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Aims: Despite the success of single-cell RNA sequencing in identifying cellular heterogeneity in ischemic stroke, clarifying the mechanisms underlying these associations of differently expressed genes remains challenging. Several studies that integrate gene expression and gene expression quantitative trait loci (eQTLs) with genome wide-association study (GWAS) data to determine their causal role have been proposed.

Methods: Here, we combined Mendelian randomization (MR) framework and single cell (sc) RNA sequencing to study how differently expressed genes (DEGs) mediating the effect of gene expression on ischemic stroke. The hub gene was further validated in the in vitro model.

Results: We identified 2339 DEGs in 10 cell clusters. Among these DEGs, 58 genes were associated with the risk of ischemic stroke. After external validation with eQTL dataset, lactate dehydrogenase B (LDHB) is identified to be positively associated with ischemic stroke. The expression of LDHB has also been validated in sc RNA-seq with dominant expression in microglia and astrocytes, and melatonin is able to reduce the LDHB expression and activity in vitro ischemic models.

Conclusion: Our study identifies LDHB as a novel biomarker for ischemic stroke via combining the sc RNA-seq and MR analysis.

Titel:	Integrated analysis of single cell-RNA sequencing and Mendelian randomization identifies lactate dehydrogenase B as a target of melatonin in ischemic stroke.
Autor/in / Beteiligte Person:	Shi, F ; Zhang, G ; Li, J ; Shu, L ; Yu, C ; Ren, D ; Zhang, Y ; Zheng, P
Link:	Zum Volltext
Zeitschrift:	CNS neuroscience & therapeutics, Jg. 30 (2024-05-01), Heft 5, S. e14741
Veröffentlichung:	Oxford, UK : Wiley-Blackwell, c2008-, 2024
Medientyp:	academicJournal
ISSN:	1755-5949 (electronic)
DOI:	10.1111/cns.14741
Schlagwort:	Animals Humans Genome-Wide Association Study methods Isoenzymes genetics Isoenzymes metabolism Quantitative Trait Loci Single-Cell Analysis methods Mice Ischemic Stroke genetics Ischemic Stroke metabolism L-Lactate Dehydrogenase metabolism L-Lactate Dehydrogenase genetics Melatonin Mendelian Randomization Analysis methods Sequence Analysis, RNA methods
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [CNS Neurosci Ther] 2024 May; Vol. 30 (5), pp. e14741. MeSH Terms: Ischemic Stroke* / genetics ; Ischemic Stroke* / metabolism ; L-Lactate Dehydrogenase* / metabolism ; L-Lactate Dehydrogenase* / genetics ; Melatonin* ; Mendelian Randomization Analysis* / methods ; Sequence Analysis, RNA* / methods ; Animals ; Humans ; Genome-Wide Association Study / methods ; Isoenzymes / genetics ; Isoenzymes / metabolism ; Quantitative Trait Loci ; Single-Cell Analysis / methods ; Mice References: Cardiovasc Res. 2018 Jul 15;114(9):1258-1270. (PMID: 29800275) ; Int J Epidemiol. 2016 Dec 1;45(6):1717-1726. (PMID: 28338968) ; Arq Neuropsiquiatr. 2020 Jan;78(1):39-43. (PMID: 32074189) ; Nat Protoc. 2016 May;11(5):905-19. (PMID: 27077332) ; Antioxidants (Basel). 2023 Feb 15;12(2):. (PMID: 36830049) ; Nat Genet. 2013 Nov;45(11):1274-1283. (PMID: 24097068) ; J Cereb Blood Flow Metab. 2022 Jan;42(1):56-73. (PMID: 34496660) ; Stat Med. 2016 May 20;35(11):1880-906. (PMID: 26661904) ; Front Neurol. 2022 Apr 06;13:816216. (PMID: 35463134) ; CNS Neurosci Ther. 2024 May;30(5):e14741. (PMID: 38702940) ; J Cereb Blood Flow Metab. 2019 Nov;39(11):2181-2195. (PMID: 29932353) ; Aging Dis. 2022 Oct 1;13(5):1436-1454. (PMID: 36186129) ; Nat Genet. 2021 Sep;53(9):1300-1310. (PMID: 34475573) ; Cell Rep. 2023 Apr 25;42(4):112335. (PMID: 37027294) ; Nat Commun. 2019 Dec 5;10(1):5566. (PMID: 31804482) ; Genet Epidemiol. 2016 May;40(4):304-14. (PMID: 27061298) ; J Neuroinflammation. 2022 Apr 7;19(1):83. (PMID: 35392936) ; Int J Stroke. 2014 Apr;9(3):349-55. (PMID: 24207029) ; Nat Neurosci. 2022 Jul;25(7):865-875. (PMID: 35726058) ; Stroke. 2023 Jan;54(1):265-269. (PMID: 36475468) ; Atherosclerosis. 2016 Oct;253:75-80. (PMID: 27591364) ; Int J Epidemiol. 2003 Feb;32(1):1-22. (PMID: 12689998) ; Int J Epidemiol. 2017 Dec 1;46(6):1985-1998. (PMID: 29040600) ; Elife. 2018 May 30;7:. (PMID: 29846171) ; Epidemiology. 2017 Jan;28(1):30-42. (PMID: 27749700) ; Nucleic Acids Res. 2017 Jan 4;45(D1):D955-D963. (PMID: 27899599) ; Int J Stroke. 2022 Oct;17(9):946-956. (PMID: 35975986) ; Nat Genet. 2018 Sep;50(9):1234-1239. (PMID: 30061737) ; Am J Epidemiol. 2015 Feb 15;181(4):251-60. (PMID: 25632051) ; Mol Oncol. 2019 Feb;13(2):358-375. (PMID: 30443978) ; Cardiovasc Drugs Ther. 2021 Jun;35(3):617-626. (PMID: 33604704) ; PLoS One. 2022 Oct 7;17(10):e0275651. (PMID: 36206280) ; Arch Med Sci. 2021 Nov 09;17(6):1804-1810. (PMID: 34900063) ; Circulation. 2019 Mar 5;139(10):e56-e528. (PMID: 30700139) ; Int J Epidemiol. 2011 Jun;40(3):755-64. (PMID: 21414999) ; Int J Epidemiol. 2015 Apr;44(2):512-25. (PMID: 26050253) ; Nat Genet. 2018 May;50(5):693-698. (PMID: 29686387) ; Front Immunol. 2024 Jan 03;14:1247131. (PMID: 38239341) ; Circulation. 1992 Sep;86(3):1046-60. (PMID: 1355411) ; Cerebrovasc Dis. 2003;16(1):76-82. (PMID: 12766366) ; Mol Hum Reprod. 2014 Nov;20(11):1067-76. (PMID: 25205674) ; J Pineal Res. 2022 Oct;73(3):e12819. (PMID: 35906194) Grant Information: YG2021QN90 the Cross Research Fund of Medicine and Engineering of Shanghai Jiaotong University; PWZxq2022-13 The Project of Key Medical Discipline Group Construction in Shanghai Pudong New Area Contributed Indexing: Keywords: LDHB; Mendelian randomization; causal effect; ischemic stroke Substance Nomenclature: 0 (Isoenzymes) ; EC 1.1.1.27 (L-Lactate Dehydrogenase) ; EC 1.1.1.27.- (lactate dehydrogenase 1) ; JL5DK93RCL (Melatonin) Entry Date(s): Date Created: 20240504 Date Completed: 20240504 Latest Revision: 20240513 Update Code: 20240513 PubMed Central ID: PMC11069049

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Integrated analysis of single cell-RNA sequencing and Mendelian randomization identifies lactate dehydrogenase B as a target of melatonin in ischemic stroke.