Identification of 20 novel loci associated with ischaemic stroke. Epigenome-wide association study

Soriano‐Tárraga, Carolina; Lazcano, Uxue; Giralt‐Steinhauer, Eva; Avellaneda-Gómez, C.; Ois, Ángel; Rodríguez-Campello, Ana; Cuadrado-Godia, Elisa; Gómez-González, Alejandra; Fernández‐Sanlés, Alba; Elosúa, Roberto; Fernández‐Cadenas, Israel; Cullell, Nàtalia; Montaner, Joan; Morán, Sebastian; Esteller, Manel; Jiménez‐Conde, Jordi; Roquer, Jaume

doi:10.1080/15592294.2020.1746507

Cited by 29 publications

(28 citation statements)

References 32 publications

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“…Finally, having demonstrated the EPICOVID signature to be associated with patients who developed severe COVID-19 symptomatology, we set out to measure the frequency of the epigenomic profile in the general population. To achieve this goal, we determined the DNA methylation status of whole blood samples of 338 healthy individuals interrogated with the same epigenomic microarray platform [59] , [60] , [61] , [62] . All of them were ≤ 61-year-old adults, as in our discovery and validation cohorts.…”

Section: Resultsmentioning

confidence: 99%

Epigenome-wide association study of COVID-19 severity with respiratory failure

et al. 2021

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Background Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. Methods Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery ( n = 207) and validation ( n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. Findings The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. Interpretation We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. Funding The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

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Section: Resultsmentioning

confidence: 99%

Epigenome-wide association study of COVID-19 severity with respiratory failure

et al. 2021

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“…Certainly, IS is a heterogeneous disease with a genetic predisposition ( Acosta et al, 2021 ). Emerging evidence has revealed the importance of epigenetic regulations in IS, particularly DNA methylation ( Gómez-Úriz et al, 2015 ; Davis Armstrong et al, 2018 ; Shen et al, 2019 ; Soriano-Tárraga et al, 2020 ). Our study presented genome-wide alterations in DNA methylation in IS patients and controls by identifying a total of 462 functional DMPs corresponding to 373 annotated genes and revealed that hypomethylated sites were eightfold more numerous than DNA hypermethylation sites in IS cases, demonstrating that the hypomethylated modification was predominant in IS.…”

Section: Discussionmentioning

confidence: 99%

“…The current epigenome-wide studies revealed that DNA methylation plays a vital part in the pathogenesis and recurrence of IS ( Soriano-Tárraga et al, 2020 ; Davis Armstrong et al, 2018 ; Gómez-Úriz et al, 2015 ; Shen et al, 2019 ), which have mainly been conducted in American and European populations ( Soriano-Tárraga et al, 2020 ; Davis Armstrong et al, 2018 ; Gómez-Úriz et al, 2015 ). An epigenetic study in a Chinese population revealed that hypomethylation of the MTRNR2L8 gene is associated with IS ( Shen et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Association of DNA Methylation Patterns in 7 Novel Genes With Ischemic Stroke in the Northern Chinese Population

Liu

et al. 2022

Front. Genet.

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Background: Ischemic stroke is a highly complex disorder. This study aims to identify novel methylation changes in ischemic stroke.Methods: We carried out an epigenome-wide study of ischemic stroke using an Infinium HumanMethylation 850K array (cases:controls = 4:4). 10 CpG sites in 8 candidate genes from gene ontology analytics top-ranked pathway were selected to validate 850K BeadChip results (cases:controls = 20:20). We further qualified the methylation level of promoter regions in 8 candidate genes (cases:controls = 188:188). Besides, we performed subgroup analysis, dose-response relationship and diagnostic prediction polygenic model of candidate genes.Results: In the discovery stage, we found 462 functional DNA methylation positions to be associated with ischemic stroke. Gene ontology analysis highlighted the “calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules” item, including 8 candidate genes (CDH2/PCDHB10/PCDHB11/PCDHB14/PCDHB16/PCDHB3/PCDHB6/PCDHB9). In the replication stage, we identified 5 differentially methylated loci in 20 paired samples and 7 differentially methylated genes (CDH2/PCDHB10/PCDHB11/PCDHB14/PCDHB16/PCDHB3/PCDHB9) in 188 paired samples. Subgroup analysis showed that the methylation level of above 7 genes remained significantly different in the male subgroup, large-artery atherosclerosis subgroup and right hemisphere subgroup. The methylation level of each gene was grouped into quartiles, and Q4 groups of the 7 genes were associated with higher risk of ischemic stroke than Q1 groups (p < 0.05). Besides, the polygenic model showed high diagnostic specificity (0.8723), sensitivity (0.883), and accuracy (0.8777).Conclusion: Our results demonstrate that DNA methylation plays a crucial part in ischemic stroke. The methylation of these 7 genes may be potential diagnostic biomarker for ischemic stroke.

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“…Although a detailed examination of methylation pertinent to LRRC26 is beyond the summary here, such a mechanism has two key features that might merit its consideration as a contributor to LRRC26-based pathologies, namely tissue specificity and reversibility. Although identification of genes that show up-or downregulation by methylation in response to different diseases and xenobiotic agents is a major cottage industry that largely just identifies associations, it is interesting to note LRRC26 is one of a set of 22 methylated CpGs in 21 gene loci associated with ischaemic stroke (Soriano-Tarraga et al 2020).…”

Section: Implications Of Low Affinity Interactions Of Lrrc26mentioning

confidence: 99%

The LRRC family of BK channel regulatory subunits: potential roles in health and disease

González-Pérez

Zhou

Ciorba

et al. 2022

The Journal of Physiology

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Large conductance K+ channels, termed BK channels, regulate a variety of cellular and physiological functions. Although universally activated by changes in voltage or [Ca2+]i, the threshold for BK channel activation varies among loci of expression, often arising from cell‐specific regulatory subunits including a family of leucine rich repeat‐containing (LRRC) γ subunits (LRRC26, LRRC52, LRRC55 and LRRC38). The ‘founding’ member of this family, LRRC26, was originally identified as a tumour suppressor in various cancers. An LRRC26 knockout (KO) mouse model recently revealed that LRRC26 is also highly expressed in secretory epithelial cells and partners with BK channels in the salivary gland and colonic goblet cells to promote sustained K+ fluxes likely essential for normal secretory function. To accomplish this, LRRC26 negatively shifts the range of BK channel activation such that channels contribute to K+ flux near typical epithelial cell resting conditions. In colon, the absence of LRRC26 increases vulnerability to colitis. LRRC26‐containing BK channels are also likely important regulators of epithelial function in other loci, including airways, female reproductive tract and mammary gland. Based on an LRRC52 KO mouse model, LRRC52 regulation of large conductance K+ channels plays a role both in sperm function and in cochlear inner hair cells. Although our understanding of LRRC‐containing BK channels remains rudimentary, KO mouse models may help define other organs in which LRRC‐containing channels support normal function. A key topic for future work concerns identification of endogenous mechanisms, whether post‐translational or via gene regulation, that may impact LRRC‐dependent pathologies.

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Identification of 20 novel loci associated with ischaemic stroke. Epigenome-wide association study

Cited by 29 publications

References 32 publications

Epigenome-wide association study of COVID-19 severity with respiratory failure

Epigenome-wide association study of COVID-19 severity with respiratory failure

Association of DNA Methylation Patterns in 7 Novel Genes With Ischemic Stroke in the Northern Chinese Population

The LRRC family of BK channel regulatory subunits: potential roles in health and disease

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