Association of SLC6A4 Methylation with Long-term Outcomes After Stroke: Focus on the Interaction with Suicidal Ideation

Serotonin (5-HT) plays an important role in cerebrovascular homeostasis and psychiatric disorders, including suicidality. Methylation of the serotonin transporter gene (SLC6A4) is associated with 5-HT expression. However, the prognostic roles of SLC6A4 methylation and suicidal ideation (SI) in long-term outcomes of stroke have not been evaluated. We investigated the independent and interactive effects of SLC6A4 methylation and SI immediately after stroke on long-term outcomes. Blood SLC6A4 methylation status and SI based on the suicide item of the Montgomery-Åsberg Depression Rating Scale were assessed in 278 patients at 2 weeks after stroke. After the index stroke, cerebro-cardiovascular events by SLC6A4 methylation status and SI were investigated over an 8-14-year follow-up period and using Cox regression models adjusted for a range of covariates. SLC6A4 hypermethylation and SI within 2 weeks of stroke both predicted worse long-term outcomes, independent of covariates. A significant interaction effect of SI and the methylation status of CpG 4 on long-term stroke outcomes was also identified. The association between SLC6A4 methylation and long-term adverse outcomes may be strengthened in the presence of SI within 2 weeks after stroke. Evaluation of methylation and SI status during the acute phase can be helpful when assessing stroke patients.