Genetic variations in the p11/tPA/BDNF pathway are associated with post stroke depression

Background: The effects of BDNF on post stroke depression (PSD) may be influenced by genetic variations in intracellular signal transduction pathways, such as the p11/tPA/BDNF pathway. In this study, we aimed to determine the association of polymorphisms in candidate genes of the gene transduction pathway with PSD, as well as the effects of the interactions between genes in our Chinese sample.

Methods: Two-hundred-fifty-four Chinese samples with acute ischaemic stroke included 122 PSD patients and 132 nonPSD patients. Sixty-five single nucleotide polymorphisms (SNPs) in six genes (p11, tPA, PAI-1, BDNF, TrkB and p75NTR) of the p11/tPA/BDNF pathway with minor allele frequencies > 5% were successfully genotyped from an initial series of 76 SNPs. The severity of depressive symptoms was assessed by the 17-item Hamilton Depression Rating scale score. Environmental factors were measured with the life events scale and social support rating scale for all patients. SNP and haplotype associations were analysed using gPLINK software. Gene-gene interactions were evaluated with generalized multifactor dimensionality reduction software.

Results: The results showed that TrkB polymorphisms (rs11140793AC genotype, rs7047042CG genotype, rs1221CT genotype, rs2277193TC genotype and rs2277192AG genotype) were significantly associated with PSD. Three haplotypes (AT, GG, and AAT) of TrkB were significantly associated with PSD. Seven haplotypes (GC, AG, ACG, CGC, GCT, ACGC and ACAT) of BDNF were significantly correlated with PSD. We identified significant gene-gene interactions between the p11 (rs11204922 SNP), tPA (rs8178895, rs2020918 SNPs) and BDNF (rs6265, rs2049046, rs16917271, rs727155 SNPs) genes in the PSD group. We also identified significant gene-gene interactions between the BDNF (rs2049046, rs7931247 SNPs) and TrkB (rs7816 SNP) genes with increased occurrence of PSD and sig gene-gene interactions between the BDNF gene (rs6265, rs56164415, rs2049046, rs4923468, rs2883187, rs16917271, rs1491850, rs727155, rs2049048 SNPs) and p75NTR gene (rs2072446, rs11466155) in the PSD group.

Conclusion: These findings provides evidence that the TrkB gene, BDNF and TrkB haplotypes, and gene-gene interactions between p11, tPA and BDNF are all associated with PSD, which suggests that genetic variations in the p11/tPA/BDNF pathway may play a central role in regulating the underlying mechanism of PSD.