An APOO Pseudogene on Chromosome 5q is Associated with LDL-C Levels
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.
- Received January 28, 2018.
- Revision received March 12, 2018.
- Accepted March 19, 2018.