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

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

Author information

1
Division of Endocrinology, Diabetes and Nutrition (M.E.M., E.A.O., X.W., A.D.H., R.M., J.A.P., K.A.R., A.R.S., B.D.M., N.A.Z., Y.-P.C.C.), Department of Medicine, University of Maryland School of Medicine, Baltimore.
2
The present affiliation for Dr O'Hare is Department of Biological Sciences, Towson University, MD.
3
Department of Biostatistics, University of Washington, Seattle (K.R.).
4
Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.E.J.).
5
Division of Cardiovascular Medicine (M.M.), Department of Medicine, University of Maryland School of Medicine, Baltimore.
6
Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.).

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.

KEYWORDS:

cholesterol, LDL; chromosome mapping; founder effect; genetics; pseudogenes

PMID:
29593015
PMCID:
PMC6162188
[Available on 2019-09-25]
DOI:
10.1161/CIRCULATIONAHA.118.034016

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