Associations of BDNF genotype and promoter methylation with acute and long-term stroke outcomes in an East Asian cohort

Jae-Min Kim, Robert Stewart, Man-Seok Park, Hee-Ju Kang, Sung-Wan Kim, Il-Seon Shin, Hye-Ran Kim, Myung-Geun Shin, Ki-Hyun Cho, Jin-Sang Yoon, Jae-Min Kim, Robert Stewart, Man-Seok Park, Hee-Ju Kang, Sung-Wan Kim, Il-Seon Shin, Hye-Ran Kim, Myung-Geun Shin, Ki-Hyun Cho, Jin-Sang Yoon

Abstract

Background: Brain derived neurotrophic factor (BDNF) has been shown to play an important role in poststroke recovery. BDNF secretion is influenced by genetic and epigenetic profiles. This study aimed to investigate whether BDNF val66met polymorphism and promoter methylation status were associated with outcomes at two weeks and one year after stroke.

Methods and findings: A total of 286 patients were evaluated at the time of admission and two weeks after stroke, and 222 (78%) were followed one year later in order to evaluate consequences of stroke at both acute and chronic stages. Stroke outcomes were dichotomised into good and poor by the modified Rankin Scale. Stroke severity (National Institutes of Health Stroke Scale), physical disability (Barthel Index), and cognitive function (Mini-Mental State Examination) were measured. Associations of BDNF genotype and methylation status on stroke outcomes and assessment scale scores were investigated using logistic regression, repeated measures ANOVA and partial correlation tests. BDNF val66met polymorphism was independently associated with poor outcome at 2 weeks and at 1 year, and with worsening physical disability and cognitive function over that period. Higher BDNF promoter methylation status was independently associated with worse outcomes at 1 year, and with the worsening of physical disability and cognitive function. No significant genotype-methylation interactions were found.

Conclusions: A role for BDNF in poststroke recovery was supported, and clinical utility of BDNF genetic and epigenetic profile as prognostic biomarkers and a target for drug development was suggested.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. BDNF promoter regions for analyzing…
Figure 1. BDNF promoter regions for analyzing methylation status.
Of the CpG-rich region of BDNF promoter, the portion analyzed by bisulfite pyrosequencing is shown. The CpGs are in underlined and bold font and numbered. Forward and backward primers and sequencer are designated. Numbering of the gene sequence is relative to the transcriptional start site.
Figure 2. Comparing scores on stroke assessment…
Figure 2. Comparing scores on stroke assessment scales between groups of BDNF val66met polymorphism over time.
Repeated measures ANOVA demonstrating the following: For NIHSS, no group effect of genotype (p-value = 0.976) or group by time interaction (p-value = 0.259); For BI, no group effect of genotype (p-value = 0.985) but a significant group by time interaction (p-value = 0.003); For MMSE, no group effect of genotype (p-value = 0.826) but a significant group by time interaction (p-value = 0.035) after adjustment for age and Hamilton Depression Rating Scale score.

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