Abstract 4879: Resequencing APOAI Identifies Common Mutation that Predicts Increased Risk of Ischemic Heart Disease and Decreased Longevity without Dyslipidemia
Apolipoprotein AI (apoAI) is the major protein constituent of high density lipoprotein. Rare mutations in APOAI may associate with:
low HDL cholesterol (HDL-C) with an unclear association to ischemic heart disease (IHD);
hereditary amyloidosis, sometimes characterized by amyloid deposition in the vascular wall and/or in the heart and misdiagnosed as IHD.
To clarify the role of apoAI in IHD in humans, we tested the hypothesis that mutations in APOAI predict risk of IHD and longevity in the general population. We resequenced APOAI in 200 individuals with extreme levels of apoAI from the general population. Effect of identified mutations on HDL-C and on risk of IHD and death was determined prospectively with 31 years follow-up by genotyping 10,440 individuals from The Copenhagen City Heart Study. Functional effects of mutations on lipid profiles and on the morphology of HDL particles were extensively examined by adenovirus transfer of mutations into apoAI-deficient mice. We identified a common mutation (1 in 500 in the general population), A164S, in an “amyloidogenic” part of APOAI, which did not associate with dyslipidemia in humans or in mice, but with normal LCAT activity and morphologically normal HDL particles. The cumulative incidence of IHD and MI in A164S heterozygotes versus non-carriers was increased (P=0.0004 and P=0.0000). Hazard ratios for IHD and MI were, respectively, 3.2 (1.6 – 6.5) and 5.5 (2.6 –11.7). The cumulative survival was decreased for heterozygotes versus non-carriers (P=0.005); the mean reduction in survival time was 9.5 years. Because of the proximity of A164S to known amyloidogenic mutations, and the lack of effect on lipids, we speculate that the mechanism underlying the effect of this mutation on IHD and longevity might be amyloid deposition. In conclusion, we have identified the first mutation in APOAI, which predicts an increased risk of IHD and decreased longevity without dyslipidemia.