DNA Methylation and Ischemic Stroke Risk: An Epigenome-Wide Association Study
Por:
Cullell, N, Soriano-Tarraga, C, Gallego-Fabrega, C, Carcel-Marquez, J, Torres-Aguila, NP, Muino, E, Lledos, M, Llucia-Carol, L, Esteller, M, de Moura, MC, Montaner, J, Fernandez-Sanles, A, Elosua, R, Delgado, P, Marti-Fabregas, J, Krupinski, J, Roquer, J, Jimenez-Conde, J and Fernandez-Cadenas, I
Publicada:
1 oct 2022
Ahead of Print:
1 jun 2022
Resumen:
Background Ischemic stroke (IS) risk heritability is partly explained by genetics. Other heritable factors, such as epigenetics, could explain an unknown proportion of the IS risk. The objective of this study is to evaluate DNA methylation association with IS using epigenome-wide association studies (EWAS). Methods We performed a two-stage EWAS comprising 1,156 subjects. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) were assessed using the Infinium 450K and EPIC BeadChip in the discovery cohort (252 IS and 43 controls). Significant DMPs were replicated in an independent cohort (618 IS and 243 controls). Stroke subtype associations were also evaluated. Differentially methylated cell-type (DMCT) was analyzed in the replicated CpG sites using EpiDISH. We additionally performed pathway enrichment analysis and causality analysis with Mendelian randomization for the replicated CpG sites. Results A total of 957 CpG sites were epigenome-wide-significant ( p <= 10 (-7) ) in the discovery cohort, being CpG sites in the top signals (logFC = 0.058, p = 2.35 x 10 (-22) ; logFC = 0.035, p = 3.22 x 10 (-22) , respectively). ZFHX3 and MAP3K1 were among the most significant DMRs. In addition, 697 CpG sites were replicated considering Bonferroni-corrected p -values ( p < 5.22 x 10 (-5) ). All the replicated DMPs were associated with risk of cardioembolic, atherothrombotic, and undetermined stroke. The DMCT analysis demonstrated that the significant associations were driven by natural killer cells. The pathway enrichment analysis showed overrepresentation of genes belonging to certain pathways including oxidative stress. ZFHX3 and MAP3K1 methylation was causally associated with specific stroke-subtype risk. Conclusion Specific DNA methylation pattern is causally associated with IS risk. These results could be useful for specifically predicting stroke occurrence and could potentially be evaluated as therapeutic targets.
Filiaciones:
Cullell, N:
Inst Invest Biomed Sant Pau IIB SANT PAU, Barcelona, Spain
Hosp Univ MutuaTerrassa, Fundacio Docencia & Recerca MutuaTerrassa, Dept Neurol, Barcelona, Spain
Univ Barcelona, Fac Med, Barcelona, Spain
Soriano-Tarraga, C:
Univ Autonoma Barcelona, DCEXS Univ Pompeu Fabra, Hosp Mar, Neurovasc Res Grp,Dept Neurol,IMIM, Barcelona, Spain
Washington Univ, Sch Med, Dept Psychiat Neurogen & Informat, St Louis, MO 63110 USA
Gallego-Fabrega, C:
Inst Invest Biomed Sant Pau IIB SANT PAU, Barcelona, Spain
Carcel-Marquez, J:
Inst Invest Biomed Sant Pau IIB SANT PAU, Barcelona, Spain
Torres-Aguila, NP:
Inst Invest Biomed Sant Pau IIB SANT PAU, Barcelona, Spain
Univ St Andrews, Scottish Oceans Inst, Evolutionary Dev Genom Res Grp, St Andrews, Fife, Scotland
Muino, E:
Inst Invest Biomed Sant Pau IIB SANT PAU, Barcelona, Spain
Lledos, M:
Inst Invest Biomed Sant Pau IIB SANT PAU, Barcelona, Spain
Llucia-Carol, L:
Inst Invest Biomed Sant Pau IIB SANT PAU, Barcelona, Spain
CSIC, Inst Invest Biomed Barcelona, Dept Brain Ischemia & Neurodegenerat, Barcelona, Spain
:
Josep Carreras Leukaemia Res Inst, Barcelona, Spain
Univ Barcelona, Sch Med & Hlth Sci, Dept Physiol Sci, Barcelona, Spain
Inst Catalana Recerca Estudis Avancats, Barcelona, Spain
Ctr Invest Biomed Red Canc, Barcelona, Spain
Montaner, J:
Univ Seville, Hosp Univ Virgen Macarena, Hosp Univ Virgen Rocio, Inst Biomed Seville,Dept Neurol,CSIC, Seville, Spain
Fernandez-Sanles, A:
IMIM, Cardiovasc Epidemiol & Genet Res Grp, Barcelona, Spain
Univ Bristol, Med Res Council Integrat Epidemiol Unit, Bristol, Avon, England
Elosua, R:
IMIM, Cardiovasc Epidemiol & Genet Res Grp, Barcelona, Spain
Inst Carlos III, CIBER Cardiovasc Dis, Barcelona, Spain
Univ Vic Cent Univ Catalonia, Sch Med, Barcelona, Spain
Delgado, P:
Vall Hebron Inst Res, Neurovasc Res Lab, Barcelona, Spain
Marti-Fabregas, J:
Hosp Santa Creu & Sant Pau, Dept Neurol, Barcelona, Spain
Krupinski, J:
Manchester Metropolitan Univ, Sch HealthCare, Ctr Biosci, Manchester, England
Roquer, J:
Univ Autonoma Barcelona, DCEXS Univ Pompeu Fabra, Hosp Mar, Neurovasc Res Grp,Dept Neurol,IMIM, Barcelona, Spain
Jimenez-Conde, J:
Univ Autonoma Barcelona, DCEXS Univ Pompeu Fabra, Hosp Mar, Neurovasc Res Grp,Dept Neurol,IMIM, Barcelona, Spain
Fernandez-Cadenas, I:
Inst Invest Biomed Sant Pau IIB SANT PAU, Barcelona, Spain
Hosp Univ MutuaTerrassa, Fundacio Docencia & Recerca MutuaTerrassa, Dept Neurol, Barcelona, Spain
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