The 3'-UTR Polymorphisms in the Thymidylate Synthase (TS) Gene Associated with the Risk of Ischemic Stroke and Silent Brain Infarction.

Jung Oh Kim,Han Sung Park,Eun Ju Ko,Jinkwon Kim,Seung Hun Oh,Ok Joon Kim,Jung Hoon Sung,Nam Keun Kim

doi:10.3390/jpm11030200

Jung Oh Kim, Han Sung Park + Show 6 more

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https://doi.org/10.3390/jpm11030200

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Abstract

Thymidylate synthase (TS) is a key gene involved in the repair of DNA damage and DNA synthesis that plays an important role in vascular development and recovery. In particular, TS gene polymorphisms play a major role in the progression of vascular disease and cancer metastasis. Therefore, the aim of this study was to investigate the association of three TS polymorphisms (1100T>C [rs699517], 1170A>G [rs2790], and 1494ins/del [rs151264360]) with ischemic stroke and silent brain infarction (SBI) in Koreans. A total of 1299 participants (507 stroke patients, 383 SBI patients, and 409 controls) were enrolled in the study. Genotyping of the three TS polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis. To examine the association between TS gene polymorphisms and the diseases, we performed statistical analyses, including multivariable logistic regression and Fisher’s exact tests. We found that TS 1100T>C and 1170A>G genotypes were strongly associated with ischemic stroke and SBI susceptibility. More specifically, the TS 1100T>C polymorphism was associated with the likelihood of ischemic stroke (TT vs. CC: AOR = 2.151, 95% CI = 1.275–3.628, P = 0.004) and SBI (TT vs. TC+CC: AOR = 1.443, 95 % CI = 1.009–2.063, P = 0.045). In contrast, the TS 1170A > G polymorphism exhibited lower correlation with the risk of stroke (AA vs. GG: AOR = 0.284, 95% CI = 0.151–0.537, P < 0.0001) and SBI (AA vs. GG: AOR = 0.070, 95% CI = 0.016–0.298, P = 0.0002). Furthermore, we confirmed that the TS 1100T>C polymorphism was synergistic with low folic acid levels (AOR = 6.749, P < 0.0001). Altogether, these results suggest that TS 1100T>C and 1170A > G polymorphisms are associated with the risk of ischemic stroke and SBI, and our study provides the first evidence that 3′-UTR variants in TS are potential biomarkers in ischemic stroke and SBI.

Highlights

Stroke is the third most common cause of death in many developed countries, and approximately 80% of strokes are ischemic in origin [1,2]
We investigated whether three miRNA binding site (3 -untranslated region (UTR)) polymorphisms of the Thymidylate synthase (TS) gene were related to Silent brain infarction (SBI) and stroke prevalence
We found that TS 1100T>C and 1170A>G genotypes were strongly associated with ischemic stroke and SBI susceptibility

Summary

Introduction

Stroke is the third most common cause of death in many developed countries, and approximately 80% of strokes are ischemic in origin [1,2]. In South Korea, stroke is the most frequent cause of death after cancer and is more frequent than heart disease [3]. Silent brain infarction (SBI) is defined as a cerebral infarction evident on brain imaging that is not accompanied by a clinical stroke syndrome characterized by the rapid development of symptoms or focal or global loss of brain function. SBIs are common in advanced age [4]. Most SBIs should be considered as a precursor to stroke because SBI increases the probability of developing a stroke by about 10 times

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