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Abstract: 119 MUTATION IN APOAI PREDICTS INCREASED RISK OF ISCHEMIC HEART DISEASE AND EARLY DEATH WITHOUT LOW HDL CHOLESTEROL
Workshop II-4 - Genetics: Genetics of High Density Lipoproteins Abstract: 119 Citation: Atherosclerosis Supplement 2009, Vol. 10, Issue 2
MUTATION IN APOAI PREDICTS INCREASED RISK OF ISCHEMIC HEART DISEASE AND EARLY DEATH WITHOUT LOW HDL CHOLESTEROL C Lundegaard1, R Frikke-Schmidt1, B Nordestgaard1, A Kateifides2,3, D Kardassis2, V Zannis2,3, P Grande1, A Tybjærg-Hansen1 1
Copenhagen University Hospital, Copenhagen; 2University of Crete Medical School, Heraklion; Boston University School of Medicine, Boston, MA
3
Objective: Mutations in apoA-I may associate with low HDL cholesterol(HDL-C), and predispose to ischemic heart disease(IHD). To clarify the role of apoA-I in IHD in humans, we tested the hypothesis that mutations in APOAI predict risk of IHD and longevity in the general population. Methods: We resequenced APOAI in 200 individuals with extreme levels of apoA-I 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 were examined by adenovirus transfer into apoA-I-deficient mice. Results: We identified a new mutation, A164S, present in 1:500 in the general population, which did not associate with dyslipidemia in humans or in mice. The cumulative incidence of IHD and MI in A164S heterozygotes versus non-carriers was increased (P=0.0004 and P=0.0000). A164S heterozygosity predicted hazard ratios for IHD, MI and early death of, respectively, 3.2(1.6-6.5), 5.5(2.6-11.7), and 2.5(1.3-4.8). Mean reduction in survival time for heterozygotes was 10 years. Similar findings were obtained in an independent study(n=14,228). Because A164S heterozygotes had normal HDL-C and apoA-I levels, confirmed in adenovirus transfected mice, low HDL-C does not explain our findings. Conclusion: This is the first mutation in APOAI which predicts an increased risk of IHD, MI, and early death without low HDL-C.
MUTATION IN APOAI PREDICTS INCREASED RISK OF ISCHEMIC HEART DISEASE AND EARLY DEATH WITHOUT LOW HDL CHOLESTEROL C Lundegaard1, R Frikke-Schmidt1, B Nordestgaard1, A Kateifides2,3, D Kardassis2, V Zannis2,3, P Grande1, A Tybjærg-Hansen1 1
Copenhagen University Hospital, Copenhagen; 2University of Crete Medical School, Heraklion; Boston University School of Medicine, Boston, MA
3
Objective: Mutations in apoA-I may associate with low HDL cholesterol(HDL-C), and predispose to ischemic heart disease(IHD). To clarify the role of apoA-I in IHD in humans, we tested the hypothesis that mutations in APOAI predict risk of IHD and longevity in the general population. Methods: We resequenced APOAI in 200 individuals with extreme levels of apoA-I 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 were examined by adenovirus transfer into apoA-I-deficient mice. Results: We identified a new mutation, A164S, present in 1:500 in the general population, which did not associate with dyslipidemia in humans or in mice. The cumulative incidence of IHD and MI in A164S heterozygotes versus non-carriers was increased (P=0.0004 and P=0.0000). A164S heterozygosity predicted hazard ratios for IHD, MI and early death of, respectively, 3.2(1.6-6.5), 5.5(2.6-11.7), and 2.5(1.3-4.8). Mean reduction in survival time for heterozygotes was 10 years. Similar findings were obtained in an independent study(n=14,228). Because A164S heterozygotes had normal HDL-C and apoA-I levels, confirmed in adenovirus transfected mice, low HDL-C does not explain our findings. Conclusion: This is the first mutation in APOAI which predicts an increased risk of IHD, MI, and early death without low HDL-C.