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

Arterioscler Thromb Vasc Biol. 2015 Jan;35(1):229-36. doi: 10.1161/ATVBAHA.114.304729. Epub 2014 Oct 30.

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.

Keywords: atherosclerosis; cardiovascular disease; genetic polymorphism; risk factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Apolipoprotein B-100 / blood
  • Atherosclerosis / blood
  • Atherosclerosis / diagnosis
  • Atherosclerosis / enzymology*
  • Atherosclerosis / genetics*
  • Atherosclerosis / mortality
  • Austria / epidemiology
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / diagnosis
  • Cardiovascular Diseases / enzymology*
  • Cardiovascular Diseases / genetics*
  • Cardiovascular Diseases / 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
  • Myocardial Infarction / genetics
  • Myocardial Infarction / mortality
  • Oxidation-Reduction
  • Phenotype
  • Phospholipids / blood
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic*
  • Proportional Hazards Models
  • Prospective Studies
  • Risk Factors
  • Stroke / enzymology
  • Stroke / genetics
  • Stroke / mortality

Substances

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