Nearly 100 Gene Variants Have Been Identified That Contribute to the Genetic Risk for High LDL Cholesterol, Including 59 New Ones.

Aug. 4, 2010 — Researchers have identified nearly 100 gene variants linked to blood lipids, which they say could explain a quarter to a third of hereditary factors influencing cholesterol — a major risk factor for heart disease.

In one of the largest gene mapping studies ever conducted, a global team of investigators scanned the genomes of more than 100,000 people from 17 countries in an effort to locate the genetic hotspots associated with high cholesterol and triglycerides.

Their efforts led to the identification of 59 new genetic variants, or mutations, which contribute to high LDL, or bad, cholesterol within families.

Focusing on one of these variants, a subgroup of researchers also identified a novel regulator of low-density lipoprotein (LDL), or bad, cholesterol, which could potentially lead to new treatments for high cholesterol and heart disease.

A researcher who led that study says the findings demonstrate the value of large-scale gene mapping studies.

Both studies appear in the Aug. 5 issue of the journal Nature.

“There has been some disappointment, especially in the lay press, that genome-wide association studies haven’t led to new therapies,” University of Pennsylvania School of Medicine professor of medicine Daniel J. Rader, MD, tells WebMD. “That is a little naive since we are really very early in the process.”

Mapping Identifies LDL ‘Hotspots’

The first gene mapping studies were conducted just five years ago, and as recently as three years ago only a few gene variants associated with blood lipids had been identified, says Christopher O’Donnell, MD, of the NIH’s National Heart Lung and Blood Institute’s (NHLBI) Framingham Heart Study.

The NHLBI funded the larger cholesterol gene mapping study, along with other NIH agencies.

The goal of large, diverse genome-wide association studies (GWAS), as they are known in research circles, is to identify previously unknown common genetic factors that influence health and disease.

The more than 100,000 genomes scanned in the latest research included people of European, Eastern Asian, Southern Asian, and African-American descent participating in 46 separate heart studies across the globe.

In all, O’Connell and colleagues identified 95 gene variants associated with LDL and triglyceride levels, including 59 new ones. These variants were seen in men and women and in different ethnic groups.

Two of the identified regions are already targets of existing cholesterol drugs, but many others had not previously been associated with cholesterol.

O’Connell tells WebMD that as many as several hundred more gene variants that help regulate cholesterol and triglyceride levels may be identified in the near future.

“We are beginning to understand the biology of lipids in a way that we never did before,” he says. “And new approaches for sequencing genes should help us find less common, but potentially more powerful, hot spots.”

Study Identifies LDL Protein

The investigation by Rader and colleagues focused on a region of chromosome 1p13 identified in the larger study.

For the first time a gene known as Sort1, which encodes a protein known as sortilin, was linked to the regulation of LDL cholesterol.

In studies in mice, the researchers were able to lower blood levels of LDL by dramatically lowering sortilin levels in the liver.

Rader says the Sort1 pathway may prove to be a new regulatory system for regulating cholesterol levels in humans.

“It makes sense that if we can figure out a way to tweak sortilin expression in a way that would reduce LDL in people, this would have a beneficial impact on heart disease risk,” Rader says.

The tricky part, he says, will be finding a way to lower LDL through this pathway without dramatically increasing sortilin in the liver.

“I’m not saying it’s going to be easy, but I do think this is a new pathway that has therapeutic potential.”

The study was partially funded through an American Recovery and Reinvestment Act grant.

O’Connell agrees the study by Rader and colleagues helps to validate the usefulness of large, ethnically diverse genomic mapping research.

“This type of research confirms the importance of large-scale, international collaborations in our attempt to discover the genetic underpinnings of disease,” he says