Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia


Dong W., Wong K. H. Y. , Liu Y., Levy-Sakin M., Hung W., Li M., ...More

JOURNAL OF LIPID RESEARCH, vol.63, no.6, 2022 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 63 Issue: 6
  • Publication Date: 2022
  • Doi Number: 10.1016/j.jlr.2022.100209
  • Journal Name: JOURNAL OF LIPID RESEARCH
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Analytical Abstracts, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, Food Science & Technology Abstracts, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Keywords: dyslipidemia, genetics, HDL, LDL, lipoproteins, prebeta-1 HDL, reverse cholesterol transport, triglycerides, HIGH-DENSITY-LIPOPROTEIN, CORONARY-HEART-DISEASE, REVERSE CHOLESTEROL TRANSPORT, HDL CHOLESTEROL, CARDIOVASCULAR-DISEASE, SERUM-LIPOPROTEINS, APOLIPOPROTEIN-B, EFFLUX, PLASMA, METABOLISM
  • Istanbul University Affiliated: No

Abstract

Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Herita-bility 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 in-dividuals with a mean HDL-C level of 27.8 & PLUSMN; 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 asso-ciation 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.