Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with progressive atherosclerosis and incident cardiovascular disease.

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.

• Authors: 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
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 35 Issue 1 Pg. 229-36 (Jan 2015) ISSN: 1524-4636 [Electronic] United States
• PMID: 25359861 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• APOB protein, human
• Apolipoprotein B-100
• Genetic Markers
• Phospholipids
• HMOX1 protein, human
• Heme Oxygenase-1

Topics

• Aged
• Aged, 80 and over
• Apolipoprotein B-100 (blood)
• Atherosclerosis (blood, diagnosis, enzymology, genetics, mortality)
• Austria (epidemiology)
• Cardiovascular Diseases (blood, diagnosis, enzymology, genetics, mortality)
• Disease Progression
• Female
• Genetic Markers
• Genetic Predisposition to Disease
• Heme Oxygenase-1 (genetics)
• Heterozygote
• Homozygote
• Humans
• Incidence
• Male
• Middle Aged
• Minisatellite Repeats
• Myocardial Infarction (enzymology, genetics, mortality)
• Oxidation-Reduction
• Phenotype
• Phospholipids (blood)
• Polymorphism, Genetic
• Promoter Regions, Genetic
• Proportional Hazards Models
• Prospective Studies
• Risk Factors
• Stroke (enzymology, genetics, mortality)