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THOC5 : A novel gene involved in HDL-cholesterol metabolism

Keller, Maria ; Schleinitz, Dorit ; Förster, Julia ; Tönjes, Anke ; Böttcher, Yvonne ; Fischer-Rosinsky, Antje ; Breitfeld, Jana ; Weidle, Kerstin ; Rayner, Nigel W. and Burkhardt, Ralph , et al. (2013) In Journal of Lipid Research 54(11). p.3170-3176
Abstract

Although numerous genes are known to regulate serum lipid traits, identified variants explain only a small proportion of the expected heritability. We intended to identify further genetic variants associated with lipid phenotypes in a self-contained population of Sorbs in Germany. We performed a genome-wide association study (GWAS) on LDL-cholesterol, HDL-cholesterol (HDL-C), and triglyceride (TG) levels in 839 Sorbs. All single-nucleotide polymorphisms with a P value <0.01 were subjected to a meta-analysis, including an independent Swedish cohort (Diabetes Genetics Initiative; n = ∼ 3,100). Novel association signals with the strongest effects were subjected to replication studies in an additional German cohort (Berlin, n = 2,031).... (More)

Although numerous genes are known to regulate serum lipid traits, identified variants explain only a small proportion of the expected heritability. We intended to identify further genetic variants associated with lipid phenotypes in a self-contained population of Sorbs in Germany. We performed a genome-wide association study (GWAS) on LDL-cholesterol, HDL-cholesterol (HDL-C), and triglyceride (TG) levels in 839 Sorbs. All single-nucleotide polymorphisms with a P value <0.01 were subjected to a meta-analysis, including an independent Swedish cohort (Diabetes Genetics Initiative; n = ∼ 3,100). Novel association signals with the strongest effects were subjected to replication studies in an additional German cohort (Berlin, n = 2,031). In the initial GWAS in the Sorbs, we identified 14 loci associated with lipid phenotypes reaching P values <10 -5 and confirmed significant effects for 18 previously reported loci. The combined meta-analysis of the three study cohorts (n(HDL) = 6041; n (LDL) = 5,995; n(TG) = 6,087) revealed a novel association for a variant in THOC5 (rs8135828) with serum HDL-C levels (P = 1.78 × 10-7; Z -score = -5.221). Consistently, the variant was also associated with circulating APOA1 levels in Sorbs. The small interfering RNA-mediated mRNA silencing of THOC5 in HepG2 cells resulted in lower mRNA levels of APOA1, SCARB1, and ABCG8 (all P < 0.05). We propose THOC5 to be a novel gene involved in the regulation of serum HDL-C levels.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Genomewide-association study, MRNA silencing, Single nucleotide polymorphism
in
Journal of Lipid Research
volume
54
issue
11
pages
7 pages
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • scopus:84885996384
  • pmid:24023261
ISSN
0022-2275
DOI
10.1194/jlr.M039420
language
English
LU publication?
yes
id
5b4c6ec6-7f84-4819-8057-8aa28014d493
date added to LUP
2018-10-01 13:52:31
date last changed
2024-04-01 11:25:08
@article{5b4c6ec6-7f84-4819-8057-8aa28014d493,
  abstract     = {{<p>Although numerous genes are known to regulate serum lipid traits, identified variants explain only a small proportion of the expected heritability. We intended to identify further genetic variants associated with lipid phenotypes in a self-contained population of Sorbs in Germany. We performed a genome-wide association study (GWAS) on LDL-cholesterol, HDL-cholesterol (HDL-C), and triglyceride (TG) levels in 839 Sorbs. All single-nucleotide polymorphisms with a P value &lt;0.01 were subjected to a meta-analysis, including an independent Swedish cohort (Diabetes Genetics Initiative; n = ∼ 3,100). Novel association signals with the strongest effects were subjected to replication studies in an additional German cohort (Berlin, n = 2,031). In the initial GWAS in the Sorbs, we identified 14 loci associated with lipid phenotypes reaching P values &lt;10 <sup>-5</sup> and confirmed significant effects for 18 previously reported loci. The combined meta-analysis of the three study cohorts (n<sub>(HDL)</sub> = 6041; n <sub>(LDL)</sub> = 5,995; n<sub>(TG)</sub> = 6,087) revealed a novel association for a variant in THOC5 (rs8135828) with serum HDL-C levels (P = 1.78 × 10<sup>-7</sup>; Z -score = -5.221). Consistently, the variant was also associated with circulating APOA1 levels in Sorbs. The small interfering RNA-mediated mRNA silencing of THOC5 in HepG2 cells resulted in lower mRNA levels of APOA1, SCARB1, and ABCG8 (all P &lt; 0.05). We propose THOC5 to be a novel gene involved in the regulation of serum HDL-C levels.</p>}},
  author       = {{Keller, Maria and Schleinitz, Dorit and Förster, Julia and Tönjes, Anke and Böttcher, Yvonne and Fischer-Rosinsky, Antje and Breitfeld, Jana and Weidle, Kerstin and Rayner, Nigel W. and Burkhardt, Ralph and Enigk, Beate and Müller, Ines and Halbritter, Jan and Koriath, Moritz and Pfeiffer, Andreas and Krohn, Knut and Groop, Leif and Spranger, Joachim and Stumvoll, Michael and Kovacs, Peter}},
  issn         = {{0022-2275}},
  keywords     = {{Genomewide-association study; MRNA silencing; Single nucleotide polymorphism}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{11}},
  pages        = {{3170--3176}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Lipid Research}},
  title        = {{THOC5 : A novel gene involved in HDL-cholesterol metabolism}},
  url          = {{http://dx.doi.org/10.1194/jlr.M039420}},
  doi          = {{10.1194/jlr.M039420}},
  volume       = {{54}},
  year         = {{2013}},
}