title: THOC5: a novel gene involved in HDL-cholesterol metabolism.
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). 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.
authors.affiliation: IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Keller
authors.forename: Dorit
authors.initials: D
authors.lastname: Schleinitz
authors.forename: Julia
authors.initials: J
authors.lastname: Förster
authors.forename: Anke
authors.initials: A
authors.lastname: Tönjes
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Böttcher
authors.forename: Antje
authors.initials: A
authors.lastname: Fischer-Rosinsky
authors.forename: Jana
authors.initials: J
authors.lastname: Breitfeld
authors.forename: Kerstin
authors.initials: K
authors.lastname: Weidle
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Rayner
authors.forename: Ralph
authors.initials: R
authors.lastname: Burkhardt
authors.forename: Beate
authors.initials: B
authors.lastname: Enigk
authors.forename: Ines
authors.initials: I
authors.lastname: Müller
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.forename: Moritz
authors.initials: M
authors.lastname: Koriath
authors.forename: Andreas
authors.initials: A
authors.lastname: Pfeiffer
authors.forename: Knut
authors.initials: K
authors.lastname: Krohn
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Joachim
authors.initials: J
authors.lastname: Spranger
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D008076:Cholesterol, HDL / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D005858:Germany / Q000208:ethnology; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D008076:Cholesterol, HDL; D009687:Nuclear Proteins; D012333:RNA, Messenger; C530378:THOC5 protein, human
keywords: genome-wide-association study; mRNA silencing; single nucleotide polymorphism
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