The association between serine hydroxymethyl transferase 1 gene hypermethylation and ischemic stroke

Abstract

This study aimed to determine the correlation between serine hydroxymethyl transferase 1 (SHMT1) gene methylation and ischemic stroke. A total of 202 age- and sex-matched individuals were included. Quantitative methylation-specific polymerase chain reaction (qMSP-PCR) was used to analyze the DNA methylation level. The plasma homocysteine (Hcy) concentration was much higher in ischemic cases than in controls (p = 0.009), while the high-density lipoprotein (HDL) levels in stroke cases were considerably lower than in controls (p = 0.005). A significantly higher level of SHMT1 methylation was observed in the ischemic strokes (58.82 ± 17.83%) compared to that in the controls (42.59 ± 20.76%, p < 0.001). The SHMT1 methylation level was strongly correlated with HDL concentration in the healthy controls (r = 0.517, p < 0.001), while the high plasma level of Hcy showed strong association with SHMT1 methylation in ischemic strokes (r = 0.346, p < 0.001). Receiver operating characteristic (ROC) analysis of curve indicated that SHMT1 methylation has been an acceptable indicator for ischemic stroke in female patients [all sexes, area under the curve (AUC) = 0.71, p < 0.001; male patients AUC = 0.62, p = 0.032; and female patients AUC = 0.79, p < 0.001] and in all ages (AUC = 0.71, p < 0.001). In our samples, DNA methylation levels of the STHMI gene were significantly correlated with ischemic stroke in Han Chinese. STHMI hypermethylation was significantly associated with the high Hcy concentration in ischemic stroke and had value as a potential indicator for female ischemic stroke.

FIGURE 1

Comparison of serine hydroxymethyl transferase 1 methylation (SHMT1) levels between cases and controls in male and female. (A) All groups, ischemic stroke versus controls: 58.82 ± 17.83 versus 42.59 ± 20.76, p < 0.001. (B) Male groups, ischemic stroke versus controls: 56.59 ± 14.35 versus 46.82 ± 20.67, p = 0.007. (C) Female groups, ischemic stroke versus controls: 60.59 ± 19.51 versus 38.28 ± 20.16, p < 0.001.

FIGURE 2

Comparison of serine hydroxymethyl transferase 1 methylation (SHMT1) level in different ages. (A) Age ≤ 60 years, ischemic stroke versus controls: 59.46 ± 17.94 versus 43.49 ± 20.63, p < 0.001. (B) Age > 60 years, ischemic stroke versus controls: 57.73 ± 16.47 versus 41.90 ± 21.02, p < 0.001.

FIGURE 3

The relationships between serine hydroxymethyl transferase 1 (SHMT1) methylation and homocysteine (Hcy), high-density lipoprotein (HDL), BMI, and low-density lipoprotein (LDL) in different groups. (A, B) SHMT1 methylation was associated with Hcy in stroke cases (stroke cases, p= 0.034, controls, p = 0.950; total, p = 0.011, (A) and HDL in controls (stroke cases, p = 0.146, controls, p < 0.0001, total, p = 0.001, (B) using regression analysis. (C, D) BMI (stroke cases, p= 0.821, controls, p = 0.937; total, p = 0.673, (C) and LDL (stroke cases, p = 0.603, controls, p = 0.646; total, p = 0.221, (D) showed no association with SHMT1 methylation though regression analysis.

FIGURE 4

ROC curves of serine hydroxymethyl transferase 1 gene DNA methylation in ischemic strokes. ROC: Receiver operating characteristic, AUC, area under the curve. (A) In the male and female patients, AUC = 0.71, p < 0.001; male patients, AUC = 0.62, p = 0.032; and female patients, AUC = 0.79, p < 0.001. (B) In the group of age ≤ 60 years, AUC = 0.71, p < 0.001; age > 60 years, AUC = 0.71, p < 0.001.