title: Epigenome-wide association study identifies TXNIP gene associated with type 2 diabetes mellitus and sustained hyperglycemia.
abstract: Type 2 diabetes mellitus (DM) is an established risk factor for a wide range of vascular diseases, including ischemic stroke (IS). Glycated hemoglobin A1c (HbA1c), a marker for average blood glucose levels over the previous 12 weeks, is used as a measure of glycemic control and also as a diagnostic criterion for diabetes (HbA1c levels ≥ 6.5%). Epigenetic mechanisms, such as DNA methylation, may be associated with aging processes and with modulation of the risk of various pathologies, such as DM. Specifically, DNA methylation could be one of the mechanisms mediating the relation between DM and environmental exposures. Our goal was to identify new CpG methylation sites associated with DM. We performed a genome-wide methylation study in whole-blood DNA from an IS patient cohorts. Illumina HumanMethylation450 BeadChip array was used to measure DNA methylation in CpG sites. All statistical analyses were adjusted for sex, age, hyperlipidemia, body mass index (BMI), smoking habit and cell count. Findings were replicated in two independent cohorts, an IS cohort and a population-based cohort, using the same array. In the discovery phase (N = 355), we identified a CpG site, cg19693031 (located in the TXNIP gene) that was associated with DM (P = 1.17 × 10(-12)); this CpG was replicated in two independent cohorts (N = 167 and N = 645). Methylation of TXNIP was inversely and intensely associated with HbA1c levels (P = 7.3 × 10(-16)), specifically related to diabetic patients with poor control of glucose levels. We identified an association between the TXNIP gene and DM through epigenetic mechanisms, related to sustained hyperglycemia levels (HbA1c ≥ 7%).
authors.affiliation: Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Soriano-Tárraga
authors.affiliation: Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain, jjimenez@imim.es.
authors.forename: Jordi
authors.initials: J
authors.lastname: Jiménez-Conde
authors.affiliation: Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Giralt-Steinhauer
authors.affiliation: Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Mola-Caminal
authors.affiliation: Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Vivanco-Hidalgo
authors.affiliation: Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Ois
authors.affiliation: Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodríguez-Campello
authors.affiliation: Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cuadrado-Godia
authors.affiliation: Cardiovascular Epidemiology and Genetics Research Group, IMIM, Barcelona, Spain and Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Sayols-Baixeras
authors.affiliation: Cardiovascular Epidemiology and Genetics Research Group, IMIM, Barcelona, Spain and.
authors.forename: Roberto
authors.initials: R
authors.lastname: Elosua
authors.affiliation: Department of Neurology, Hospital del Mar, Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Roquer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000097:blood / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D006442:Glycated Hemoglobin / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D020521:Stroke / Q000097:blood / Q000235:genetics* / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D006442:Glycated Hemoglobin; C486715:TXNIP protein, human; C517652:hemoglobin A1c protein, human