Single Nucleotide Polymorphism of Rs1801133 Associated with Elevated Hcy Levels Affects Susceptibility to Cerebral Small Vessel Disease

Overview

Journal PeerJ

Specialties Biology
Environmental Health
General Medicine

Date 2020 Mar 3

PMID 32117640

Citations 4

Authors

Hongyu Yuan

Man Fu

Xianzhang Yang

Kun Huang

Xiaoyan Ren

Affiliations

Soon will be listed here.

Abstract

Background: Methylenetetrahydrofolate reductase (MTHFR) is indispensable for the conversion of homocysteine (Hcy) to methionine. The single nucleotide polymorphism (SNP) of MTHFR gene (rs1801133, C667T) is correlated with decreased enzyme activity that eventually results in elevated plasma Hcy levels. Hyperhomocysteinemia has been confirmed to be involved in the pathogenesis of stroke, cerebral small vessel disease (CSVD), various metabolic disorders and so on. However, the relationship between the MTHFR gene polymorphisms, Hcy, and CSVD has not been investigated. In this study, the relationship between SNPs of MTHFR gene and CSVD was determined after adjusting for cardiovascular risk factors, and the potential mechanism based on Hcy levels was explored.

Methods: A total of 163 consecutive CSVD patients were collected as the case group. In the corresponding period, 326 healthy people were selected as the control group, who were matched to these cases according to age (±2 years) and gender at a ratio of 2:1. SNPs of MTHFR rs1801133, rs1801131, rs2274976, rs4846048, rs4846049, rs13306561 and rs3737964, were genotyped with TaqMan Pre-Designed SNP Genotyping Assays. Plasma Hcy levels were detected using Hcy reagent through enzymatic cycling assay. Multivariate analysis was used to identify the SNPs associated with CSVD susceptibility. Plasma Hcy levels were compared between different genotypes.

Results: The MTHFR rs1801133 TT and CT genotype had increased risk for CSVD, and the was higher in the TT genotype than in the CT genotype (2.307 vs 1.473). The plasma Hcy levels of different genotypes showed the tendency of the TT genotype > CT genotype > CC genotype (19.91 ± 8.73 pg/ml vs 17.04 ± 5.68 pg/ml vs 14.96 ± 4.85 pg/ml).

Conclusions: The SNP of MTHFR rs1801133 was correlated with CSVD, and the TT and CT genotypes had increased risk for CSVD compared to the CC genotype. The potential mechanism was associated with elevated Hcy levels.

Citing Articles

Factors Influencing Collateral Circulation Formation After Indirect Revascularization for Moyamoya Disease: a Narrative Review.

Gao G, Liu S, Hao F, Wang Q, Wang X, Wang M Transl Stroke Res. 2023; 15(6):1005-1014.

PMID: 37592190 DOI: 10.1007/s12975-023-01185-x.

Genetic Modulation of the Erythrocyte Phenotype Associated with Retinopathy of Prematurity-A Multicenter Portuguese Cohort Study.

Fevereiro-Martins M, Santos A, Marques-Neves C, Guimaraes H, Bicho M, The GenE-Rop Study Group Int J Mol Sci. 2023; 24(14).

PMID: 37511576 PMC: 10380881. DOI: 10.3390/ijms241411817.

Surgical outcomes following encephaloduroarteriosynangiosis in moyamoya disease associated with hyperhomocysteinemia.

Gao G, Hao F, Wang Q, Wang X, Liu S, Wang M Brain Behav. 2023; 13(8):e3093.

PMID: 37386744 PMC: 10454250. DOI: 10.1002/brb3.3093.

Gene-Gene Interaction Study Between Genetic Polymorphisms of Folate Metabolism and MTR SNPs on Prognostic Features Impact for Breast Cancer.

Omran M, Fotouh B, Shosha W, Ismail A, Ramadan S Rep Biochem Mol Biol. 2022; 11(1):89-101.

PMID: 35765535 PMC: 9208558. DOI: 10.52547/rbmb.11.1.89.

References

Wardlaw J, Smith E, Biessels G, Cordonnier C, Fazekas F, Frayne R . Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013; 12(8):822-38. PMC: 3714437. DOI: 10.1016/S1474-4422(13)70124-8. View

Kloppenborg R, Nederkoorn P, van der Graaf Y, Geerlings M . Homocysteine and cerebral small vessel disease in patients with symptomatic atherosclerotic disease. The SMART-MR study. Atherosclerosis. 2011; 216(2):461-6. DOI: 10.1016/j.atherosclerosis.2011.02.027. View

Jeon S, Kang D, Kim J, Kwon S . Homocysteine, small-vessel disease, and atherosclerosis: an MRI study of 825 stroke patients. Neurology. 2014; 83(8):695-701. DOI: 10.1212/WNL.0000000000000720. View

Engbersen A, Franken D, Boers G, STEVENS E, Trijbels F, Blom H . Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet. 1995; 56(1):142-50. PMC: 1801334. View

Rutten-Jacobs L, Traylor M, Adib-Samii P, Thijs V, Sudlow C, Rothwell P . Association of MTHFR C677T Genotype With Ischemic Stroke Is Confined to Cerebral Small Vessel Disease Subtype. Stroke. 2016; 47(3):646-51. PMC: 4760380. DOI: 10.1161/STROKEAHA.115.011545. View

Sacco R, Anand K, Lee H, Boden-Albala B, Stabler S, Allen R . Homocysteine and the risk of ischemic stroke in a triethnic cohort: the NOrthern MAnhattan Study. Stroke. 2004; 35(10):2263-9. DOI: 10.1161/01.STR.0000142374.33919.92. View

Cui L, Shin M, Kim H, Song H, Piao J, Kweon S . Methylenetetrahydrofolate reductase C677T polymorphism in patients with lung cancer in a Korean population. BMC Med Genet. 2011; 12:28. PMC: 3048494. DOI: 10.1186/1471-2350-12-28. View

Wu W, Guan Y, Xu K, Fu X, Lei X, Lei L . Plasma Homocysteine Levels Predict the Risk of Acute Cerebral Infarction in Patients with Carotid Artery Lesions. Mol Neurobiol. 2015; 53(4):2510-7. DOI: 10.1007/s12035-015-9226-y. View

Qin X, Shen L, Zhang R, Li Y, Wang X, Wang B . Effect of folic acid supplementation on cancer risk among adults with hypertension in China: A randomized clinical trial. Int J Cancer. 2016; 141(4):837-847. DOI: 10.1002/ijc.30094. View

10.

Li Y, Li M, Yang L, Qin W, Yang S, Yuan J . The relationship between blood-brain barrier permeability and enlarged perivascular spaces: a cross-sectional study. Clin Interv Aging. 2019; 14:871-878. PMC: 6519012. DOI: 10.2147/CIA.S204269. View

11.

Inamoto N, Katsuya T, Kokubo Y, Mannami T, Asai T, Baba S . Association of methylenetetrahydrofolate reductase gene polymorphism with carotid atherosclerosis depending on smoking status in a Japanese general population. Stroke. 2003; 34(7):1628-33. DOI: 10.1161/01.STR.0000075769.09092.82. View

12.

Polyzos S, Kountouras J, Anastasilakis A, Margouta A, Mantzoros C . Association between circulating irisin and homocysteine in patients with nonalcoholic fatty liver disease. Endocrine. 2014; 49(2):560-2. DOI: 10.1007/s12020-014-0473-x. View

13.

Robien K, Ulrich C . 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. Am J Epidemiol. 2003; 157(7):571-82. DOI: 10.1093/aje/kwg024. View

14.

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

15.

Chutinet A, Suwanwela N, Snabboon T, Chaisinanunkul N, Furie K, Phanthumchinda K . Association between genetic polymorphisms and sites of cervicocerebral artery atherosclerosis. J Stroke Cerebrovasc Dis. 2011; 21(5):379-85. DOI: 10.1016/j.jstrokecerebrovasdis.2010.10.002. View

16.

Bostom A, Rosenberg I, Silbershatz H, Jacques P, Selhub J, DAgostino R . Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Ann Intern Med. 1999; 131(5):352-5. DOI: 10.7326/0003-4819-131-5-199909070-00006. View

17.

Shi Y, Wardlaw J . Update on cerebral small vessel disease: a dynamic whole-brain disease. Stroke Vasc Neurol. 2017; 1(3):83-92. PMC: 5435198. DOI: 10.1136/svn-2016-000035. View

18.

Pavlovic A, Pekmezovic T, Obrenovic R, Novakovic I, Tomic G, Mijajlovic M . Increased total homocysteine level is associated with clinical status and severity of white matter changes in symptomatic patients with subcortical small vessel disease. Clin Neurol Neurosurg. 2011; 113(9):711-5. DOI: 10.1016/j.clineuro.2011.07.004. View

19.

Perry I, Refsum H, Morris R, Ebrahim S, Ueland P, Shaper A . Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet. 1995; 346(8987):1395-8. DOI: 10.1016/s0140-6736(95)92407-8. View

20.

Tan R, Traylor M, Rutten-Jacobs L, Markus H . New insights into mechanisms of small vessel disease stroke from genetics. Clin Sci (Lond). 2017; 131(7):515-531. DOI: 10.1042/CS20160825. View