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      Circulating Brain‐Derived Neurotrophic Factor Concentrations and the Risk of Cardiovascular Disease in the Community

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          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).

          Methods and 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).

          Conclusion

          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.

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          Most cited references 21

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          An investigation of coronary heart disease in families. The Framingham offspring study.

          The Framingham Heart Study (FHS) was started in 1948 as a prospective investigation of cardiovascular disease in a cohort of adult men and women. Continuous surveillance of this sample of 5209 subjects has been maintained through biennial physical examinations. In 1971 examinations were begun on the children of the FHS cohort. This study, called the Framingham Offspring Study (FOS), was undertaken to expand upon knowledge of cardiovascular disease, particularly in the area of familial clustering of the disease and its risk factors. This report reviews the sampling design of the FHS and describes the nature of the FOS sample. The FOS families appear to be of typical size and age structure for families with parents born in the late 19th or early 20th century. In addition, there is little evidence that coronary heart disease (CHD) experience and CHD risk factors differ in parents of those who volunteered for this study and the parents of those who did not volunteer.
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            BDNF regulates eating behavior and locomotor activity in mice.

            Brain-derived neurotrophic factor (BDNF) was studied initially for its role in sensory neuron development. Ablation of this gene in mice leads to death shortly after birth, and abnormalities have been found in both the peripheral and central nervous systems. BDNF and its tyrosine kinase receptor, TrkB, are expressed in hypothalamic nuclei associated with satiety and locomotor activity. In heterozygous mice, BDNF gene expression is reduced and we find that all heterozygous mice exhibit abnormalities in eating behavior or locomotor activity. We also observe this phenotype in independently derived inbred and hybrid BDNF mutant strains. Infusion with BDNF or NT4/5 can transiently reverse the eating behavior and obesity. Thus, we identify a novel non-neurotrophic function for neurotrophins and indicate a role in behavior that is remarkably sensitive to alterations in BDNF activity.
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              Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study.

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                Author and article information

                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                ahaoa
                jah3
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                Blackwell Publishing Ltd
                2047-9980
                March 2015
                11 March 2015
                : 4
                : 3
                Affiliations
                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.)
                Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.R.P., A.S.B., Q.Y.)
                Institute of Epidemiology, Christian‐Albrechts‐University, Kiel, Germany (W.L.)
                Department of Neurology, Boston University School of Medicine, Boston, MA (A.S.B., S.S.)
                Sections of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, MA (T.C.C.)
                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.)
                Sections of Preventive Medicine and Epidemiology and Cardiology, Boston University School of Medicine, Boston, MA (R.S.V.)
                Author notes
                Correspondence to: Ramachandran S. Vasan, MD, Framingham Heart Study, 73 Mt Wayte Ave, Suite 2, Framingham, MA 01702‐5803. E‐mail: vasan@ 123456bu.edu Bernhard M. Kaess, MD, Deutsches Herzzentrum München, Lazarettstr. 36, 80363 Munich, Germany. E‐mail: bernhard_kaess@ 123456gmx.de

                An accompanying Appendix S1, which list the members of the CARDIoGRAM Consortium is available at http://jaha.ahajournals.org/content/4/3/e001544/suppl/DC1

                Article
                jah3893
                10.1161/JAHA.114.001544
                4392437
                25762803
                © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Categories
                Original Research
                Epidemiology

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