Dataset Information

Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS).

ABSTRACT: Genome-wide association studies have identified numerous variants associated with lipid levels; yet, the majority are located in non-coding regions with unclear mechanisms. In the Insulin Resistance Atherosclerosis Family Study (IRASFS), heritability estimates suggest a strong genetic basis: low-density lipoprotein (LDL, h2?=?0.50), high-density lipoprotein (HDL, h2?=?0.57), total cholesterol (TC, h2?=?0.53), and triglyceride (TG, h2?=?0.42) levels. Exome sequencing of 1,205 Mexican Americans (90 pedigrees) from the IRASFS identified 548,889 variants and association and linkage analyses with lipid levels were performed. One genome-wide significant signal was detected in APOA5 with TG (rs651821, PTG?=?3.67?×?10-10, LODTG?=?2.36, MAF?=?14.2%). In addition, two correlated SNPs (r2?=?1.0) rs189547099 (PTG?=?6.31?×?10-08, LODTG?=?3.13, MAF?=?0.50%) and chr4:157997598 (PTG?=?6.31?×?10-08, LODTG?=?3.13, MAF?=?0.50%) reached exome-wide significance (P??3 with the strongest signal at rs1141070 (LODLDL?=?4.30, PLDL?=?0.33, MAF?=?21.6%) in DFFB. A total of 53 nominally associated variants (P?

SUBMITTER: Gao C

PROVIDER: S-EPMC5884862 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS).

Gao Chuan C Tabb Keri L KL Dimitrov Latchezar M LM Taylor Kent D KD Wang Nan N Guo Xiuqing X Long Jirong J Rotter Jerome I JI Watanabe Richard M RM Curran Joanne E JE Blangero John J Langefeld Carl D CD Bowden Donald W DW Palmer Nicholette D ND

Scientific reports 20180404 1

Genome-wide association studies have identified numerous variants associated with lipid levels; yet, the majority are located in non-coding regions with unclear mechanisms. In the Insulin Resistance Atherosclerosis Family Study (IRASFS), heritability estimates suggest a strong genetic basis: low-density lipoprotein (LDL, h2 = 0.50), high-density lipoprotein (HDL, h2 = 0.57), total cholesterol (TC, h2 = 0.53), and triglyceride (TG, h2 = 0.42) levels. Ex ...[more]

PMID: 29618726

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Project description:BackgroundDyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism. We aimed to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits.MethodsWe analyzed whole-exome (WES) and whole-genome sequencing (WGS) data of 481 and 474 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 79 serum lipid and apolipoprotein phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance spectroscopy.ResultsThe single-variant analysis identified an association between the LIPC p.Thr405Met (rs113298164) and serum apolipoprotein A1 concentrations (p=7.8×10-8). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, GTF3C5, MARCHF10, and RYR3 (p<2.9×10-6). The RBM47 gene is required for apolipoprotein B post-translational modifications, and in our data, the association between RBM47 and apolipoprotein C-III concentrations was due to a rare 21 base pair p.Ala496-Ala502 deletion; in replication, the burden of rare deleterious variants in RBM47 was associated with lower triglyceride concentrations in WES of >170,000 individuals from multiple ancestries (p=0.0013). Two PAVs in GTF3C5 were highly enriched in the Finnish population and associated with cardiovascular phenotypes in the general population. In the previously known APOB gene, we identified novel associations at two protein-truncating variants resulting in lower serum non-HDL cholesterol (p=4.8×10-4), apolipoprotein B (p=5.6×10-4), and LDL cholesterol (p=9.5×10-4) concentrations.ConclusionsWe identified lipid and apolipoprotein-associated variants in the previously known LIPC and APOB genes, as well as PAVs in GTF3C5 associated with LDLC, and in RBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in the PCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD.

Dataset Information

Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS).

Publications

Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS).

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