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29-07-2010 | Cardiometabolic | Article

Rare genetic variants contribute to hypertriglyceridemia


Free abstract

MedWire News: Rare mutations in four genes contribute considerably to the unexplained genetic component of hypertriglyceridemia, suggests a study published in the journal Nature Genetics.

Lead researcher Robert Hegele, from the University of Western Ontario in London, Canada, said it was instructive that a single gene was not solely responsible for high triglyceride levels, but rather a mosaic of rare and common variations in several genes.

He added: "It means that to get a full picture of a patient's genetic risk, you need to consider both common and rare variants in many genes simultaneously, and to use methods that will detect both types of variation."

Genome-wide association studies (GWAS) to identify loci associated with population-based plasma lipid levels have generally only been able to identify less than 10% of the variation observed, say the researchers.

The question has therefore arisen whether other forms of genetic variation, such as rare variants with large individual effects, could contribute to the heritability of complex traits such as lipid concentrations.

To investigate further, the team studied 555 individuals with hypertriglyceridemia and mean triglyceride levels of 14.3 mmol/l (1266.6 mg/dl) and compared them with 1319 control individuals with plasma levels of less than 2.3 mmol/l (203.7 mg/dl).

An unbiased GWAS that included 463 affected individuals and 1197 control participants identified common variants in the genes APOA5, GCKR, LPL and APOB that were associated with hypertriglyceridemia.

The team then resequenced the coding regions of these four genes in other individuals and identified a significant accumulation of rare variants among those with hypertriglyceridemia.

This included 154 rare missense or nonsense variants in 438 individuals with hypertriglyceridemia, compared with 53 variants in 327 control individuals.

This corresponded to a significantly higher carrier frequency of these mutations in affected individuals of 28.1% versus 15.3% in control participants.

A model including clinical variables and both common and rare genetic variants explained 41.6% of the total variation in hypertriglyceridemia diagnoses.

Clinical variables accounted for 19.7%, common genetic variants in seven hypertriglyceridemia-associated loci explained 20.8%, and rare genetic variants in four hypertriglyceridemia-associated loci explained 1.1% of the variation.

The researchers conclude: "Our results suggest that a complex genetic architecture of both common and rare variants in a spectrum of triglyceride-associated genes is responsible for hypertriglyceridemia."

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

By Anita Wilkinson