Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemiaopen access
- Authors
- Dong, Weila; Wong, Karen H. Y.; Liu, Youbin; Levy-Sakin, Michal; Hung, Wei-Chien; Li, Mo; Li, Boyang; Jin, Sheng Chih; Choi, Jungmin; Lopez-Giraldez, Francesc; Vaka, Dedeepya; Poon, Annie; Chu, Catherine; Lao, Richard; Balamir, Melek; Movsesyan, Irina; Malloy, Mary J.; Zhao, Hongyu; Kwok, Pui-Yan; Kane, John P.; Lifton, Richard P.; Pullinger, Clive R.
- Issue Date
- 6월-2022
- Publisher
- ELSEVIER
- Keywords
- dyslipidemia; genetics; HDL; LDL; lipoproteins; prebeta-1 HDL; reverse cholesterol transport; triglycerides
- Citation
- JOURNAL OF LIPID RESEARCH, v.63, no.6
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF LIPID RESEARCH
- Volume
- 63
- Number
- 6
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/142999
- DOI
- 10.1016/j.jlr.2022.100209
- ISSN
- 0022-2275
- 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.
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Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
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