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International Team IDs Rare and Common Variants behind Extreme Blood Triglyceride Condition

By Andrea Anderson

NEW YORK (GenomeWeb News) – Both rare and common variants contribute to individuals' genetic risk for very high blood triglyceride levels, according to a paper appearing in the early, online edition of Nature Genetics yesterday.

An international research team led by investigators in Canada used a combination of microarrays and selective re-sequencing to pin down common and rare variants associated with high triglyceride levels in the blood. In the process, the researchers found what they call a mosaic of rare and common variants, with affected individuals carrying a preponderance of rare genetic changes in the same genes identified using the GWAS approach.

"Our study shows that an accumulation of rare variants is present in GWAS-identified genes and that these contribute to the heritability of complex traits among individuals at the extreme of a lipid phenotype," senior author Robert Hegele, a physician and biochemistry researcher at the University of Western Ontario's Robarts Research Institute, and his co-authors wrote.

Although individuals with hypertriglyceridemia — high triglyceride lipid levels in the blood — are at risk of heart attack, stroke, and other serious conditions, the course of action for patients with high triglyceride levels is not as straightforward as it is for individuals with elevated levels of some other blood lipids, Hegele told GenomeWeb Daily News. And while a number of large GWAS have explored the genetics of lipid levels, he added, most have looked across populations that are essentially healthy.

Hegele and his team decided to take a different tack for the current study, focusing on individuals with the highest detectable triglyceride levels in the hopes of finding out more about how to diagnose and treat hypertriglyceridemia.

For the first phase of the study, researchers used the Affymetrix Genome-Wide Human SNP 6.0 array to genotype 463 individuals with extremely high blood triglyceride levels and 1,197 control individuals with normal triglyceride levels. All of the study participants were of European ancestry.

Rather than uncovering new loci linked to the highest triglyceride levels, the GWAS turned up variants affecting a sub-set of the same genes associated triglyceride levels in past GWAS of healthy populations. In particular, the team found ties between hypertriglyceridemia and common variants the APOA5, GCKR, LPL, and APOB genes.

Common variants in these genes seem to explain a bit more of the triglyceride level heritability in individuals with extreme triglyceride levels than they do across the general population, Hegele said. "The common variants are actually more important in the diseased patients than they are in the general population."

But these common variants still only explained a fraction of the overall genetic susceptibility to extremely high blood triglyceride levels.

In an effort to explain more of hypertriglyceridemia's heritability, the team then used Sanger sequencing to re-sequence the four genes identified in their GWAS, looking for rare variants not represented on microarrays.

The researchers found 53 rare variants in these four genes when they looked at 327 healthy control individuals. But individuals with high blood triglycerides had far more rare variants in the same four genes — in a group of 438 affected individuals, the team found 154 rare missense or nonsense variants.

Each of the rare variants turned up in just one or two patients, Hegele said. Overall, though, individuals with very high blood triglyceride levels had far more rare variants than the control individuals, including some mutations predicted of having functional consequences.

Based on these findings, the team argued that "a complex genetic architecture of both common and rare variants in a spectrum of triglyceride-associated genes is responsible for" hypertriglyceridemia.

And the same pattern likely holds true for other genes suspected of contributing to triglyceride levels — as well as for genes involved in other complex traits and conditions, Hegele noted, though he predicts that the relative importance of common and rare variant repertoires will probably vary from one trait to the next.

"We're of the opinion that this is just kind of the tip of the iceberg and that if we had the capacity to sequence more extensively that we would find a lot more rare variants" in hypertriglyceridemia, he said. "My bias is that they're going to be more important than the common variants."

The team is starting on follow-up studies using Sanger sequencing to look for rare variants in genes implicated through studies of mouse models of hypertriglyceridemia, Hegele said. They also plan to employ high-throughput sequencing strategies for more extensive rare variant searches, starting with exome sequencing studies of individuals with very high triglyceride lipid levels.

In the long run, Hegele added, researchers hope that cataloguing such rare and common variants will point to new treatments for hypertriglyceridemia and provide insights into how individuals respond to existing interventions.

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