THOC5: a novel gene involved in HDL-cholesterol metabolism

Abstract

There is strong evidence for the heritability of lipid traits and the genetic risk of cardiovascular diseases ( 1-6 ). During the last two decades, genetic linkage studies have dominated efforts aimed at identifying genes and polymorphisms that contribute to susceptibility for common diseases ( 7 ). However, current advances in high-throughput genotyping technologies have resulted in the recent discovery of numerous loci potentially affecting variability in complex traits, including total cholesterol, LDL-cholesterol (LDL-C), HDLcholesterol (HDL-C), and/or triglycerides (TGs). More than 100 loci-infl uencing lipid phenotypes have been identifi ed in genome-wide association studies (GWASs) and replicated in independent cohorts ( 1-6, 8-11 ). Well-powered GWASs, combined with fi ne mapping of the susceptibility loci, were able to detect even variants with small effect size ( 11-14 ). Nevertheless, only 10-12% of the total variance for plasma lipid traits can be explained by these variants ( 5 ). Newly developed statistical approaches, family-based studies, or epigenetic analyses might facilitate the discovery of further novel Abstract Although numerous genes are known to regulate serum lipid traits, identifi ed 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 = ‫ف‬ 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 identifi ed 14 loci associated with lipid phenotypes reaching P values <10؊ 5 and confi rmed signifi cant 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. -Keller,

Genome-Wide Identification of Rare and Common Variants Driving Triglyceride Levels in a Nevada Population

“…As Supplementary Figure 1 shows, 144 variants in the well-known triglyceride hotspot 11q23.3 were shown to be associated with strong significance to triglyceride levels in the HNPT_EU. There are published associations within this multi-gene region ( BUD13 , ZPR1 , APOC3 , SIK3 , and APOA5 ), as well as MLXIPL, LPL , and GCKR to triglyceride levels: we list only a few here ( Kathiresan et al, 2008 ; Willer et al, 2008 ; Hegele et al, 2009 ; Hindorff et al, 2009 ; Murray et al, 2009 ; Ariza et al, 2010 ; Johansen et al, 2010 ; Ken-Dror et al, 2010 ; Teslovich et al, 2010 ; Waterworth et al, 2010 ; Kraja et al, 2011 ; Comuzzie et al, 2012 ; Kettunen et al, 2012 ; Coram et al, 2013 ; Keller et al, 2013 ; Lutz et al, 2015 ; Yamasaki et al, 2015 ; Hoffmann et al, 2018b ; van der Harst and Verweij, 2018 ; Wojcik et al, 2019 ).…”

“…Variants in well-known triglyceride-related genes such as BUD13 and SIK3 are known to be associated with triglyceride levels, lipid traits, overall lipid homeostasis, or metabolic syndrome ( Kathiresan et al, 2008 ; Kraja et al, 2011 ; Keller et al, 2013 ; Sakamoto et al, 2018 ). Other expected single-variant associations include those in ZPR1 , which codes for a regulatory protein known to bind several transcription factors that may influence obesity ( Ueyama et al, 2015 ); variants within ZPR1 are known to affect triglyceride levels, as well as modulate HDL and total cholesterol levels ( Comuzzie et al, 2012 ; Hoffmann et al, 2018b ; Wojcik et al, 2019 ).…”

Enrichment analyses identify shared associations for 25 quantitative traits in over 600,000 individuals from seven diverse ancestries

“…LPL is one of the most well-studied genes in the regulation of triglyceride levels. It has previously been associated with triglyceride levels in European ancestry cohorts [110][111][112][113][114][115][116][117][119][120][121]141,[141][142][143][144][145][146][147][148][149][150][151][152][153] , East Asian ancestry cohorts 118,154 , and African ancestry cohorts as well as Hispanic and Latin American ancestry cohorts [110][111][112]114,119,152,153,155,156 . The final gene that was genome-wide significant in both the European and East Asian ancestry cohorts, ANGPTL3, has no previous associations in the GWAS catalog and presents a novel candidate gene within the network.…”

Genetic variants in AKR1B10 associate with human eating behavior

“…No further exclusion criteria were used in this study. All individuals underwent extensive phenotyping [ 30 , 34 ] including a standardized interview for past medical history, family history, measurements of anthropometric parameters (waist, hip, BMI, waist to hip ratio (WHR)), measurements of glucose and insulin metabolism (75 g OGTT, blood glucose and insulin levels at several time points (0, 30 and 120 min after meal) [ 35 ]) and measurements of lipid metabolism (total cholesterol levels, high and low density lipoprotein cholesterol levels (HDL-C and LDL-C), and triglyceride concentration (TG)) [ 36 ]. Insulin was measured with the Auto-DELFIA Insulin assay (PerkinElmer Life and Analytical Sciences, Turku, Finland).…”