An APOO Pseudogene on Chromosome 5q Is Associated With Low-Density Lipoprotein Cholesterol Levels.

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.

• Authors: May E Montasser, Elizabeth A O'Hare, Xiaochun Wang, Alicia D Howard, Rebecca McFarland, James A Perry, Kathleen A Ryan, Kenneth Rice, Cashell E Jaquish, Alan R Shuldiner, Michael Miller, Braxton D Mitchell, Norann A Zaghloul, Yen-Pei C Chang
• Journal: Circulation (Circulation) Vol. 138 Issue 13 Pg. 1343-1355 (09 25 2018) ISSN: 1524-4539 [Electronic] United States
• PMID: 29593015 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cholesterol, LDL

Topics

• Amish (genetics)
• Animals
• Animals, Genetically Modified
• Atherosclerosis (blood, diagnosis, ethnology, genetics)
• Cholesterol, LDL (blood)
• Chromosomes, Human, Pair 5
• Dyslipidemias (blood, diagnosis, ethnology, genetics)
• Founder Effect
• Genetic Association Studies
• Genetic Predisposition to Disease
• Haplotypes
• Humans
• Phenotype
• Pseudogenes
• Recombination, Genetic
• Risk Factors
• Zebrafish (genetics)