Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia

Weilai Dong; Karen H.Y. Wong; Youbin Liu; Michal Levy-Sakin; Wei-Chien Hung; Mo Li; Boyang Li; Sheng Chih Jin; Jungmin Choi; Francesc Lopez-Giraldez; Dedeepya Vaka; Annie Poon; Catherine Chu; Richard Lao; Melek Balamir; Irina Movsesyan; Mary J. Malloy; Hongyu Zhao; Pui-Yan Kwok; John P. Kane; Richard P. Lifton; Clive R. Pullinger

Journal of Lipid Research (Jun 2022)

Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia

Weilai Dong,
Karen H.Y. Wong,
Youbin Liu,
Michal Levy-Sakin,
Wei-Chien Hung,
Mo Li,
Boyang Li,
Sheng Chih Jin,
Jungmin Choi,
Francesc Lopez-Giraldez,
Dedeepya Vaka,
Annie Poon,
Catherine Chu,
Richard Lao,
Melek Balamir,
Irina Movsesyan,
Mary J. Malloy,
Hongyu Zhao,
Pui-Yan Kwok,
John P. Kane,
Richard P. Lifton,
Clive R. Pullinger

Affiliations

Weilai Dong: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Karen H.Y. Wong: Cardiovascular Research Institute, University of California, San Francisco, CA, USA
Youbin Liu: Department of Cardiology, The Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
Michal Levy-Sakin: Cardiovascular Research Institute, University of California, San Francisco, CA, USA
Wei-Chien Hung: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Mo Li: Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA
Boyang Li: Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA
Sheng Chih Jin: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
Jungmin Choi: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA; Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea
Francesc Lopez-Giraldez: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Dedeepya Vaka: Institute for Human Genetics, University of California, San Francisco, CA, USA
Annie Poon: Institute for Human Genetics, University of California, San Francisco, CA, USA
Catherine Chu: Institute for Human Genetics, University of California, San Francisco, CA, USA
Richard Lao: Institute for Human Genetics, University of California, San Francisco, CA, USA
Melek Balamir: Department of Internal Medicine, Istanbul University, Istanbul, Turkey
Irina Movsesyan: Cardiovascular Research Institute, University of California, San Francisco, CA, USA
Mary J. Malloy: 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
Hongyu Zhao: Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA
Pui-Yan Kwok: 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
John P. Kane: 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
Richard P. Lifton: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Clive R. Pullinger: Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Physiological Nursing, University of California, San Francisco, CA, USA; For correspondence: Clive R. Pullinger

Journal volume & issue: Vol. 63, no. 6
p. 100209

Abstract

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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.

Published in Journal of Lipid Research

ISSN: 0022-2275 (Print); 1539-7262 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry
Website: https://www.journals.elsevier.com/journal-of-lipid-research

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