A massive gene study has uncovered 157 changes in DNA that alter cholesterol levels, which could change how we think about blood fats.
Many of the DNA changes point to genes not previously linked to blood fats, also called lipids. A surprising number of the variations were also associated with coronary artery disease, type 2 diabetes, obesity, and high blood pressure.
The research also reveals that triglycerides—another type of blood lipid—likely play a larger role in heart disease risk than previously thought.
The results, published in the journal Nature Genetics, come from the Global Lipids Genetics Consortium—a worldwide team of scientists who pooled genetic and clinical information from more than 188,000 people from many countries and heritages.
A team from the University of Michigan led the analysis of the combined data. They used sophisticated computing and statistical techniques to search for genetic variations that modify blood lipid levels.
The results increase by more than a third the total number of genetic variants linked to blood lipids. All but one of the variants associated with blood lipids are near stretches of DNA that encode proteins.
“These results give us 62 new clues about lipid biology, and more places to look than we had before,” says Cristen Willer, the lead author of one paper and an assistant professor of internal medicine, human genetics, and computational medicine and bioinformatics at the University of Michigan. “Once we take the time to truly understand these clues, we’ll have a better understanding of lipid biology and cardiovascular disease—and potentially new targets for treatment.”
But, cautions senior author Gonçalo Abecasis, a professor at the University of Michigan School of Public Health, it will take much further work to study the implicated genes and to find and test potential drugs that could target them. The consortium’s “open science” approach will include publishing further detail online for other researchers to use freely toward this goal.
Rethinking LDL and HDL
A further analysis of the dataset published as a letter accompanying the study was written by lead author Ron Do and senior author Sekar Kathiresan from the Broad Institute and Massachusetts General Hospital. They suggest triglyceride levels have more impact on coronary artery disease risk than previously thought.
This analysis found that genetic variations that increase triglyceride or LDL-cholesterol levels are also associated with higher risk for coronary artery disease. But the analysis also casts further doubt on the role of high-density lipoprotein, known commonly as HDL or “good cholesterol,” in coronary artery disease risk. In recent years, many drugs that modify HDL cholesterol have failed to show a benefit in preventing coronary artery disease.
“Our analysis using more than 185 DNA sequence variants across the genome shows that having genetically elevated triglycerides is associated with increased risk for coronary artery disease, even after accounting for effects on plasma LDL cholesterol and HDL cholesterol. These data suggest that plasma triglyceride-rich lipoproteins reflect processes causal for coronary artery disease,” says Do, a fellow in the human genetics research laboratory of Kathiresan and director of preventive cardiology at Mass General.
“We couldn’t have done this on our own. Great scientists are usually very competitive, but it is great when we come together and accelerate progress,” says Abecasis.
Willer says the research should fuel drug development and experiments in animal models of cardiovascular risk. But in her specialty, probing huge amounts of genetic data, the next steps include looking for “networks” of genes that interact with one another, to try to glean clues about the function of the lesser-understood genes.
Looking for rare genetic variants that are linked with the most severe forms of lipid disorder and heart disease is another challenge, she says. The overlap between these rare, serious variations, and the more common but less severe variations, could help understanding of basic lipid biology.
A Pathway to Independence Award from the National Heart, Lung, and Blood Institute and a National Science Foundation Open Data fellowship partially supported the study.
Source: University of Michigan