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Identification of four novel genes contributing to familial elevated plasma HDL cholesterol in humans.
- Source :
-
Journal of lipid research [J Lipid Res] 2014 Aug; Vol. 55 (8), pp. 1693-701. Date of Electronic Publication: 2014 Jun 02. - Publication Year :
- 2014
-
Abstract
- While genetic determinants strongly influence HDL cholesterol (HDLc) levels, most genetic causes underlying variation in HDLc remain unknown. We aimed to identify novel rare mutations with large effects in candidate genes contributing to extreme HDLc in humans, utilizing family-based Mendelian genetics. We performed next-generation sequencing of 456 candidate HDLc-regulating genes in 200 unrelated probands with extremely low (≤10th percentile) or high (≥90th percentile) HDLc. Probands were excluded if known mutations existed in the established HDLc-regulating genes ABCA1, APOA1, LCAT, cholesteryl ester transfer protein (CETP), endothelial lipase (LIPG), and UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2). We identified 93 novel coding or splice-site variants in 72 candidate genes. Each variant was genotyped in the proband's family. Family-based association analyses were performed for variants with sufficient power to detect significance at P < 0.05 with a total of 627 family members being assessed. Mutations in the genes glucokinase regulatory protein (GCKR), RNase L (RNASEL), leukocyte immunoglobulin-like receptor 3 (LILRA3), and dynein axonemal heavy chain 10 (DNAH10) segregated with elevated HDLc levels in families, while no mutations associated with low HDLc. Taken together, we have identified mutations in four novel genes that may play a role in regulating HDLc levels in humans.<br /> (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- ATP Binding Cassette Transporter 1 genetics
Adult
Aged
Apolipoprotein A-I genetics
Cholesterol Ester Transfer Proteins genetics
Cholesterol, HDL genetics
Female
Humans
Lipase genetics
Male
Middle Aged
N-Acetylgalactosaminyltransferases genetics
Phosphatidylcholine-Sterol O-Acyltransferase genetics
Polypeptide N-acetylgalactosaminyltransferase
Adaptor Proteins, Signal Transducing genetics
Axonemal Dyneins genetics
Cholesterol, HDL blood
Endoribonucleases genetics
Mutation
Receptors, Immunologic genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1539-7262
- Volume :
- 55
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of lipid research
- Publication Type :
- Academic Journal
- Accession number :
- 24891332
- Full Text :
- https://doi.org/10.1194/jlr.M048710