title: Associations of functional alanine-glyoxylate aminotransferase 2 gene variants with atrial fibrillation and ischemic stroke.
abstract: Asymmetric and symmetric dimethylarginines (ADMA and SDMA) impair nitric oxide bioavailability and have been implicated in the pathogenesis of atrial fibrillation (AF). Alanine-glyoxylate aminotransferase 2 (AGXT2) is the only enzyme capable of metabolizing both of the dimethylarginines. We hypothesized that two functional AGXT2 missense variants (rs37369, V140I; rs16899974, V498L) are associated with AF and its cardioembolic complications. Association analyses were conducted using 1,834 individulas with AF and 7,159 unaffected individuals from two coronary angiography cohorts and a cohort comprising patients undergoing clinical exercise testing. In coronary angiography patients without structural heart disease, the minor A allele of rs16899974 was associated with any AF (OR = 2.07, 95% CI 1.59-2.68), and with paroxysmal AF (OR = 1.98, 95% CI 1.44-2.74) and chronic AF (OR = 2.03, 95% CI 1.35-3.06) separately. We could not replicate the association with AF in the other two cohorts. However, the A allele of rs16899974 was nominally associated with ischemic stroke risk in the meta-analysis of WTCCC2 ischemic stroke cohorts (3,548 cases, 5,972 controls) and with earlier onset of first-ever ischemic stroke (360 cases) in the cohort of clinical exercise test patients. In conclusion, AGXT2 variations may be involved in the pathogenesis of AF and its age-related thromboembolic complications.
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Seppälä
authors.affiliation: Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Kleber
authors.affiliation: School of Life Science, University of Lincoln, Lincoln, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Bevan
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Leo-Pekka
authors.initials: LP
authors.lastname: Lyytikäinen
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.|Division of Vascular Surgery, Department of Surgery, Tampere University Hospital, Tampere, Finland.
authors.forename: Niku
authors.initials: N
authors.lastname: Oksala
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.|Heart Hospital, Tampere University Hospital, Tampere, Finland.
authors.forename: Jussi A
authors.initials: JA
authors.lastname: Hernesniemi
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Kari-Matti
authors.initials: KM
authors.lastname: Mäkelä
authors.affiliation: Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Rothwell
authors.affiliation: Division of Clinical Neurosciences and Insititute of Genetics and Molecular Medicine, University of Edinburgh, UK.
authors.forename: Cathie
authors.initials: C
authors.lastname: Sudlow
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany &Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Mononen
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Efthymia
authors.initials: E
authors.lastname: Vlachopoulou
authors.affiliation: Heart and Lung Center, Helsinki University Hospital and Helsinki University, Helsinki, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Sinisalo
authors.affiliation: Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Graciela E
authors.initials: GE
authors.lastname: Delgado
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Reijo
authors.initials: R
authors.lastname: Laaksonen
authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.|Satakunta Central Hospital, Department of Surgery, Pori, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Koskinen
authors.affiliation: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
authors.forename: Hubert
authors.initials: H
authors.lastname: Scharnagl
authors.affiliation: Department of Clinical Physiology, Tampere University Hospital and University of Tampere, Tampere, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.affiliation: Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
authors.affiliation: Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.|Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.|Synlab Academy, Synlab Services GmbH, Mannheim, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
mesh_terms: D000368:Aged; D000483:Alleles; D000792:Angiography; D001281:Atrial Fibrillation / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002908:Chronic Disease; D015331:Cohort Studies; D003331:Coronary Vessels / Q000000981:diagnostic imaging; D005260:Female; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D020521:Stroke / Q000235:genetics* / Q000473:pathology; D000637:Transaminases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000637:Transaminases; C019635:Alanine-glyoxylate transaminase