Scientists from the U.S. Department of Energy's Lawrence Berkeley National Laboratory have learned how an interval of DNA in an unexplored region of the human genome increases the risk for coronary artery disease, the leading cause of death worldwide.
Their research paints a fuller picture of a genetic risk for the disease that was discovered only three years ago and which lurks in one out of two people.
It also reinforces the tantalizing possibility that many more disease risks - and potential therapies - are hidden in the vast and uncharted part of the genome that doesn't contain instructions for making proteins.
The research is reported in the February 21 advance online publication of the journal Nature.
The team focused on an interval of DNA in chromosome 9p21. People who carry variations of this interval have an increased chance of developing coronary artery disease, which is an accumulation of plaque in coronary arteries that restricts blood flow to the heart and causes heart attacks.
Determining how this DNA contributes to the disease is difficult because it's in the poorly understood part of the genome that doesn't code for proteins, the workhorses of cellular function.
In groundbreaking research, the Berkeley Lab scientists found that the DNA interval regulates a pair of genes that inhibit cell division, and that bad copies of the interval reduce the genes' expression. Although more work is needed to understand how this mechanism contributes to coronary artery disease, the researchers speculate that the hobbled genes allow vascular cells to proliferate unchecked and narrow coronary arteries.
"We show that this non-coding interval affects the expression of two cell cycle inhibitor genes located almost 100,000 base pairs away. We believe that something goes awry in variants of this interval, causing vascular cells to divide and multiply more quickly than usual," says Len Pennacchio, a geneticist with Berkeley Lab's Genomics Division who conducted the research with Axel Visel and several other scientists from Berkeley Lab, as well as Jonathan Cohen of the University of Texas Southwestern Medical Center.
The link between an interval of DNA in chromosome 9p21 and a risk for coronary artery disease was established in several recent studies, one of which was published in the journal Science in 2007. In that study, led by Cohen and co-authored by several scientists including Pennacchio, the researchers scoured the human genome for differences in people who have coronary artery disease versus people who don't.
This genome-wide association analysis alighted on a stretch of DNA in chromosome 9p21 that spans 58,000 base pairs of DNA. The study found that people with bad copies of this interval have a moderately higher risk of developing coronary artery disease. In addition, 50 percent of people have one bad copy and 25 percent have two bad copies.
"The risk of coronary artery disease isn't very high in any give person with bad copies. But they are so common that population-wide the effect is significant," says Pennacchio.
Remarkably, the study also found that the DNA interval isn't associated with known risks for coronary artery disease such as diabetes, high blood pressure, and high cholesterol level. An unknown mechanism was at work.
"We landed on this risk interval and immediately said 'wow!' why doesn't it link to problems that we know cause coronary artery disease?" says Pennacchio. "So the big question became: what is this DNA doing?"