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. KaneRichard P. Lifton, Clive R. Pullinger

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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 ¼ 20), STAB1 (n ¼ 9), OSBPL1A (n ¼ 8), CPS1 (n ¼ 8), CD36 (n ¼ 7), LRP1 (n ¼ 6), ABCA8 (n ¼ 6), GOT2 (n ¼ 5), AMPD3 (n ¼ 5), WWOX (n ¼ 4), and IRS1 (n ¼ 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.

Original languageEnglish
Article number100209
JournalJournal of Lipid Research
Volume63
Issue number6
DOIs
Publication statusPublished - 2022 Jun

Bibliographical note

Publisher Copyright:
© 2022 THE AUTHORS. Published by Elsevier Inc

Keywords

  • HDL
  • LDL
  • dyslipidemia
  • genetics
  • lipoproteins
  • prebeta-1 HDL
  • reverse cholesterol transport
  • triglycerides

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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