Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia

Weilai Dong¹, Karen H Y Wong², Youbin Liu³, Michal Levy-Sakin², Wei-Chien Hung¹, Mo Li⁴, Boyang Li⁴, Sheng Chih Jin⁵, Jungmin Choi⁶, Francesc Lopez-Giraldez¹, Dedeepya Vaka⁷, Annie Poon⁷, Catherine Chu⁷, Richard Lao⁷, Melek Balamir⁸, Irina Movsesyan², Mary J Malloy⁹, Hongyu Zhao⁴, Pui-Yan Kwok¹⁰, John P Kane¹¹, Richard P Lifton¹, Clive R Pullinger¹²

Affiliations

¹ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
² Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
³ Department of Cardiology, The Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
⁴ Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
⁵ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
⁶ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA; Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea.
⁷ Institute for Human Genetics, University of California, San Francisco, CA, USA.
⁸ Department of Internal Medicine, Istanbul University, Istanbul, Turkey.
⁹ Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA; Department of Pediatrics, University of California, San Francisco, CA, USA.
¹⁰ Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA; Department of Dermatology, University of California, San Francisco, CA, USA.
¹¹ Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
¹² Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Physiological Nursing, University of California, San Francisco, CA, USA. Electronic address: clive.pullinger@ucsf.edu.

PMID: 35460704
PMCID: PMC9126845
DOI: 10.1016/j.jlr.2022.100209

Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia

Weilai Dong et al. J Lipid Res. 2022 Jun.

. 2022 Jun;63(6):100209.

doi: 10.1016/j.jlr.2022.100209. Epub 2022 Apr 20.

Authors

Affiliations

¹ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
² Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
³ Department of Cardiology, The Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
⁴ Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
⁵ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
⁶ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA; Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea.
⁷ Institute for Human Genetics, University of California, San Francisco, CA, USA.
⁸ Department of Internal Medicine, Istanbul University, Istanbul, Turkey.
⁹ Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA; Department of Pediatrics, University of California, San Francisco, CA, USA.
¹⁰ Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA; Department of Dermatology, University of California, San Francisco, CA, USA.
¹¹ Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
¹² Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Physiological Nursing, University of California, San Francisco, CA, USA. Electronic address: clive.pullinger@ucsf.edu.

PMID: 35460704
PMCID: PMC9126845
DOI: 10.1016/j.jlr.2022.100209

Abstract

Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4-36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics.

Keywords: HDL; LDL; dyslipidemia; genetics; lipoproteins; prebeta-1 HDL; reverse cholesterol transport; triglycerides.

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Conflict of interest statement

Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.

Figures

**Fig. 1**
Histogram showing the distribution among participants with low HDL cholesterol of 120 probably damaging rare HDL candidate gene variants. These variants were found within 45 of the 104 candidate genes. HDL, high density lipoprotein.

**Fig. 2**
Individuals with low levels of plasma HDL-C who carry rare, potentially damaging, *LDLR* variants. Twelve of these 14 variants are pathogenic, or probably so.

**Fig. 3**
Enrichment for damaging heterozygous gene variants. Q–Q plots comparing observed versus expected P values in participants with low HDL-C compared to controls. Binomial analysis for D-Mis and LoF variants at MAF of ≤0.0001 (A) and ≤0.001 (B). The significance of the difference between the observed and expected number of heterozygous variants was calculated using a one-sided binomial test. *ABCA1* and *LDLR* show genome-wide threshold significance of increased burden of damaging heterozygous variants at both MAFs. In addition, *HK3* and *CFTR* are significant at an MAF of ≤0.001. LoF, loss-of-function.

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References

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Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia

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Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia

Authors

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Conflict of interest statement

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