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. 2021 Feb 1;11(1):2710.
doi: 10.1038/s41598-021-81854-9.

Association of SLC6A4 methylation with long-term outcomes after stroke: focus on the interaction with suicidal ideation

Hee-Ju Kang  1 , Eun-Hye Lee  1 , Ju-Wan Kim  1 , Sung-Wan Kim  1 , Il-Seon Shin  1 , Joon-Tae Kim  2 , Man-Seok Park  2 , Ki-Hyun Cho  2 , Jung-Soo Han  3 , In Kyoon Lyoo  4 , Jae-Min Kim  5
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Association of SLC6A4 methylation with long-term outcomes after stroke: focus on the interaction with suicidal ideation

Hee-Ju Kang et al. Sci Rep. .

Abstract

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Study outline and participant recruitment process.
Figure 2
Figure 2
Association of the average SLC6A4 methylation value with the cumulative incidence (%) of composite cerebro-cardiovascular events, stratified by SI status immediately after stroke (within 2 weeks). Cox proportional hazards models were used for analyses of the overall cohort, and for analyses stratified by SI after adjustment for age, NIHSS score, previous history of stroke, presence of cardiac disease, and depression (according to the DSM-IV criteria) within 2 weeks after stroke. The interaction effect between average SLC6A4 methylation value and SI on composite CCVEs was not significant (p = 0.113). Abbreviations: SI, suicidal ideation; NIHSS, National Institutes of Health Stroke Scale; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition.
Figure 3
Figure 3
Association of the methylation status of CpG 4 with the cumulative incidence (%) of composite cerebro-cardiovascular events, stratified by SI status immediately after stroke (within 2 weeks). Cox proportional hazards models were used for analyses of the overall cohort, and for analyses stratified by SI after adjustment for age, NIHSS score, previous history of stroke, presence of cardiac disease, and depression (according to the DSM-IV criteria) within 2 weeks after stroke. The interaction effect between methylation status of CpG 4 and SI on composite CCVEs was significant (p = 0.012).
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