Brain-derived neurotrophic factor rs6265 (Val66Met) single nucleotide polymorphism as a master modifier of human pathophysiology

Brain-derived neurotrophic factor is the most prevalent member of the nerve growth factor family. Since its discovery in 1978, this enigmatic molecule has spawned more than 27,000 publications, most of which are focused on neurological disorders. Brain-derived neurotrophic factor is indispensable during embryogenesis and postnatally for the normal development and function of both the central and peripheral nervous systems. It is becoming increasingly clear, however, that brain-derived neurotrophic factor likewise plays crucial roles in a variety of other biological functions independently of sympathetic or parasympathetic involvement. Brain-derived neurotrophic factor is also increasingly recognized as a sophisticated environmental sensor and master coordinator of whole organismal physiology. To that point, we recently found that a common nonsynonymous (Val66→Met) single nucleotide polymorphism in the brain-derived neurotrophic factor gene (rs6265) not only substantially alters basal cardiac transcriptomics in mice but subtly influences heart gene expression and function differentially in males and females. In addition to a short description of recent results from associative neuropsychiatric studies, this review provides an eclectic assortment of research reports that support a modulatory role for rs6265 including and beyond the central nervous system.