Genetically Reduced Antioxidative Protection and Increased Ischemic Heart Disease Risk: The Copenhagen City Heart Study

Abstract

Background-Extracellular superoxide dismutase (EC-SOD) is an antioxidative enzyme found in high concentrations in the arterial wall. Two to three percent of all people in Denmark carry an R213G substitution, which increases plasma concentration 10-fold. This may reduce arterial wall EC-SOD concentrations, increase intimal LDL oxidation, and therefore may accelerate atherogenesis. Our primary hypothesis was that EC-SOD-R213G predisposes to ischemic heart disease (IHD). The secondary hypothesis was that EC-SOD-R213G offers predictive ability with respect to IHD beyond that offered by measurements of plasma EC-SOD and autoantibodies against oxidized LDL (oxLDL). Methods and Results-The primary hypothesis was tested in a prospective, population-based study of 9188 participants from The Copenhagen City Heart Study with 956 incident IHD events during 23 years of follow-up and retested cross-sectionally with independent case populations of patients with IHD (n=943) or ischemic cerebrovascular disease (ICVD) (n=617). Case populations were compared with unmatched IHD/ICVD-free control subjects from The Copenhagen City Heart Study (n=7992). The secondary hypothesis was tested by using a nested case-control study comparing patients with IHD (n=956) with age- and gender-matched control subjects (n=956). Age- and gender-adjusted relative risk for IHD in heterozygotes (n=221, 2.4%) versus noncarriers (n=8965, 97.6%) was 1.5 (95% CI, 1.1 to 2.1). Retesting confirmed this: Age- and gender-adjusted odds ratios for IHD was 1.4 (1.0 to 2.0) and for ICVD 1.7 (1.1 to 2.7). Additional adjustment for plasma EC-SOD produced an odds ratio for IHD in heterozygotes versus noncarriers of 9.2 (1.2 to 72), whereas adjustment for autoantibodies against oxLDL produced an odds ratio of 2.5 (1.2 to 5.3). Conclusions-Heterozygosity for EC-SOD-R213G is associated with increased IHD risk. Genotyping offers predictive ability with respect to IHD beyond that offered by plasma EC-SOD and autoantibodies against oxLDL.