May E Montasser1, Elizabeth A O'Hare1,2, Xiaochun Wang1, Alicia D Howard1, Rebecca McFarland1, James A Perry1, Kathleen A Ryan1, Kenneth Rice3, Cashell E Jaquish4, Alan R Shuldiner1, Michael Miller5, Braxton D Mitchell1,6, Norann A Zaghloul1, Yen-Pei C Chang1. 1. Division of Endocrinology, Diabetes and Nutrition (M.E.M., E.A.O., X.W., A.D.H., R.M., J.A.P., K.A.R., A.R.S., B.D.M., N.A.Z., Y.-P.C.C.), Department of Medicine, University of Maryland School of Medicine, Baltimore. 2. The present affiliation for Dr O'Hare is Department of Biological Sciences, Towson University, MD. 3. Department of Biostatistics, University of Washington, Seattle (K.R.). 4. Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.E.J.). 5. Division of Cardiovascular Medicine (M.M.), Department of Medicine, University of Maryland School of Medicine, Baltimore. 6. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.).
Abstract
BACKGROUND: Elevated levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for cardiovascular disease via its contribution to the development and progression of atherosclerotic lesions. Although the genetic basis of LDL-C has been studied extensively, currently known genetic variants account for only ≈20% of the variation in LDL-C levels. METHODS: Through an array-based association analysis in 1102 Amish subjects, we identified a variant strongly associated with LDL-C levels. Using a combination of genetic analyses, zebrafish models, and in vitro experiments, we sought to identify the causal gene driving this association. RESULTS: We identified a founder haplotype associated with a 15 mg/dL increase in LDL-C on chromosome 5. After recombination mapping, the associated region contained 8 candidate genes. Using a zebrafish model to evaluate the relevance of these genes to cholesterol metabolism, we found that expression of the transcribed pseudogene, APOOP1, increased LDL-C and vascular plaque formation. CONCLUSIONS: Based on these data, we propose that APOOP1 regulates levels of LDL-C in humans, thus identifying a novel mechanism of lipid homeostasis.
BACKGROUND: Elevated levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for cardiovascular disease via its contribution to the development and progression of atherosclerotic lesions. Although the genetic basis of LDL-C has been studied extensively, currently known genetic variants account for only ≈20% of the variation in LDL-C levels. METHODS: Through an array-based association analysis in 1102 Amish subjects, we identified a variant strongly associated with LDL-C levels. Using a combination of genetic analyses, zebrafish models, and in vitro experiments, we sought to identify the causal gene driving this association. RESULTS: We identified a founder haplotype associated with a 15 mg/dL increase in LDL-C on chromosome 5. After recombination mapping, the associated region contained 8 candidate genes. Using a zebrafish model to evaluate the relevance of these genes to cholesterol metabolism, we found that expression of the transcribed pseudogene, APOOP1, increased LDL-C and vascular plaque formation. CONCLUSIONS: Based on these data, we propose that APOOP1 regulates levels of LDL-C in humans, thus identifying a novel mechanism of lipid homeostasis.
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