Thrombosis
Heme Oxygenase-1 Gene Promoter Microsatellite Polymorphism Is Associated With Progressive Atherosclerosis and Incident Cardiovascular Disease
Raimund Pechlaner, Peter Willeit, Monika Summerer, Peter Santer, Georg Egger, Florian Kronenberg, Egon Demetz, Günter Weiss, Sotirios Tsimikas, Joseph L. Witztum, Karin Willeit, Bernhard Iglseder, Bernhard Paulweber, Lyudmyla Kedenko, Margot Haun, Christa Meisinger, Christian Gieger, Martina Müller-Nurasyid, Annette Peters, Johann Willeit, Stefan Kiechl
https://doi.org/10.1161/ATVBAHA.114.304729
Arteriosclerosis, Thrombosis, and Vascular Biology. 2014;ATVBAHA.114.304729
Originally published October 30, 2014Raimund Pechlaner
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Peter Willeit
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Monika Summerer
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Peter Santer
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Georg Egger
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Florian Kronenberg
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Egon Demetz
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Günter Weiss
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Sotirios Tsimikas
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Joseph L. Witztum
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Karin Willeit
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Bernhard Iglseder
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Bernhard Paulweber
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Lyudmyla Kedenko
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Margot Haun
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Christa Meisinger
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Christian Gieger
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Martina Müller-Nurasyid
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Annette Peters
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Johann Willeit
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Stefan Kiechl
From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Division of Genetic Epidemiology (M.S., F.K., M.H.), Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (P.W.); Departments of Laboratory Medicine (P.S.) and Internal Medicine (G.E.), Hospital of Bruneck, Bruneck, Italy; Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria (E.D., G.W.); Department of Medicine, University of California San Diego, La Jolla (S.T., J.L.W.); Department of Geriatric Medicine (B.I.) and First Department of Internal Medicine (B.P., L.K.), Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria; Institute of Epidemiology II (C.M., A.P.), Institute of Genetic Epidemiology (C.G., M.M.-N.), Research unit of Molecular Epidemiology (C.G.), Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany (M.M.-N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.M.-N., A.P.).
Abstract
Objective—The enzyme heme oxygenase-1 (HO-1) exerts cytoprotective effects in response to various cellular stressors. A variable number tandem repeat polymorphism in the HO-1 gene promoter region has previously been linked to cardiovascular disease. We examined this association prospectively in the general population.
Approach and Results—Incidence of stroke, myocardial infarction, or vascular death was registered between 1995 and 2010 in 812 participants of the Bruneck Study aged 45 to 84 years (49.4% males). Carotid atherosclerosis progression was quantified by high-resolution ultrasound. HO-1 variable number tandem repeat length was determined by polymerase chain reaction. Subjects with ≥32 tandem repeats on both HO-1 alleles compared with the rest of the population (recessive trait) featured substantially increased cardiovascular disease risk (hazard ratio [95% confidence interval], 5.45 [2.39, 12.42]; P<0.0001), enhanced atherosclerosis progression (median difference in atherosclerosis score [interquartile range], 2.1 [0.8, 5.6] versus 0.0 [0.0, 2.2] mm; P=0.0012), and a trend toward higher levels of oxidized phospholipids on apolipoprotein B-100 (median oxidized phospholipids/apolipoprotein B level [interquartile range], 11364 [4160, 18330] versus 4844 [3174, 12284] relative light units; P=0.0554). Increased cardiovascular disease risk in those homozygous for ≥32 repeats was also detected in a pooled analysis of 7848 participants of the Bruneck, SAPHIR, and KORA prospective studies (hazard ratio [95% confidence interval], 3.26 [1.50, 7.33]; P=0.0043).
Conclusions—This study found a strong association between the HO-1 variable number tandem repeat polymorphism and cardiovascular disease risk confined to subjects with a high number of repeats on both HO-1 alleles and provides evidence for accelerated atherogenesis and decreased antioxidant defense in this vascular high-risk group.
- Received March 28, 2014.
- Accepted October 14, 2014.
- © 2014 American Heart Association, Inc.
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- Heme Oxygenase-1 Gene Promoter Microsatellite Polymorphism Is Associated With Progressive Atherosclerosis and Incident Cardiovascular DiseaseRaimund Pechlaner, Peter Willeit, Monika Summerer, Peter Santer, Georg Egger, Florian Kronenberg, Egon Demetz, Günter Weiss, Sotirios Tsimikas, Joseph L. Witztum, Karin Willeit, Bernhard Iglseder, Bernhard Paulweber, Lyudmyla Kedenko, Margot Haun, Christa Meisinger, Christian Gieger, Martina Müller-Nurasyid, Annette Peters, Johann Willeit and Stefan KiechlArteriosclerosis, Thrombosis, and Vascular Biology. 2014;ATVBAHA.114.304729, originally published October 30, 2014https://doi.org/10.1161/ATVBAHA.114.304729
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- Heme Oxygenase-1 Gene Promoter Microsatellite Polymorphism Is Associated With Progressive Atherosclerosis and Incident Cardiovascular DiseaseRaimund Pechlaner, Peter Willeit, Monika Summerer, Peter Santer, Georg Egger, Florian Kronenberg, Egon Demetz, Günter Weiss, Sotirios Tsimikas, Joseph L. Witztum, Karin Willeit, Bernhard Iglseder, Bernhard Paulweber, Lyudmyla Kedenko, Margot Haun, Christa Meisinger, Christian Gieger, Martina Müller-Nurasyid, Annette Peters, Johann Willeit and Stefan KiechlArteriosclerosis, Thrombosis, and Vascular Biology. 2014;ATVBAHA.114.304729, originally published October 30, 2014https://doi.org/10.1161/ATVBAHA.114.304729Permalink:
