JOSE EDUARDO KRIEGER

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Departamento de Cardio-Pneumologia, Faculdade de Medicina - Docente
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder

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  • article 24 Citação(ões) na Scopus
    CYP2C9 and VKORC1 Polymorphisms Are Differently Distributed in the Brazilian Population According to Self-Declared Ethnicity or Genetic Ancestry
    (2012) SOARES, Renata Alonso Gadi; SANTOS, Paulo Caleb Junior Lima; MACHADO-COELHO, George Luiz Lins; NASCIMENTO, Raimundo Marques do; MILL, Jose Geraldo; KRIEGER, Jose Eduardo; PEREIRA, Alexandre Costa
    Background: Warfarin-dosing pharmacogenetic algorithms have presented different performances across ethnicities, and the impact in admixed populations is not fully known. Aims: To evaluate the CYP2C9 and VKORC1 polymorphisms and warfarin-predicted metabolic phenotypes according to both self-declared ethnicity and genetic ancestry in a Brazilian general population plus Amerindian groups. Methods: Two hundred twenty-two Amerindians (Tupinikin and Guarani) were enrolled and 1038 individuals from the Brazilian general population who were self-declared as White, Intermediate (Brown, Pardo in Portuguese), or Black. Samples of 274 Brazilian subjects from Sao Paulo were analyzed for genetic ancestry using an Affymetrix 6.0 (R) genotyping platform. The CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), and VKORC1 g.-1639G>A (rs9923231) polymorphisms were genotyped in all studied individuals. Results: The allelic frequency for the VKORC1 polymorphism was differently distributed according to self-declared ethnicity: White (50.5%), Intermediate (46.0%), Black (39.3%), Tupinikin (40.1%), and Guarani (37.3%) (p < 0.001), respectively. The frequency of intermediate plus poor metabolizers (IM + PM) was higher in White (28.3%) than in Intermediate (22.7%), Black (20.5%), Tupinikin (12.9%), and Guarani (5.3%), (p < 0.001). For the samples with determined ancestry, subjects carrying the GG genotype for the VKORC1 had higher African ancestry and lower European ancestry (0.14 +/- 0.02 and 0.62 +/- 0.02) than in subjects carrying AA (0.05 +/- 0.01 and 0.73 +/- 0.03) (p = 0.009 and 0.03, respectively). Subjects classified as IM + PM had lower African ancestry (0.08 +/- 0.01) than extensive metabolizers (0.12 +/- 0.01) (p = 0.02). Conclusions: The CYP2C9 and VKORC1 polymorphisms are differently distributed according to self-declared ethnicity or genetic ancestry in the Brazilian general population plus Amerindians. This information is an initial step toward clinical pharmacogenetic implementation, and it could be very useful in strategic planning aiming at an individual therapeutic approach and an adverse drug effect profile prediction in an admixed population.
  • article 9 Citação(ões) na Scopus
    Screening of ABCG5 and ABCG8 Genes for Sitosterolemia in a Familial Hypercholesterolemia Cascade Screening Program
    (2022) TADA, Mauricio Teruo; ROCHA, Viviane Zorzanelli; LIMA, Isabella Ramos; OLIVEIRA, Theo Gremen Mimary; CHACRA, Ana Paula; MINAME, Marcio Hiroshi; NUNES, Valeria Sutti; NAKANDAKARE, Edna Regina; CASTELO, Maria Helane Costa Gurgel; JANNES, Cinthia Elim; SANTOS, Raul D.; KRIEGER, Jose Eduardo; PEREIRA, Alexandre Costa
    Background: Sitosterolemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants in ABCG5/ABCG8. The disease is characterized by increased plasma plant sterols. Small case series suggest that patients with sitosterolemia have wide phenotypic heterogeneity with great variability on either plasma cholesterol levels or development of atherosclerotic cardiovascular disease. The present study aims to characterize the prevalence and clinical features of sitosterolemia participating in a familial hypercholesterolemia genetic cascade screening program. Methods: From 443 familial hypercholesterolemia index cases, 260 were negative for familial hypercholesterolemia genes and were sequenced for the ABCG5/8 genes. Clinical and laboratory characteristics of affected individuals were determined. Results: Eight (3.1%) index cases were found to be homozygous or compound heterozygous variant for ABCG5/ABCG8 genes, confirming the genetic diagnosis of sitosterolemia. Screening their relatives led to the identification of 6 additional confirmed sitosterolemia cases (3 homozygous and 3 compound heterozygous variant) and 18 carriers (heterozygous). The mean age of identified sitosterolemia cases (n=14) was 37.2 +/- 19.8 years, 50% were females, and 78.6% (all adults) presented either clinical or subclinical atherosclerotic cardiovascular disease. As expected, affected individuals presented elevated plasma plant sterol levels (mean beta-Sitosterol and campesterol, respectively, 160.3 +/- 107.1 and 32.0 +/- 19.6 mu g/mL) and the highest plasma LDL (low-density lipoprotein)-cholesterol was 269.0 +/- 120.0 mg/dL (range: 122-521 mg/dL). LDL-cholesterol mean reduction with therapy among cases was 65%. Eighty-three percent (83%) of identified sitosterolemia patients presented hematologic abnormalities. Conclusions: Testing genes associated with sitosterolemia in the molecular routine workflow of a familial hypercholesterolemia cascade screening program allowed the precise diagnosis of sitosterolemia in a substantial number of patients with varying LDL-C levels and high incidence of early atherosclerotic cardiovascular disease and hematologic abnormalities.
  • article 12 Citação(ões) na Scopus
    Heritability of arterial stiffness in a Brazilian population: Baependi Heart Study
    (2017) ALVIM, Rafael O.; HORIMOTO, Andrea R. V. R.; OLIVEIRA, Camila M.; BORTOLOTTO, Luiz A.; KRIEGER, Jose E.; PEREIRA, Alexandre C.
    Background: Increased arterial stiffness is an important determinant of cardiovascular disease risk. In addition, it has been recognized that arterial stiffness has familial aggregation; however, there are no studies involving Brazilian families. Thus, the aim of this study was to evaluate the heritability of arterial stiffness in a Brazilian population. Methods: In this study, 1675 eligible individuals (both sexes and aged 18-102 years) were distributed in 125 families resident in the municipality of Baependi, a city located in the southeast of Brazil. Carotid-femoral pulse wave velocity (PWV) was measured with a noninvasive automatic device (Complior; Artech Medical, Pantin, France). Variance component approaches, implemented in the SOLAR computer package (San Antonio, Texas, USA), were applied to estimate the heritability of the studied phenotype under different statistical models. Results: Heritability estimates for carotid-femoral PWV stratified by age ranging from 11 to 35% (higher in individuals aged <= 45 years and lower in individuals aged 18-102 years). Age and hypertension showed significant effects on the PWV trait and significantly affect heritability estimates in all models. Conclusion: We conclude that the heritability of carotid-femoral PWV in a Brazilian population is intermediate, and therefore genetic studies evolving arterial stiffness phenotypes should be encouraged.
  • article 66 Citação(ões) na Scopus
    Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats
    (2012) LUZ, Protasio L. da; TANAKA, Leonardo; BRUM, Patricia Chakur; DOURADO, Paulo Magno Martins; FAVARATO, Desiderio; KRIEGER, Jose Eduardo; LAURINDO, Francisco Rafael M.
    Objective: To investigate, in male Wistar rats, the effects of long-term moderate red wine (RW) consumption (equivalent to similar to 0.15 mg% resveratrol RS), or RS in low (L, 0.15 mg%) or high (H, 400 mg%) doses in chow. Background: Both RW and RS exhibit cardioprotection. RS extends lifespan in obese rats. It is unclear whether RW consumption or low-dose RS delay vascular aging and prolong life span in the absence of overt risk factors. Methods: Endpoints were aerobic performance, exercise capacity, aging biomarkers (p53,p16,p21, telomere length and telomerase activity in aortic homogenates), vascular reactivity. Data were compared with controls (C) given regular chow. Results: Expressions of p53 decreased similar to 50% similar to with RW and LRS (p < 0.05 vs. C), p16 by similar to 29% with RW (p < 0.05 vs. C) and p21 was unaltered. RW and LRS increased telomere length >6.5-fold vs. C, and telomerase activity increased with LRS and HRS. All treatments increased aerobic capacity (C 32.5 +/- 1.2, RW 38.7 + 1.7, LRS 38.5 + 1.6, HRS 38.3 + 1.8 mlO2 min(-1) kg(-1)), and RW or LRS also improved time of exercise tolerance vs. C (p < 0.05). Endothelium-dependent relaxation improved with all treatments vs. C. Life span, however, was unaltered with each treatment vs. C = 673 +/- 30 days, p = NS. Conclusions: RW and LRS can preserve vascular function indexes in normal rats, although not extending life span. These effects were translated into better aerobic performance and exercise capacity.
  • article 9 Citação(ões) na Scopus
    Evaluation of the applicability and effectiveness of a molecular strategy for identifying weakD and DEL phenotype among D- blood donors of mixed origin exhibiting high frequency of RHD*
    (2018) DEZAN, Marcia Regina; GUARDALINI, Luis Giovani O.; PESSOA, Elaine; RIBEIRO, Ingrid Helena; OLIVEIRA, Valeria Brito; LUZ, Fabio; NOVAC, Denise Rossite; GALLUCCI, Antonio; BONIFACIO, Silvia; GOMES, Francisco; LEVI, Jose E.; PEREIRA, Alexandre C.; KRIEGER, Jose E.; MENDRONE-JUNIOR, Alfredo; ROCHA, Vanderson; DINARDO, Carla Luana
    BACKGROUNDMolecular tests designed to detect the presence of active RHD gene among D- donors have been successfully applied in people of European ancestry, but not in admixed populations with a considerable frequency of RHD*. Our goal was to evaluate the performance of a molecular screening tool for identifying active RHD alleles among Brazilian blood donors classified as D- C+ and/or E+. STUDY DESIGN AND METHODSPools of five DNA samples of serologically D- C+ and/or E+ donors were checked by a RHD polymerase chain reaction (PCR) assay specific for RHD Intron 4 and Exon 7. When a pool result was positive, samples were genotyped individually for RHD Intron 4 and Exon 7, RHD*, RHCE*Cc, and RHD zygosity. Donors suspected of active RHD gene were further evaluated by whole-coding region and flanking intron direct sequencing. RESULTSA total of 405 donors were included. Two percent exhibited active RHD gene, codifying D-weak (38 and 45) or DEL phenotype. The most prevalent DEL allele was RHD*DEL1 (c.1227G>A), which is proven to be immunogenic. A high frequency of RHD* was detected in the donors with nondeleted RHD alleles (31%), far superior to the frequency of RHD variant alleles (15.5%). The proposed approach presented sensitivity of 100% and specificity of 85.7% for identifying active RHD gene. CONCLUSIONThe strategy of checking D- donors with RHD PCR followed by exclusion of RHD* allele has proved efficient in identifying weak-D and DEL phenotype in the Brazilian population.
  • article 19 Citação(ões) na Scopus
    Temporal trends in the contribution of Chagas cardiomyopathy to mortality among patients with heart failure
    (2018) NADRUZ, Wilson; GIOLI-PEREIRA, Luciana; BERNARDEZ-PEREIRA, Sabrina; MARCONDES-BRAGA, Fabiana G.; FERNANDES-SILVA, Miguel M.; SILVESTRE, Odilson M.; SPOSITO, Andrei C.; RIBEIRO, Antonio L.; BACAL, Fernando; FERNANDES, Fabio; KRIEGER, Jose E.; MANSUR, Alfredo J.; PEREIRA, Alexandre C.
    Background Chagas cardiomyopathy (ChC) prevalence is decreasing in Brazil and medical therapies for heart failure (HF) have improved in the last decade. Whether these changes modified the prognosis of ChC relative to non-Chagas cardiomyopathies (NChC) remains unknown. This study evaluated the temporal trends in population attributable risk (PAR) of ChC for 2-year mortality among patients with HF enrolled at years 2002-2004 (era 1) and 2012-2014 (era 2) in a Brazilian university hospital. Methods We prospectively studied 362 (15% with ChC) and 582 (18% with ChC) HF patients with ejection fraction <= 50% in eras 1 and 2, respectively and estimated the PAR of ChC for 2-year mortality. Results There were 145 deaths (29 in ChC) in era 1 and 85 deaths (26 in ChC) in era 2. In multivariable Cox-regression analysis adjusted for age, sex, ejection fraction, heart rate, body mass index, hypertension, diabetes mellitus, systolic blood pressure and ischaemic/valvar aetiology, ChC was associated with higher risk of death in era 1 (HR (95% CI)=1.92 (1.00 to 3.71), p=0.05) and era 2 (HR (95% CI)=3.51 (1.94 to 6.36), p<0.001). In fully adjusted analysis, the PAR of ChC for mortality increased twofold from era 1 (PAR (95% CI)=11.0 (2.8 to 18.5)%) to era 2 (PAR (95% CI)=21.9 (16.5 to 26.9)%; p=0.023 versus era 1). Conclusion Although the absolute death rates decreased over time in the ChC and NChC groups, the PAR of ChC for mortality increased among patients with HF, driven by increases in the HR associated with ChC. Our results highlight the need for additional efforts aiming to prevent and treat ChC.
  • article 7 Citação(ões) na Scopus
    Glycemic control and arterial stiffness in a Brazilian rural population: Baependi Heart Study
    (2015) ALVIM, Rafael de Oliveira; MOURAO-JUNIOR, Carlos Alberto; OLIVEIRA, Camila Maciel de; LIMA, Rerisson de Faria; HORIMOTO, Andrea Roseli Vancan Russo; HONG, Valeria Aparecida Costa; BORTOLOTTO, Luiz Aparecido; KRIEGER, Jose Eduardo; PEREIRA, Alexandre Costa
    Background: Increased arterial stiffness predicts morbidity and mortality, independently of other cardiovascular risk factors, and glycemic control impairments are related to higher vascular stiffness. The aim of this study was to evaluate the association between HbA1c levels and increased arterial stiffness in a Brazilian rural population. Methods: For this study were selected 1675 individuals (both genders and aged over 18 years) resident in the municipality of Baependi, a city located in the Southeast of Brazil. HbA1c levels were determined by HPLC. Pulse wave velocity (PWV) was measured with a non-invasive automatic device (Complior). Results: HbA1c levels were associated with an increased PWV. This was more relevant for the third tertile of age. In addition, logistic regression multivariate model including age, blood pressure, gender, BMI and fasting glucose showed that the elevation of a single unit percentage of HbA1c represented an increase of 54 % in the odds of increased arterial stiffness [OR 1.54 (95 % CI 1.01-2.17)]. Both, HbA1c and fasting glucose showed higher discriminatory power in the risk assessment for increased arterial stiffness in the non-diabetic when compared to the diabetic group (AUC of HbA1c = 0.71 vs 0.57, p = 0.02; AUC of fasting glucose = 0.66 vs 0.45, p = 0.0007, respectively). Conclusion: Our findings indicate that a increase in HbA1c levels is associated with increased arterial stiffness and that both, HbA1c and fasting glucose, presented higher discriminatory power in the risk assessment for increased arterial stiffness in the non-diabetic group as compared to diabetic individuals.
  • article 7 Citação(ões) na Scopus
    Genetic and ElectroNic medIcal records to predict oUtcomeS in Heart Failure patients (GENIUS-HF) - design and rationale
    (2014) GIOLI-PEREIRA, Luciana; BERNARDEZ-PEREIRA, Sabrina; MARCONDES-BRAGA, Fabiana Goulart; SPINA, Joceli Mabel Rocha; SILVA, Rafael Muniz Miranda da; FERREIRA, Noely Evangelista; BACAL, Fernando; FERNANDES, Fabio; MANSUR, Alfredo Jose; KRIEGER, Jose Eduardo; PEREIRA, Alexandre Costa
    Background: Studies adopting electronic medical records and genomic information are becoming widespread. Through this new modality in research, it is possible to study how genetic variants influence susceptibility towards chronic conditions and can improve patient care. Our aim is to develop a biobank with 2,000 heart failure patients treated in a tertiary cardiology hospital containing electronic medical records data and biologic samples for performing genome-wide association studies for validation and development of medical decision routines aimed at helping the clinical management of patients. Methods/Design: Patients between 18 and 80 years old with heart failure diagnosis of different etiologies and left ventricular ejection fraction <= 50% in the past 2 years will be eligible for enrollment on the cohort. After consent, patients will be submitted to clinical baseline, echocardiography, cardiograph impedance and biochemical evaluation. Study data will be collected and managed using Research Electronic Data Capture tools. The follow up will take place every 6 months to assess cardiovascular outcomes ( all-cause mortality, cardiovascular mortality, hospitalization for worsening heart failure and current medication use). Initial analytical strategy will focus on the establishment of the accuracy of electronic medical records extraction protocols for main predictor factors of morbidity and mortality in heart failure. Discussion: Building a biobank with biologic samples and clinical data of 2,000 heart failure patients we will perform genome- wide association studies. By this way, we pretend to study how genetic variants influence susceptibility towards chronic conditions. Besides, it will be created a working group focused on the development and implementation of algorithms for validation and application of medical routines using the electronic medical records of the Heart Institute (InCor - HCFMUSP).
  • article 2 Citação(ões) na Scopus
    Genome-wide association study for Chagas Cardiomyopathy identify a new risk locus on chromosome 18 associated with an immune-related protein and transcriptional signature
    (2022) SABINO, Ester Cerdeira; FRANCO, Lucas Augusto Moyses; VENTURINI, Gabriela; RODRIGUES, Mariliza Velho; MARQUES, Emanuelle; SILVA, Lea Campos de Oliveira-da; MARTINS, Larissa Natany Almeida; FERREIRA, Ariela Mota; ALMEIDA, Paulo Emilio Clementino; SILVA, Felipe Dias Da; LEITE, Samara Fernandes; NUNES, Maria do Carmo Pereira; HAIKAL, Desiree Sant'Ana; OLIVEIRA, Claudia Di Lorenzo; CARDOSO, Clareci Silva; SEIDMAN, Jonathan G.; SEIDMAN, Christine E.; CASAS, Juan P.; RIBEIRO, Antonio Luiz Pinho; KRIEGER, Jose E.; PEREIRA, Alexandre C.
    Background Chronic Chagas Cardiomyopathy (CCC) usually develops between 10 and 20 years after the first parasitic infection and is one of the leading causes of end-stage heart failure in Latin America. Despite the great inter-individual variability in CCC susceptibility (only 30% of infected individuals ever present CCC), there are no known predictors for disease development in those chronically infected. Methodology/Principal findings We describe a new susceptibility locus for CCC through a GWAS analysis in the SaMi-Trop cohort, a population-based study conducted in a Chagas endemic region from Brazil. This locus was also associated with CCC in the REDS II Study. The newly identified locus (rs34238187, OR 0.73, p-value 2.03 x 10(-9)) spans a haplotype of approximately 30Kb on chromosome 18 (chr18: 5028302-5057621) and is also associated with 80 different traits, most of them blood protein traits significantly enriched for immune-related biological pathways. Hi-C data show that the newly associated locus is able to interact with chromatin sites as far as 10Mb on chromosome 18 in a number of different cell types and tissues. Finally, we were able to confirm, at the tissue transcriptional level, the immune-associated blood protein signature using a multi-tissue differential gene expression and enrichment analysis. Conclusions/Significance We suggest that the newly identified locus impacts CCC risk among T cruzi infected individuals through the modulation of a downstream transcriptional and protein signature associated with host-parasite immune response. Functional characterization of the novel risk locus is warranted.
  • article 447 Citação(ões) na Scopus
    Multi-ethnic genome-wide association study for atrial fibrillation
    (2018) ROSELLI, Carolina; CHAFFIN, Mark D.; WENG, Lu-Chen; AESCHBACHER, Stefanie; AHLBERG, Gustav; ALBERT, Christine M.; ALMGREN, Peter; ALONSO, Alvaro; ANDERSON, Christopher D.; ARAGAM, Krishna G.; ARKING, Dan E.; BARNARD, John; BARTZ, Traci M.; BENJAMIN, Emelia J.; BIHLMEYER, Nathan A.; BIS, Joshua C.; BLOOM, Heather L.; BOERWINKLE, Eric; BOTTINGER, Erwin B.; BRODY, Jennifer A.; CALKINS, Hugh; CAMPBELL, Archie; CAPPOLA, Thomas P.; CARLQUIST, John; CHASMAN, Daniel I.; CHEN, Lin Y.; CHEN, Yii-Der Ida; CHOI, Eue-Keun; CHOI, Seung Hoan; CHRISTOPHERSEN, Ingrid E.; CHUNG, Mina K.; COLE, John W.; CONEN, David; COOK, James; CRIJNS, Harry J.; CUTLER, Michael J.; DAMRAUER, Scott M.; DANIELS, Brian R.; DARBAR, Dawood; DELGADO, Graciela; DENNY, Joshua C.; DICHGANS, Martin; DOERR, Marcus; DUDINK, Elton A.; DUDLEY, Samuel C.; ESA, Nada; ESKO, Tonu; ESKOLA, Markku; FATKIN, Diane; FELIX, Stephan B.; FORD, Ian; FRANCO, Oscar H.; GEELHOED, Bastiaan; GREWAL, Raji P.; GUDNASON, Vilmundur; GUO, Xiuqing; GUPTA, Namrata; GUSTAFSSON, Stefan; GUTMANN, Rebecca; HAMSTEN, Anders; HARRIS, Tamara B.; HAYWARD, Caroline; HECKBERT, Susan R.; HERNESNIEMI, Jussi; HOCKING, Lynne J.; HOFMAN, Albert; HORIMOTO, Andrea R. V. R.; HUANG, Jie; HUANG, Paul L.; HUFFMAN, Jennifer; INGELSSON, Erik; IPEK, Esra Gucuk; ITO, Kaoru; JIMENEZ-CONDE, Jordi; JOHNSON, Renee; JUKEMA, J. Wouter; KAEAEB, Stefan; KAHONEN, Mika; KAMATANI, Yoichiro; KANE, John P.; KASTRATI, Adnan; KATHIRESAN, Sekar; KATSCHNIG-WINTER, Petra; KAVOUSI, Maryam; KESSLER, Thorsten; KIETSELAER, Bas L.; KIRCHHOF, Paulus; KLEBER, Marcus E.; KNIGHT, Stacey; KRIEGER, Jose E.; KUBO, Michiaki; LAUNER, Lenore J.; LAURIKKA, Jari; LEHTIMAKI, Terho; LEINEWEBER, Kirsten; LEMAITRE, Rozenn N.; LI, Man; LIM, Hong Euy; LIN, Henry J.; LIN, Honghuang; LIND, Lars; LINDGREN, Cecilia M.; LOKKI, Marja-Liisa; LONDON, Barry; LOOS, Ruth J. F.; LOW, Siew-Kee; LU, Yingchang; LYYTIKAINEN, Leo-Pekka; MACFARLANE, Peter W.; MAGNUSSON, Patrik K.; MAHAJAN, Anubha; MALIK, Rainer; MANSUR, Alfredo J.; MARCUS, Gregory M.; MARGOLIN, Lauren; MARGULIES, Kenneth B.; MAERZ, Winfried; MCMANUS, David D.; MELANDER, Olle; MOHANTY, Sanghamitra; MONTGOMERY, Jay A.; MORLEY, Michael P.; MORRIS, Andrew P.; MUELLER-NURASYID, Martina; NATALE, Andrea; NAZARIAN, Saman; NEUMANN, Benjamin; NEWTON-CHEH, Christopher; NIEMEIJER, Maartje N.; NIKUS, Kjell; NILSSON, Peter; NOORDAM, Raymond; OELLERS, Heidi; OLESEN, Morten S.; ORHO-MELANDER, Marju; PADMANABHAN, Sandosh; PAK, Hui-Nam; PARE, Guillaume; PEDERSEN, Nancy L.; PERA, Joanna; PEREIRA, Alexandre; PORTEOUS, David; PSATY, Bruce M.; PULIT, Sara L.; PULLINGER, Clive R.; RADER, Daniel J.; REFSGAARD, Lena; RIBASES, Marta; RIDKER, Paul M.; RIENSTRA, Michiel; RISCH, Lorenz; RODEN, Dan M.; ROSAND, Jonathan; ROSENBERG, Michael A.; ROST, Natalia; ROTTER, Jerome I.; SABA, Samir; SANDHU, Roopinder K.; SCHNABEL, Renate B.; SCHRAMM, Katharina; SCHUNKERT, Heribert; SCHURMAN, Claudia; SCOTT, Stuart A.; SEPPALA, Ilkka; SHAFFER, Christian; SHAH, Svati; SHALABY, Alaa A.; SHIM, Jaemin; SHOEMAKER, M. Benjamin; SILAND, Joylene E.; SINISALO, Juha; SINNER, Moritz F.; SLOWIK, Agnieszka; SMITH, Albert V.; SMITH, Blair H.; SMITH, J. Gustav; SMITH, Jonathan D.; SMITH, Nicholas L.; SOLIMAN, Elsayed Z.; SOTOODEHNIA, Nona; STRICKER, Bruno H.; SUN, Albert; SUN, Han; SVENDSEN, Jesper H.; TANAKA, Toshihiro; TANRIVERDI, Kahraman; TAYLOR, Kent D.; TEDER-LAVING, Maris; TEUMER, Alexander; THERIAULT, Sebastien; TROMPET, Stella; TUCKER, Nathan R.; TVEIT, Arnljot; UITTERLINDEN, Andre G.; HARST, Pim Van Der; GELDER, Isabelle C. Van; WAGONER, David R. Van; VERWEIJ, Niek; VLACHOPOULOU, Efthymia; VOELKER, Uwe; WANG, Biqi; WEEKE, Peter E.; WEIJS, Bob; WEISS, Raul; WEISS, Stefan; WELLS, Quinn S.; WIGGINS, Kerri L.; WONG, Jorge A.; WOO, Daniel; WORRALL, Bradford B.; YANG, Pil-Sung; YAO, Jie; YONEDA, Zachary T.; ZELLER, Tanja; ZENG, Lingyao; LUBITZ, Steven A.; LUNETTA, Kathryn L.; ELLINOR, Patrick T.
    Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). 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.