Serine hydroxymethyltransferase 1 promoter hypermethylation increases the risk of essential hypertension

Xu, Guodong; Wang, Changyi; Ying, Xiuru; Kong, Fansen; Ji, Huihui; Zhao, Jinshun; Zhang, Xiao­hong; Duan, Shiwei; Han, Liyuan; Li, Li

doi:10.1002/jcla.22712

Cited by 5 publications

(7 citation statements)

References 30 publications

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“…However, no statistical difference in the use of antihypertensive treatment was found between IS cases and controls.Age is one of the risk factors for IS, and the level of methylation changes as age increases 20. Previous studies have found positive associations between decreased DNA promoter methylation and older age for ADD1,21 LINE-1,22 and SHMT1 23. Consistent with these studies, we found a weak inverse correlation (r = −.178) between age and DHFR promoter methylation level.…”

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confidence: 90%

Significant association between DHFR promoter methylation and ischemic stroke in a Chinese hypertensive population

Zhu

et al. 2020

Clinical Laboratory Analysis

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Objective DHFR encodes dihydrofolate reductase, a major enzyme in the metabolism of folate, and is a candidate gene for ischemic stroke (IS). Therefore, we aimed to investigate the association between DHFR promoter methylation and IS in a Chinese population with primary hypertension. Methods Quantitative methylation‐specific PCR was used to measure the level of DHFR promoter methylation. A multivariate logistic regression model was used to investigate the association between DHFR promoter methylation and IS. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic value of DHFR promoter methylation for IS. Results The level of methylation of the DHFR promoter in the IS group was significantly lower than that in the hypertensive group (median [interquartile range]: 9.11 [2.81‐16.20] vs 24.94 [7.16‐56.45], P < .001). DHFR promoter methylation and homocysteine (Hcy) levels were both related to IS, with an ORs (95% CI) of 0.976 (0.967‐0.984) and 1.057 (1.027‐1.108), respectively. The areas under the curve for the diagnosis of DHFR promoter hypomethylation in IS were 0.603 (95% CI, 0.527‐0.678) in men and 0.754 (95% CI, 0.693‐0.815) in women. A dual‐luciferase reporter assay revealed that the target sequence in the DHFR promoter upregulated gene expression. Conclusion There is a significant association between methylation of the DHFR promoter and IS in this Chinese hypertensive population. Hypomethylation of the DHFR promoter may serve as a novel marker for the diagnosis of IS in women.

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Significant association between DHFR promoter methylation and ischemic stroke in a Chinese hypertensive population

Zhu

et al. 2020

Clinical Laboratory Analysis

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“…In addition, the altered expression of SHMT1 could block folic acid metabolism and abnormal Hcy remethylation pathways. This causes excessive accumulation of Hcy, which could increase the risk of was confirmed in both essential hypertension and hyperhomocysteinemia patients [13].…”

Section: Introductionmentioning

confidence: 97%

“…SHMT1 variants may be involved in Hcy metabolism and, therefore, contribute to an increased risk of ischemic stroke [ 12 ]. The methylation of SHMT1 gene may affect the expression of SHMT1 [ 13 ], a protein that plays a key role in promoting the conversion of serine and tetrahydrofolate to glycine and 5,10-methylenetetrahydrofolate [ 14 ]. Moreover, SHMT1 expression was shown to be associated with phosphate-induced vascular smooth muscle cell calcification [ 15 ] and a SHMT1 variant was suggested as a risk factor in early-onset ischemic stroke [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…This causes excessive accumulation of Hcy, which could increase the risk of ischemic stroke [ 17 ]. A previous study showed that SHMT1 promoter hypermethylation was confirmed in both, patients with essential hypertension, and patients with hyperhomocysteinemia [ 13 ]. However, DNA methylation of this gene had not been examined in the context of ischemic stroke.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Huang

et al. 2020

Bosn J of Basic Med Sci

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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 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 have 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.

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“…[ 6 ] DNA methyltransferase transfers a methyl group to cytosine nucleotides on the promoter, likely leading to the transcriptional silencing of gene expression. [ 7 ] Compelling evidence has indicated that aberrant DNA methylation of the ADD1 ,[ 8 ] GCK ,[ 9 ] and SHMT1 [ 10 ] genes contributes to the risk of hypertension.…”

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confidence: 99%

Hypermethylation of dihydrofolate reductase promoter increases the risk of hypertension in Chinese

Wang

et al. 2020

J Res Med Sci

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Background: DNA methylation was considered to play an important role in hypertension. However, the direct association between dihydrofolate reductase ( DHFR ) promoter methylation and hypertension remains unclear. We thus aimed to investigate the relationship between DNA methylation of DHFR promoter and hypertension. Materials and Methods: A total of 371 hypertensive patients (diastolic blood pressure ≥90 mmHg and/or systolic blood pressure ≥140 mmHg or a history of antihypertensive treatment) and 320 age- and sex-matched healthy controls from the Hypertension Management Information System in Nanshan Community Health Service Centers were included in this case–control study. Quantitative methylation-specific polymerase chain reaction was used to measure the level of DHFR promoter methylation, which was presented as the percentage of methylated reference (PMR). A multivariate logistic regression model was used to explore the risk of DHFR promoter methylation. Results: Our results indicated that the level of DHFR promoter methylation was higher in hypertensive patients (median PMR, 34.32%; interquartile range, 11.34–119.60) than in healthy controls (median PMR, 18.45%; interquartile range, 8.16–35.40) ( P < 0.001). Multivariable analysis showed that the risk of DHFR promoter hypermethylation was significantly higher in hypertensive patients than in healthy controls (odds ratio = 3.94, 95% confidence interval = 2.56–6.02, P < 0.001). Furthermore, hypermethylation was positively associated with sex, high blood homocysteine levels, and alcohol drinking. In particular, the area under the receiver operating characteristic curve was 0.688 (0.585–0.668) for the male hypertensive patients, suggesting the potential diagnostic value of DHFR promoter methylation in male hypertension. Conclusion: Our results demonstrated that DHFR promoter hypermethylation is positively associated with the risk of hypertension in Chinese.

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Serine hydroxymethyltransferase 1 promoter hypermethylation increases the risk of essential hypertension

Cited by 5 publications

References 30 publications

Significant association between DHFR promoter methylation and ischemic stroke in a Chinese hypertensive population

Significant association between DHFR promoter methylation and ischemic stroke in a Chinese hypertensive population

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

Hypermethylation of dihydrofolate reductase promoter increases the risk of hypertension in Chinese

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