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18-10-2010 | Cardiometabolic | Article

Exome sequencing reveals new mechanism for lipid regulation


Free abstract

MedWire News: Mutations in the gene encoding the angiopoietin-like 3 protein (ANGPTL3) influence plasma levels of low-density lipoprotein (LDL) cholesterol, US investigators have shown.

They say their discovery underscores the potential of sequencing all protein-coding regions of the genome, otherwise known as the "exome," as a means for better understanding inherited disorders.

The study was conducted by Sekar Kathiresan (Massachusetts General Hospital and Harvard Medical School, Boston) and team and is reported this week in the New England Journal of Medicine.

Kathiresan's team applied "next-generation" sequencing - ie, the most recent sequencing methods enabling low-cost, rapid, broad sequencing - to exomes from two siblings with hypobetalipoproteinemia (low plasma levels of apolipoprotein B). Linkage analysis had already ruled out APOB as the causative gene

In addition, DNA samples were available from 38 members across three generations, along with full lipid profiles. A solution hybrid selection method was used to isolate DNA of the exome, before 28,646,006 bases in 164,688 exons from 15,994 genes were targeted for sequencing.

For each participant around 270 new single nucleotide polymorphisms were found, of which approximately 150 were missense and approximately six were nonsense (premature termination) mutations.

The two siblings were found to be compound heterozygotes for two distinct nonsense mutations in ANGPTL3, which encodes the angiopoietin-like 3 protein. This gene has been reported to inhibit lipoprotein lipase and endothelial lipase.

In the affected siblings, the nonsense mutations - S17X and E129X - were significantly associated with both triglyceride and high-density lipoprotein (HDL) cholesterol levels, acting in a dose-dependent manner.

Linkage analyses provided additional evidence that the mutations were causal for combined hypolipidemia (low plasma levels of HDL and LDL cholesterol, and triglycerides). Furthermore, sequencing of ANGPTL3 in an independent population-based cohort, the Dallas Heart Study, showed that carriers of the mutations had significantly lower LDL cholesterol levels than noncarriers.

Kathiresan et al conclude: "We found that nonsense mutations in ANGPTL3 resulted in decreased plasma LDL cholesterol levels and, in persons harboring two nonsense alleles, a phenotype of familial combined hypolipidemia.

"This finding highlights the promise of exome sequencing in medical genetics. It also underscores a new mechanism for the lowering of LDL cholesterol in humans."

MedWire ( is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

By Joanna Lyford