目的 本研究旨在揭示血清叶酸与首发缺血性脑卒中(IS)之间的关系,并探讨长链非编码RNA ANRIL(lncRNA ANRIL)的中介效应。方法 选用病例对照研究,对112例首发缺血性脑卒中患者及142例同期健康体检者进行描述性分析、相关性分析、中介分析;采用百分位Bootstrap法检验中介效应的显著性。结果 调整年龄、性别、BMI、教育水平、吸烟史、饮酒史、高血压病史、糖尿病史和高胆固醇血症病史等因素后,lncRNA ANRIL水平与患缺血性脑卒中风险增加相关(lncRNA ANRIL≥1.64: OR, 5.52; 95% CI: 3.07~10.12);叶酸水平较低与患缺血性脑卒中风险增加有关(叶酸<7.00 nmol/L: OR, 2.12; 95% CI: 1.15~3.90);血清叶酸水平与lncRNA ANRIL水平呈负相关(β=-0.26; 95% CI: –0.44~–0.08);中介效应分析显示,lncRNA ANRIL在血清叶酸对IS的影响中存在部分中介效应,中介效应占其总效应的比例为51.27%。结论 高水平血清叶酸补充能够显著降低首发IS的风险,lncRNA ANRIL不仅增加了IS的发生风险,并且在血清叶酸与IS的关系中起部分中介作用。
Abstract
Objective To explore the association between serum folate and first-onset ischemic stroke (IS), and to investigate the mediating effects of long non-coding RNA ANRIL (lncRNA ANRIL). Methods A case-control study was conducted by descriptive analysis, correlation analysis, and mediation analysis on 112 first-ever ischemic stroke patients and 142 healthy controls. The percentile Bootstrap method was used to test the significance of the mediating effects. Results After adjusting for factors such as age, gender, BMI, education level, smoking, alcohol consumption, hypertension, diabetes, and hypercholesterolemia, lncRNA ANRIL levels were found to be associated with an increased risk of ischemic stroke (lncRNA ANRIL≥1.64: OR, 5.52; 95% CI: 3.07-10.12). Lower serum folate levels were associated with an increased risk of ischemic stroke (folate <7.00 nmol/L: OR, 2.12; 95% CI: 1.15-3.90). Serum folate levels were negatively correlated with lncRNA ANRIL levels (β=–0.26; 95% CI: –0.44-–0.08). Mediation analysis showed that lncRNA ANRIL had a partial mediating effect on the association between serum folate and IS, accounting for 51.27% of the total effect. Conclusion High serum folate level significantly reduces the risk of first-ever IS, while lncRNA ANRIL not only increases the risk of IS but also plays a partial mediating role in the association between serum folate and IS.
关键词
缺血性脑卒中 /
lncRNA ANRIL /
叶酸 /
中介效应
Key words
ischemic stroke /
lncRNA ANRIL /
folate /
mediating effect
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] Saini V, Guada L, Yavagal DR.Global epidemiology of stroke and access to acute ischemic stroke interventions
[J]. Neurology, 2021, 97(20_Supplement_2): S6–S16.
[2] Giles WH, Kittner SJ, Anda RF, et al. Serum folate and risk for ischemic stroke: First National Health and Nutrition Examination Survey epidemiologic follow-up study[J]. Stroke, 1995, 26: 1166–1170.
[3] Van Guelpen B, Hultdin J, Johansson I, et al. Folate, vitamin B12, and risk of ischemic and hemorrhagic stroke: a prospective, nested case-referent study of plasma concentrations and dietary intake[J]. Stroke, 2005, 36: 1426–1431.
[4] Xu X, Wei W, Jiang W, et al. Association of folate intake with cardiovascular-disease mortality and all-cause mortality among people at high risk of cardiovascular disease[J]. Clin Nutr, 2022, 41: 246–254.
[5] Zhou L, Wang J, Wu H, et al. Serum levels of vitamin B12 combined with folate and plasma total homocysteine predict ischemic stroke disease: a retrospective case-control study[J]. Nutr J, 2024, 23: 76.
[6] He K, Merchant A, Rimm EB, et al. Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men[J]. Stroke, 2004, 35: 169–174.
[7] Larsson SC, Männistö S, Virtanen MJ, et al. Folate, vitamin B6, vitamin B12, and methionine intakes and risk of stroke subtypes in male smokers[J]. Am J Epidemiol, 2008, 167: 954–961.
[8] Al-Delaimy WK, Rexrode KM, Hu FB, et al. Folate intake and risk of stroke among women[J]. Stroke, 2004, 35: 1259–1263.
[9] Doshi SN, McDowell IFW, Moat SJ, et al. Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering[J]. Circulation, 2002, 105: 22–26.
[10] Gareev I, Kudriashov V, Sufianov A, et al. The role of long non-coding RNA ANRIL in the development of atherosclerosis[J]. Noncoding RNA Res, 2022, 7: 212–216.
[11] Yao J, Du Y, Liu J, et al. Hypoxia related long non-coding RNAs in ischemic stroke[J]. Noncoding RNA Res, 2021, 6: 153–158.
[12] Huang T, Zhao HY, Zhang XB, et al. LncRNA ANRIL regulates cell proliferation and migration via sponging miR-339-5p and regulating FRS2 expression in atherosclerosis[J]. Eur Rev Med Pharmacol Sci, 2020, 24:1956–1969.
[13] Zhao JH, Wang B, Wang XH, et al. Influence of lncRNA ANRIL on neuronal apoptosis in rats with cerebral infarction by regulating the NF-κB signaling pathway[J]. Eur Revr Med Pharmacol Sci, 2019, 23:10092–10100.
[14] Guo F, Tang C, Li Y, et al. The interplay of Lnc RNA ANRIL and miR-181b on the inflammation-relevant coronary artery disease through mediating NF-κB signalling pathway[J]. J Cell Mol Med, 2018, 22: 5062–5075.
[15] Moghaddasi M, Mamarabadi M, Mirzadeh S, et al. Homocysteine, vitamin B12 and folate levels in Iranian patients with ischemic stroke[J]. Neurol Res, 2010 ,32:953–956.
[16] Tian T, Yang KQ, Cui JG, et al. Folic acid supplemen-tation for stroke prevention in patients with cardiovascular disease[J]. Am J Med Sci, 2017 354:379–387.
[17] Wu H, Zhang Y, Li H, et al.Interaction of serum calcium and folic acid treatment on first stroke in hypertensive males[J]. Clin Nutr,2021,40:2381–2388.
[18] Kim HN, Eun YM, Song SW.Serum folate and vitamin B12 levels are not associated with the incidence risk of atherosclerotic events over 12years: the Korean Genome and Epidemiology Study[J]. Nutr Res,2019 63:34–41.
[19] Weikert C, Dierkes J, Hoffmann K,et al. B vitamin plasma levels and the risk of ischemic stroke and transient ischemic attack in a German cohort[J]. Stroke,2007 38:2912–2918.
[20] Tan Z, Li W, Cheng X, et al. Non-coding RNAs in the regulation of hippocampal neurogenesis and potential treatment targets for related disorders[J]. Biomolecules 2022, 13: 18.
[21] Lauretti E, Dabrowski K, Praticò D. The neurobiology of non-coding RNAs and Alzheimer’s disease pathogenesis: pathways, mechanisms and translational opportunities[J]. Age Res Rev, 2021, 71: 101425.
[22] Zhang B, Wang D, Ji TF, et al. Overexpression of lncRNA ANRIL up-regulates VEGF expression and promotes angiogenesis of diabetes mellitus combined with cerebral infarction by activating NF-κB signaling pathway in a rat model[J]. Oncotarget, 2017, 8: 17347.
[23] Zhang W, Chen Y, Liu P, et al. Variants on chromosome 9p21. 3 correlated with ANRIL expression contribute to stroke risk and recurrence in a large prospective stroke population[J]. Stroke, 2012, 43: 14–21.
[24] Bai Y, Nie S, Jiang G, et al. Regulation of CARD8 expression by ANRIL and association of CARD8 single nucleotide polymorphism rs2043211 (p. C10X) with ischemic stroke[J]. Stroke, 2014, 45: 383–388.
[25] Ning S, Wang P, Ye J, et al. A global map for dissecting phenotypic variants in human lincRNAs[J]. Eur J Hum Genet, 2013, 21: 1128–1133.
[26] da Cunha Agostini L, Almeida TC, da Silva GN. ANRIL, H19 and TUG1: a review about critical long non-coding RNAs in cardiovascular diseases[J]. Mol Biol Rep, 2024, 51: 31.
[27] Yuan Y, Xu L, Geng Z, et al. The role of non-coding RNA network in atherosclerosis[J]. Life Sci, 2021, 265: 118756.
[28] Ghafouri-Fard S, Gholipour M, Taheri M.The emerging role of long non-coding RNAs and circular RNAs in coronary artery disease[J]. Front Cardiovasc Med, 2021, 8: 632393.
[29] Nordestgaard BG, Varbo A.Triglycerides and cardio-vascular disease[J]. Lancet, 2014, 384: 626–635.
[30] Ali KM, Wonnerth A, Huber K, et al. Cardiovascular disease risk reduction by raising HDL cholesterol-current therapies and future opportunities[J]. Br J Pharmacol, 2012, 167: 1177–1194.
[31] Asbaghi O, Ashtary-Larky D, Bagheri R, et al. Beneficial effects of folic acid supplementation on lipid markers in adults: a GRADE-assessed systematic review and dose-response meta-analysis of data from 21,787 participants in 34 randomized controlled trials[J]. Crit Rev Food Sci Nutr, 2022,62: 8435–8453.
[32] Razeghian-Jahromi I, Karimi Akhormeh A, Zibaeenezhad MJ.The role of ANRIL in atherosclerosis[J]. Dis Markers, 2022,2022: 8859677.