Citation:
Circulation. 2018;[Epub ahead of print] doi:10.1161/CIRCULATIONAHA.118.034016
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 APOOP1 regulates levels of LDL-C in humans, thus identifying a novel mechanism of lipid homeostasis.
Epub:
Not Epub
Link to Publication:
http://circ.ahajournals.org/content/early/2018/03/27/CIRCULATIONAHA.118.034016
Organism or Cell Type:
zebrafish