Genetic Variation Contributes to Gene Expression Response in Ischemic Stroke: an EQTL Study

Overview

Journal Ann Clin Transl Neurol

Specialty Neurology

Date 2020 Aug 14

PMID 32785988

Citations 8

Authors

Hajar Amini

Natasha Shroff

Boryana Stamova

Eva Ferino

Paulina Carmona-Mora

Xinhua Zhan

Preston P Sitorus

Heather Hull

Glen C Jickling

Frank R Sharp

Bradley P Ander

Affiliations

Soon will be listed here.

Abstract

Objective: Single nucleotide polymorphisms (SNPs) contribute to complex disorders such as ischemic stroke (IS). Since SNPs could affect IS by altering gene expression, we studied the association of common SNPs with changes in mRNA expression (i.e. expression quantitative trait loci; eQTL) in blood after IS.

Methods: RNA and DNA were isolated from 137 patients with acute IS and 138 vascular risk factor controls (VRFC). Gene expression was measured using Affymetrix HTA 2.0 microarrays and SNP variants were assessed with Axiom Biobank Genotyping microarrays. A linear model with a genotype (SNP) × diagnosis (IS and VRFC) interaction term was fit for each SNP-gene pair.

Results: The eQTL interaction analysis revealed significant genotype × diagnosis interaction for four SNP-gene pairs as cis-eQTL and 70 SNP-gene pairs as trans-eQTL. Cis-eQTL involved in the inflammatory response to IS included rs56348411 which correlated with neurogranin expression (NRGN), rs78046578 which correlated with CXCL10 expression, rs975903 which correlated with SMAD4 expression, and rs62299879 which correlated with CD38 expression. These four genes are important in regulating inflammatory response and BBB stabilization. SNP rs148791848 was a strong trans-eQTL for anosmin-1 (ANOS1) which is involved in neural cell adhesion and axonal migration and may be important after stroke.

Interpretation: This study highlights the contribution of genetic variation to regulating gene expression following IS. Specific inflammatory response to stroke is at least partially influenced by genetic variation. This has implications for progressing toward personalized treatment strategies. Additional research is required to investigate these genes as therapeutic targets.

Citing Articles

The association between polymorphism of LDL-R gene and ischemic stroke risk in Chinese population: A meta-analysis.

Dai Z, Wang Y, Li P, Zhang H, Gou X Heliyon. 2024; 10(4):e26314.

PMID: 38390048 PMC: 10881424. DOI: 10.1016/j.heliyon.2024.e26314.

Proteome Profiling of Brain Vessels in a Mouse Model of Cerebrovascular Pathology.

Haqqani A, Mianoor Z, Star A, Detcheverry F, Delaney C, Stanimirovic D Biology (Basel). 2023; 12(12).

PMID: 38132326 PMC: 10740654. DOI: 10.3390/biology12121500.

Monocyte, neutrophil, and whole blood transcriptome dynamics following ischemic stroke.

Carmona-Mora P, Knepp B, Jickling G, Zhan X, Hakoupian M, Hull H BMC Med. 2023; 21(1):65.

PMID: 36803375 PMC: 9942321. DOI: 10.1186/s12916-023-02766-1.

Early peripheral blood gene expression associated with good and poor 90-day ischemic stroke outcomes.

Amini H, Knepp B, Rodriguez F, Jickling G, Hull H, Carmona-Mora P J Neuroinflammation. 2023; 20(1):13.

PMID: 36691064 PMC: 9869610. DOI: 10.1186/s12974-022-02680-y.

Bioinformatic analysis and clinical diagnostic value of hsa_circ_0004099 in acute ischemic stroke.

Zheng J, Luo S, Long Y PLoS One. 2022; 17(11):e0277832.

PMID: 36399471 PMC: 9674149. DOI: 10.1371/journal.pone.0277832.

References

Matarin M, Brown W, Scholz S, Simon-Sanchez J, Fung H, Hernandez D . A genome-wide genotyping study in patients with ischaemic stroke: initial analysis and data release. Lancet Neurol. 2007; 6(5):414-20. PMC: 2613843. DOI: 10.1016/S1474-4422(07)70081-9. View

Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M . Mapping complex disease traits with global gene expression. Nat Rev Genet. 2009; 10(3):184-94. PMC: 4550035. DOI: 10.1038/nrg2537. View

Shabalin A . Matrix eQTL: ultra fast eQTL analysis via large matrix operations. Bioinformatics. 2012; 28(10):1353-8. PMC: 3348564. DOI: 10.1093/bioinformatics/bts163. View

Miao L, Yin R, Yang S, Huang F, Chen W, Cao X . Association between single nucleotide polymorphism rs9534275 and the risk of coronary artery disease and ischemic stroke. Lipids Health Dis. 2017; 16(1):193. PMC: 5629769. DOI: 10.1186/s12944-017-0584-5. View

Franceschini N, Giambartolomei C, de Vries P, Finan C, Bis J, Huntley R . GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. Nat Commun. 2018; 9(1):5141. PMC: 6277418. DOI: 10.1038/s41467-018-07340-5. View

. Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study. Lancet Neurol. 2015; 15(2):174-184. PMC: 4912948. DOI: 10.1016/S1474-4422(15)00338-5. View

Glynne R, Ghandour G, Rayner J, Mack D, Goodnow C . B-lymphocyte quiescence, tolerance and activation as viewed by global gene expression profiling on microarrays. Immunol Rev. 2000; 176:216-46. DOI: 10.1034/j.1600-065x.2000.00614.x. View

Devireddy L, Green M . Transcriptional program of apoptosis induction following interleukin 2 deprivation: identification of RC3, a calcium/calmodulin binding protein, as a novel proapoptotic factor. Mol Cell Biol. 2003; 23(13):4532-41. PMC: 164849. DOI: 10.1128/MCB.23.13.4532-4541.2003. View

Traylor M, Malik R, Nalls M, Cotlarciuc I, Radmanesh F, Thorleifsson G . Genetic variation at 16q24.2 is associated with small vessel stroke. Ann Neurol. 2016; 81(3):383-394. PMC: 5366092. DOI: 10.1002/ana.24840. View

10.

Strober B, Elorbany R, Rhodes K, Krishnan N, Tayeb K, Battle A . Dynamic genetic regulation of gene expression during cellular differentiation. Science. 2019; 364(6447):1287-1290. PMC: 6623972. DOI: 10.1126/science.aaw0040. View

11.

. Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2016; 15(7):695-707. PMC: 4943223. DOI: 10.1016/S1474-4422(16)00102-2. View

12.

Ng B, White C, Klein H, Sieberts S, McCabe C, Patrick E . An xQTL map integrates the genetic architecture of the human brain's transcriptome and epigenome. Nat Neurosci. 2017; 20(10):1418-1426. PMC: 5785926. DOI: 10.1038/nn.4632. View

13.

Soderholm M, Pedersen A, Lorentzen E, Stanne T, Bevan S, Olsson M . Genome-wide association meta-analysis of functional outcome after ischemic stroke. Neurology. 2019; 92(12):e1271-e1283. PMC: 6511098. DOI: 10.1212/WNL.0000000000007138. View

14.

Cassandri M, Smirnov A, Novelli F, Pitolli C, Agostini M, Malewicz M . Zinc-finger proteins in health and disease. Cell Death Discov. 2017; 3:17071. PMC: 5683310. DOI: 10.1038/cddiscovery.2017.71. View

15.

Jickling G, Xu H, Stamova B, Ander B, Zhan X, Tian Y . Signatures of cardioembolic and large-vessel ischemic stroke. Ann Neurol. 2010; 68(5):681-92. PMC: 2967466. DOI: 10.1002/ana.22187. View

16.

Rannikmae K, Davies G, Thomson P, Bevan S, Devan W, Falcone G . Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurology. 2015; 84(9):918-26. PMC: 4351667. DOI: 10.1212/WNL.0000000000001309. View

17.

Bevan S, Traylor M, Adib-Samii P, Malik R, Paul N, Jackson C . Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genomewide associations. Stroke. 2012; 43(12):3161-7. DOI: 10.1161/STROKEAHA.112.665760. View

18.

Choe C, Lardong K, Gelderblom M, Ludewig P, Leypoldt F, Koch-Nolte F . CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia. PLoS One. 2011; 6(5):e19046. PMC: 3097994. DOI: 10.1371/journal.pone.0019046. View

19.

Arning A, Hiersche M, Witten A, Kurlemann G, Kurnik K, Manner D . A genome-wide association study identifies a gene network of ADAMTS genes in the predisposition to pediatric stroke. Blood. 2012; 120(26):5231-6. DOI: 10.1182/blood-2012-07-442038. View

20.

Li Y, van de Geijn B, Raj A, Knowles D, Petti A, Golan D . RNA splicing is a primary link between genetic variation and disease. Science. 2016; 352(6285):600-4. PMC: 5182069. DOI: 10.1126/science.aad9417. View