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

Circulation. 2018 Sep 25;138(13):1343-1355. doi: 10.1161/CIRCULATIONAHA.118.034016.


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.

Keywords: cholesterol, LDL; chromosome mapping; founder effect; genetics; pseudogenes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

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


  • Cholesterol, LDL