Raimund Pechlaner1, Peter Willeit1, Monika Summerer1, Peter Santer1, Georg Egger1, Florian Kronenberg1, Egon Demetz1, Günter Weiss1, Sotirios Tsimikas1, Joseph L Witztum1, Karin Willeit1, Bernhard Iglseder1, Bernhard Paulweber1, Lyudmyla Kedenko1, Margot Haun1, Christa Meisinger1, Christian Gieger1, Martina Müller-Nurasyid1, Annette Peters1, Johann Willeit1, Stefan Kiechl2. 1. From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Department of Medical Genetics, Molecular and Clinical Pharmacology, 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.). 2. From the Department of Neurology (R.P., P.W., K.W., J.W., S.K.) and Department of Medical Genetics, Molecular and Clinical Pharmacology, 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@i-med.ac.at.
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.
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.
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