PUBLICATION
An APOO Pseudogene on Chromosome 5q is Associated with LDL-C Levels
- Authors
- Montasser, M.E., O'Hare, E.A., Wang, X., Howard, A.D., McFarland, R., Perry, J.A., Ryan, K.A., Rice, K., Jaquish, C.E., Shuldiner, A.R., Miller, M., Mitchell, B.D., Zaghloul, N.A., Chang, Y.C.
- ID
- ZDB-PUB-180330-2
- Date
- 2018
- Source
- Circulation 138(13): 1343-1355 (Journal)
- Registered Authors
- McFarland, Rebecca, Zaghloul, Norann A.
- Keywords
- founder, gene mapping, genetics, low-density lipoprotein cholesterol, pseudogene
- MeSH Terms
-
- Amish/genetics*
- Animals
- Animals, Genetically Modified
- Atherosclerosis/blood
- Atherosclerosis/diagnosis
- Atherosclerosis/ethnology
- Atherosclerosis/genetics*
- Cholesterol, LDL/blood*
- Chromosomes, Human, Pair 5*
- Dyslipidemias/blood
- Dyslipidemias/diagnosis
- Dyslipidemias/ethnology
- Dyslipidemias/genetics*
- Founder Effect
- Genetic Association Studies
- Genetic Predisposition to Disease
- Haplotypes
- Humans
- Phenotype
- Pseudogenes*
- Recombination, Genetic
- Risk Factors
- Zebrafish/genetics
- PubMed
- 29593015 Full text @ Circulation
Citation
Montasser, M.E., O'Hare, E.A., Wang, X., Howard, A.D., McFarland, R., Perry, J.A., Ryan, K.A., Rice, K., Jaquish, C.E., Shuldiner, A.R., Miller, M., Mitchell, B.D., Zaghloul, N.A., Chang, Y.C. (2018) An APOO Pseudogene on Chromosome 5q is Associated with LDL-C Levels. Circulation. 138(13):1343-1355.
Abstract
Background
-Elevated levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for CVD via its contribution to the development and progression of atherosclerotic lesions. While 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 1,102 Amish subjects, we identified a variant strongly associated with LDL-C levels. Using a combination of genetic analyses, zebrafish models, and in 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 APOOP1regulates levels of LDL-C in humans, thus identifying a novel mechanism of lipid homeostasis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping