MTHFR C677T, Hyperhomocysteinemia, and Their Interactions with Traditional Risk Factors in Early Neurological Deterioration in Chinese Patients with Ischemic Stroke

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 May 24

PMID 38784530

Authors

Qiang Zhou

Zhiyao Xu

Yuanyuan Duan

Hui Tang

Haitao Zhang

Hua Liu

Affiliations

Soon will be listed here.

Abstract

Objective: This study aimed to investigate the relationship between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and early neurological deterioration (END) in patients with acute ischemic stroke (AIS) and any possible interactions between specific MTHFR alleles and traditional risk factors among a Han Chinese cohort.

Methods: 434 AIS patients were consecutively recruited between January 2017 and June 2019, including 129 END and 305 non-END cases. A candidate gene association study design was used to analyze the association between MTHFR gene polymorphism and END risk. The polymerase chain reaction-restriction fragment length polymorphism (RFLP) method was employed to genotype the MTHFR C677T polymorphism. The interactional analyses were performed using the multifactor dimensionality reduction test.

Results: Hyperglycemia (odds ratio [OR]: 2.410, 95 % confidence interval [CI]: 1.436-4.046, p = 0.001), neurological function impairment (NIHSS score >5) (OR: 2.158, 95%CI: 1.337-3.484, = 0.002) on admission, and hyperhomocysteinemia (HHcy) (OR: 2.570, 95%CI: 1.229-5.376, = 0.012) were independently associated with END. The TT genotype (OR: 1.710, 95%CI: 1.021-2.863, p = 0.043) and T allele (OR: 1.710, 95%CI: 1.021-2.863, p = 0.043) of this C677T polymorphism were associated with susceptibility to END, and the TT genotype was more common in the subjects with HHcy (OR: 2.525, 95%CI: 1.111-5.739, P = 0.023). In addition, we also found interactions for END risk between the C677T polymorphism and traditional risk factors for END, including: hyperglycemia on admission, drinking, and moderate to severe neurological deficits (OR 1.237, 95 % CI 0.227-6.734), although the results were not statistically significant (p = 0.806).

Conclusions: Our results show a possible association between MTHFR C677T polymorphism and gene-environment interactions with END susceptibility in a Han Chinese cohort.

References

Zhang X, Sun Z, Ding C, Tang Y, Jiang X, Xie Y . Metabolic Syndrome Augments the Risk of Early Neurological Deterioration in Acute Ischemic Stroke Patients Independent of Inflammatory Mediators: A Hospital-Based Prospective Study. Oxid Med Cell Longev. 2016; 2016:8346301. PMC: 4828543. DOI: 10.1155/2016/8346301. View

Xiong L, Liu W, Gao L, Mu Q, Liu X, Feng Y . The ANRIL Genetic Variants and Their Interactions with Environmental Risk Factors on Atherothrombotic Stroke in a Han Chinese Population. J Stroke Cerebrovasc Dis. 2018; 27(9):2336-2347. DOI: 10.1016/j.jstrokecerebrovasdis.2018.04.020. View

Wu S, Wu B, Liu M, Chen Z, Wang W, Anderson C . Stroke in China: advances and challenges in epidemiology, prevention, and management. Lancet Neurol. 2019; 18(4):394-405. DOI: 10.1016/S1474-4422(18)30500-3. View

Luo Z, Lu Z, Muhammad I, Chen Y, Chen Q, Zhang J . Associations of the MTHFR rs1801133 polymorphism with coronary artery disease and lipid levels: a systematic review and updated meta-analysis. Lipids Health Dis. 2018; 17(1):191. PMC: 6097444. DOI: 10.1186/s12944-018-0837-y. View

Seners P, Turc G, Oppenheim C, Baron J . Incidence, causes and predictors of neurological deterioration occurring within 24 h following acute ischaemic stroke: a systematic review with pathophysiological implications. J Neurol Neurosurg Psychiatry. 2014; 86(1):87-94. DOI: 10.1136/jnnp-2014-308327. View

Hui J, Zhang J, Mao X, Li Z, Li X, Wang F . The initial glycemic variability is associated with early neurological deterioration in diabetic patients with acute ischemic stroke. Neurol Sci. 2018; 39(9):1571-1577. DOI: 10.1007/s10072-018-3463-6. View

Liu L . [2010 Chinese guidelines for the management of hypertension]. Zhonghua Xin Xue Guan Bing Za Zhi. 2011; 39(7):579-615. View

Wei L, Au A, Menon S, Gan S, Griffiths L . Clinical Relevance of MTHFR, eNOS, ACE, and ApoE Gene Polymorphisms and Serum Vitamin Profile among Malay Patients with Ischemic Stroke. J Stroke Cerebrovasc Dis. 2015; 24(9):2017-25. DOI: 10.1016/j.jstrokecerebrovasdis.2015.04.011. View

Frosst P, Blom H, Milos R, Goyette P, Sheppard C, Matthews R . A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995; 10(1):111-3. DOI: 10.1038/ng0595-111. View

10.

Wei L, Au A, Menon S, Griffiths L, Kooi C, Irene L . Polymorphisms of MTHFR, eNOS, ACE, AGT, ApoE, PON1, PDE4D, and Ischemic Stroke: Meta-Analysis. J Stroke Cerebrovasc Dis. 2017; 26(11):2482-2493. DOI: 10.1016/j.jstrokecerebrovasdis.2017.05.048. View

11.

Fu H, Zhao L, Xue J, Wu Z, Huang Y, Liu W . Elevated Serum Homocysteine (Hcy) Levels May Contribute to the Pathogenesis of Cerebral Infarction. J Mol Neurosci. 2015; 56(3):553-61. DOI: 10.1007/s12031-015-0497-6. View

12.

Mohamed E, Tan K, Mohd Ali J, Mohamed Z . TT genotype of the methylenetetrahydrofolate reductase C677T polymorphism is an important determinant for homocysteine levels in multi-ethnic Malaysian ischaemic stroke patients. Ann Acad Med Singap. 2011; 40(4):186-91. View

13.

Kwon H, Lee Y, Bae H, Kang D . Homocysteine as a predictor of early neurological deterioration in acute ischemic stroke. Stroke. 2014; 45(3):871-3. DOI: 10.1161/STROKEAHA.113.004099. View

14.

Hu W, Liu D, Li Q, Wang L, Tang Q, Wang G . Decreasing serum 25-hydroxyvitamin D levels and risk of early neurological deterioration in patients with ischemic stroke. Brain Behav. 2019; 9(3):e01227. PMC: 6422815. DOI: 10.1002/brb3.1227. View

15.

Sato T, Sato S, Yamagami H, Komatsu T, Mizoguchi T, Yoshimoto T . D-dimer level and outcome of minor ischemic stroke with large vessel occlusion. J Neurol Sci. 2020; 413:116814. DOI: 10.1016/j.jns.2020.116814. View

16.

Martin A, Price C . A Systematic Review and Meta-Analysis of Molecular Biomarkers Associated with Early Neurological Deterioration Following Acute Stroke. Cerebrovasc Dis. 2018; 46(5-6):230-241. DOI: 10.1159/000495572. View

17.

Liu Y, Wang J, Zhang L, Wang C, Wu J, Zhou Y . Relationship between C-reactive protein and stroke: a large prospective community based study. PLoS One. 2014; 9(9):e107017. PMC: 4156395. DOI: 10.1371/journal.pone.0107017. View

18.

Siegler J, Boehme A, Kumar A, Gillette M, Albright K, Martin-Schild S . What change in the National Institutes of Health Stroke Scale should define neurologic deterioration in acute ischemic stroke?. J Stroke Cerebrovasc Dis. 2012; 22(5):675-82. PMC: 5535077. DOI: 10.1016/j.jstrokecerebrovasdis.2012.04.012. View

19.

Thanvi B, Treadwell S, Robinson T . Early neurological deterioration in acute ischaemic stroke: predictors, mechanisms and management. Postgrad Med J. 2008; 84(994):412-7. DOI: 10.1136/pgmj.2007.066118. View

20.

Zhang T, Jiang Y, Zhang S, Tie T, Cheng Y, Su X . The association between homocysteine and ischemic stroke subtypes in Chinese: A meta-analysis. Medicine (Baltimore). 2020; 99(12):e19467. PMC: 7220264. DOI: 10.1097/MD.0000000000019467. View