BDNF Val66Met polymorphism is associated with HPA axis reactivity to psychological stress characterized by genotype and gender interactions

Idan Shalev, Elad Lerer, Salomon Israel, Florina Uzefovsky, Inga Gritsenko, David Mankuta, Richard P. Ebstein, Marsha Kaitz

Research output: Contribution to journalArticlepeer-review

156 Scopus citations


Background: A key protein in maintaining neuronal integrity throughout the life span is brain-derived neurotrophic factor (BDNF). The BDNF gene is characterized by a functional polymorphism, which has been associated with stress-related disorders such as anxiety-related syndromes and depression, prompting us to examine individual responses by Genotype and Sex to a standardized social stress paradigm. Gender differences in BDNF × stress responses were posited because estrogen induces synthesis of BDNF in several brain regions. Methods: 97 university students (51 females and 46 males) participated in a social stress procedure (Trier Social Stress Test, TSST). Indices of stress were derived from repeated measurement of cortisol, blood pressure, and heart rate during the TSST. All subjects were genotyped for the Val66Met polymorphism. Results: Tests of within-subject effects showed a significant three-way interaction (SPSS GLM repeated measures: Time (eight levels) × BDNF (val/val, val/met) × Sex: p = 0.0002), which reflects gender differences in the pattern of cortisol rise and decline during the social challenge. In male subjects, val/val homozygotes showed a greater rise in salivary cortisol than val/met heterozygotes. In female subjects, there was a trend for the opposite response, which is significant when area under the curve increase (AUCi) was calculated for the val/val homozygotes to show the lowest rise. Overall, the same pattern of results was observed for blood pressure and heart rate. Conclusions: These results indicate that a common, functionally significant polymorphism in the BDNF gene modulates HPA axis reactivity and regulation during the TSST differently in men and women. Findings may be related to gender differences in reactivity and vulnerability to social stress.

Original languageEnglish
Pages (from-to)382-388
Number of pages7
Issue number3
StatePublished - 1 Apr 2009
Externally publishedYes


  • Brain-derived neurotrophic factor (BDNF)
  • Gender differences
  • Polymorphism
  • Salivary cortisol
  • Trier Social Stress Test

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Psychiatry and Mental health
  • Biological Psychiatry


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