title: Circulating brain-derived neurotrophic factor concentrations and the risk of cardiovascular disease in the community.
abstract: BACKGROUND
  Brain-derived neurotrophic factor (BDNF) is a pleiotropic peptide involved in maintaining endothelial integrity. It is unknown if circulating BDNF levels are associated with risk of cardiovascular disease (CVD).
  
  
  RESULTS
  We prospectively investigated the association of circulating BDNF levels with cardiovascular events and mortality in 3687 participants (mean age 65 years, 2068 women) from the Framingham Heart Study (FHS). Using a common nonsynonomous single nucleotide polymorphism (SNP) in the BDNF gene (rs6265), we then performed a Mendelian randomization experiment in the CARDIoGRAM (Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis) consortium (>22,000 coronary artery disease [CAD] cases, >60,000 controls) to investigate whether SNP rs6265 was associated with CAD in CARDIoGRAM and, if so, whether the effect estimate differed from that predicted based on FHS data. On follow-up (median 8.9 years), 467 individuals (261 women) in FHS experienced a CVD event, and 835 (430 women) died. In multivariable-adjusted Cox regression, serum BDNF was associated inversely with CVD risk (hazard ratio [HR] per 1-SD increase 0.88, 95% CI 0.80 to 0.97, P=0.01) and with mortality (HR 0.87, 95% CI 0.80 to 0.93, P=0.0002). SNP rs6265 was associated with BDNF concentrations (0.772 ng/mL increase per minor allele copy) in FHS. In CARDIoGRAM, SNP rs6265 was associated with CAD (odds ratio 0.957, 95% CI 0.923 to 0.992), a magnitude consistent with the predicted effect (HR per minor allele copy 0.99, 95% CI 0.98 to 1.0; P=0.06 for difference between predicted and observed effect).
  
  
  CONCLUSIONS
  Higher serum BDNF is associated with a decreased risk of CVD and mortality. Mendelian randomization suggests a causal protective role of BDNF in the pathogenesis of CVD.
authors.affiliation: National Heart, Blood, and Lung Institute's Framingham Heart Study, Framingham, MA (B.M.K., S.R.P., A.S.B., Q.Y., S.S., R.S.V.) Deutsches Herzzentrum München, Technische Universität München, Germany (B.M.K., C.H., H.S.) DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, München, Germany (B.M.K., C.H., H.S.).
authors.forename: Bernhard M
authors.initials: BM
authors.lastname: Kaess
authors.affiliation: National Heart, Blood, and Lung Institute's Framingham Heart Study, Framingham, MA (B.M.K., S.R.P., A.S.B., Q.Y., S.S., R.S.V.) Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.R.P., A.S.B., Q.Y.).
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Preis
authors.affiliation: Institute of Epidemiology, Christian-Albrechts-University, Kiel, Germany (W.L.).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: National Heart, Blood, and Lung Institute's Framingham Heart Study, Framingham, MA (B.M.K., S.R.P., A.S.B., Q.Y., S.S., R.S.V.) Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.R.P., A.S.B., Q.Y.) Department of Neurology, Boston University School of Medicine, Boston, MA (A.S.B., S.S.).
authors.forename: Alexa S
authors.initials: AS
authors.lastname: Beiser
authors.affiliation: National Heart, Blood, and Lung Institute's Framingham Heart Study, Framingham, MA (B.M.K., S.R.P., A.S.B., Q.Y., S.S., R.S.V.) Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.R.P., A.S.B., Q.Y.).
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Sections of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, MA (T.C.C.).
authors.forename: Tai C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Deutsches Herzzentrum München, Technische Universität München, Germany (B.M.K., C.H., H.S.) DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, München, Germany (B.M.K., C.H., H.S.).
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.affiliation: Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Germany (J.E.) DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany (J.E.).
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.affiliation: Deutsches Herzzentrum München, Technische Universität München, Germany (B.M.K., C.H., H.S.) DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, München, Germany (B.M.K., C.H., H.S.).
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.affiliation: National Heart, Blood, and Lung Institute's Framingham Heart Study, Framingham, MA (B.M.K., S.R.P., A.S.B., Q.Y., S.S., R.S.V.) Department of Neurology, Boston University School of Medicine, Boston, MA (A.S.B., S.S.).
authors.forename: Sudha
authors.initials: S
authors.lastname: Seshadri
authors.affiliation: National Heart, Blood, and Lung Institute's Framingham Heart Study, Framingham, MA (B.M.K., S.R.P., A.S.B., Q.Y., S.S., R.S.V.) Sections of Preventive Medicine and Epidemiology and Cardiology, Boston University School of Medicine, Boston, MA (R.S.V.).
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Themistocles L
authors.initials: TL
authors.lastname: Assimes
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Hilma
authors.initials: H
authors.lastname: Holm
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Inke R
authors.initials: IR
authors.lastname: König
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.forename: Robert
authors.initials: R
authors.lastname: Roberts
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood* / Q000235:genetics; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics / Q000401:mortality; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D016014:Linear Models; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D008875:Middle Aged; D015999:Multivariate Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D065840:Protective Factors; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; C579455:BDNF protein, human
keywords: Mendelian randomization; cardiovascular disease; growth factors; mortality; risk factors