydam, Natalie R and Doney, Alex S F and Palmer, Colin N A and Morris, Andrew D and Rotter, Jerome I and Tai, E Shyong and Gudnason, Vilmundur and Vingerling, Johannes R and Siscovick, David S and Wang, Jie Jin and Wong, Tien Y} } @article {6155, title = {Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.}, journal = {Circulation}, volume = {128}, year = {2013}, month = {2013 Sep 17}, pages = {1310-24}, abstract = {

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34\% to 50\%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2\%) of its variation.

METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5{\texttimes}10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7\% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.

CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

}, keywords = {Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Cardiovascular Diseases, Coronary Artery Disease, European Continental Ancestry Group, Female, Fibrinogen, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic Americans, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Risk Factors, Stroke, Venous Thromboembolism, Young Adult}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.113.002251}, author = {Sabater-Lleal, Maria and Huang, Jie and Chasman, Daniel and Naitza, Silvia and Dehghan, Abbas and Johnson, Andrew D and Teumer, Alexander and Reiner, Alex P and Folkersen, Lasse and Basu, Saonli and Rudnicka, Alicja R and Trompet, Stella and M{\"a}larstig, Anders and Baumert, Jens and Bis, Joshua C and Guo, Xiuqing and Hottenga, Jouke J and Shin, So-Youn and Lopez, Lorna M and Lahti, Jari and Tanaka, Toshiko and Yanek, Lisa R and Oudot-Mellakh, Tiphaine and Wilson, James F and Navarro, Pau and Huffman, Jennifer E and Zemunik, Tatijana and Redline, Susan and Mehra, Reena and Pulanic, Drazen and Rudan, Igor and Wright, Alan F and Kolcic, Ivana and Polasek, Ozren and Wild, Sarah H and Campbell, Harry and Curb, J David and Wallace, Robert and Liu, Simin and Eaton, Charles B and Becker, Diane M and Becker, Lewis C and Bandinelli, Stefania and R{\"a}ikk{\"o}nen, Katri and Widen, Elisabeth and Palotie, Aarno and Fornage, Myriam and Green, David and Gross, Myron and Davies, Gail and Harris, Sarah E and Liewald, David C and Starr, John M and Williams, Frances M K and Grant, Peter J and Spector, Timothy D and Strawbridge, Rona J and Silveira, Angela and Sennblad, Bengt and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Hofman, Albert and van Dongen, Jenny and Willemsen, Gonneke and Boomsma, Dorret I and Yao, Jie and Swords Jenny, Nancy and Haritunians, Talin and McKnight, Barbara and Lumley, Thomas and Taylor, Kent D and Rotter, Jerome I and Psaty, Bruce M and Peters, Annette and Gieger, Christian and Illig, Thomas and Grotevendt, Anne and Homuth, Georg and V{\"o}lzke, Henry and Kocher, Thomas and Goel, Anuj and Franzosi, Maria Grazia and Seedorf, Udo and Clarke, Robert and Steri, Maristella and Tarasov, Kirill V and Sanna, Serena and Schlessinger, David and Stott, David J and Sattar, Naveed and Buckley, Brendan M and Rumley, Ann and Lowe, Gordon D and McArdle, Wendy L and Chen, Ming-Huei and Tofler, Geoffrey H and Song, Jaejoon and Boerwinkle, Eric and Folsom, Aaron R and Rose, Lynda M and Franco-Cereceda, Anders and Teichert, Martina and Ikram, M Arfan and Mosley, Thomas H and Bevan, Steve and Dichgans, Martin and Rothwell, Peter M and Sudlow, Cathie L M and Hopewell, Jemma C and Chambers, John C and Saleheen, Danish and Kooner, Jaspal S and Danesh, John and Nelson, Christopher P and Erdmann, Jeanette and Reilly, Muredach P and Kathiresan, Sekar and Schunkert, Heribert and Morange, Pierre-Emmanuel and Ferrucci, Luigi and Eriksson, Johan G and Jacobs, David and Deary, Ian J and Soranzo, Nicole and Witteman, Jacqueline C M and de Geus, Eco J C and Tracy, Russell P and Hayward, Caroline and Koenig, Wolfgang and Cucca, Francesco and Jukema, J Wouter and Eriksson, Per and Seshadri, Sudha and Markus, Hugh S and Watkins, Hugh and Samani, Nilesh J and Wallaschofski, Henri and Smith, Nicholas L and Tregouet, David and Ridker, Paul M and Tang, Weihong and Strachan, David P and Hamsten, Anders and O{\textquoteright}Donnell, Christopher J} } @article {6548, title = {Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e99798}, abstract = {

BACKGROUND: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.

METHODS AND RESULTS: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] >= 1\%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF<= 1\% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).

CONCLUSION: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.

}, keywords = {Cell Adhesion Molecules, Neuronal, European Continental Ancestry Group, Female, Genetic Association Studies, Genetic Heterogeneity, Humans, Introns, Ischemia, Male, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies, Sequence Analysis, DNA}, issn = {1932-6203}, doi = {10.1371/journal.pone.0099798}, author = {Bis, Joshua C and DeStefano, Anita and Liu, Xiaoming and Brody, Jennifer A and Choi, Seung Hoan and Verhaaren, Benjamin F J and Debette, Stephanie and Ikram, M Arfan and Shahar, Eyal and Butler, Kenneth R and Gottesman, Rebecca F and Muzny, Donna and Kovar, Christie L and Psaty, Bruce M and Hofman, Albert and Lumley, Thomas and Gupta, Mayetri and Wolf, Philip A and van Duijn, Cornelia and Gibbs, Richard A and Mosley, Thomas H and Longstreth, W T and Boerwinkle, Eric and Seshadri, Sudha and Fornage, Myriam} } @article {6220, title = {Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.}, journal = {Stroke}, volume = {45}, year = {2014}, month = {2014 Feb}, pages = {403-12}, abstract = {

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged >=55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.

RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3{\texttimes}10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7{\texttimes}10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).

CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Area Under Curve, Case-Control Studies, Cohort Studies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Regression Analysis, Risk Factors, ROC Curve, Sex Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.113.003044}, author = {Ibrahim-Verbaas, Carla A and Fornage, Myriam and Bis, Joshua C and Choi, Seung Hoan and Psaty, Bruce M and Meigs, James B and Rao, Madhu and Nalls, Mike and Fontes, Jo{\~a}o D and O{\textquoteright}Donnell, Christopher J and Kathiresan, Sekar and Ehret, Georg B and Fox, Caroline S and Malik, Rainer and Dichgans, Martin and Schmidt, Helena and Lahti, Jari and Heckbert, Susan R and Lumley, Thomas and Rice, Kenneth and Rotter, Jerome I and Taylor, Kent D and Folsom, Aaron R and Boerwinkle, Eric and Rosamond, Wayne D and Shahar, Eyal and Gottesman, Rebecca F and Koudstaal, Peter J and Amin, Najaf and Wieberdink, Renske G and Dehghan, Abbas and Hofman, Albert and Uitterlinden, Andr{\'e} G and DeStefano, Anita L and Debette, Stephanie and Xue, Luting and Beiser, Alexa and Wolf, Philip A and DeCarli, Charles and Ikram, M Arfan and Seshadri, Sudha and Mosley, Thomas H and Longstreth, W T and van Duijn, Cornelia M and Launer, Lenore J} } @article {6875, title = {Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0140496}, abstract = {

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.

METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).

RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0{\texttimes}10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction >= 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

}, keywords = {African Americans, Aged, Antihypertensive Agents, Cardiovascular Diseases, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Hypertension, Incidence, Male, Middle Aged, Polymorphism, Single Nucleotide, Treatment Outcome}, issn = {1932-6203}, doi = {10.1371/journal.pone.0140496}, author = {Bis, Joshua C and Sitlani, Colleen and Irvin, Ryan and Avery, Christy L and Smith, Albert Vernon and Sun, Fangui and Evans, Daniel S and Musani, Solomon K and Li, Xiaohui and Trompet, Stella and Krijthe, Bouwe P and Harris, Tamara B and Quibrera, P Miguel and Brody, Jennifer A and Demissie, Serkalem and Davis, Barry R and Wiggins, Kerri L and Tranah, Gregory J and Lange, Leslie A and Sotoodehnia, Nona and Stott, David J and Franco, Oscar H and Launer, Lenore J and St{\"u}rmer, Til and Taylor, Kent D and Cupples, L Adrienne and Eckfeldt, John H and Smith, Nicholas L and Liu, Yongmei and Wilson, James G and Heckbert, Susan R and Buckley, Brendan M and Ikram, M Arfan and Boerwinkle, Eric and Chen, Yii-Der Ida and de Craen, Anton J M and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Ford, Ian and Hofman, Albert and Sattar, Naveed and Slagboom, P Eline and Westendorp, Rudi G J and Gudnason, Vilmundur and Vasan, Ramachandran S and Lumley, Thomas and Cummings, Steven R and Taylor, Herman A and Post, Wendy and Jukema, J Wouter and Stricker, Bruno H and Whitsel, Eric A and Psaty, Bruce M and Arnett, Donna} }