Risk of Heart Disease Linked to Inflammation Signal Transducer Gene

A genome wide association study (GWAS) conducted on lymphoblastoid cells taken from subjects homozygous for CAD (coronary artery disease) risk established a link between CAD genetic susceptibility and the response to inflammatory signaling.

One of the challenges for a successful GWAS is to apply the findings in a way that accelerates drug and diagnostics development, including better integration of genetic studies into the drug-development process and a focus on the role of genetic variation in maintaining health as a blueprint for designing new drugs and diagnostics.

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the 9p21 gene desert – a region of "junk” DNA - associated with CAD and type II diabetes. Despite evidence for a role of the associated interval in neighboring gene regulation, the biological foundations of these genetic associations with CAD or type II diabetes have not yet been explained.

Most of the SNP variations associated with disease are not in the region of DNA that codes for a protein. Instead, they are usually in the large noncoding regions on the chromosome between genes, or in the intron sequences that are edited out of the DNA sequence when proteins are processed. These are presumably sequences of DNA that control other genes, but usually, their protein function is not known.

In the current study, investigators at the Scripps Research Institute (La Jolla, CA, USA) analyzed the genetic profiles of 50 adults of European ancestry that were taken from a pool of 244 Caucasian males. Of this group, 25 samples had genetic risk markers for CAD, 24 samples had nonrisk CAD genetic markers, and one individual was nonrisk with a mixed genetic marker.

Results published in the February 10, 2011, issue of the journal Nature revealed that they had found 33 enhancers in 9p21. The interval represented the second densest gene desert for predicted enhancers and was six times denser than the whole genome. The enhancers in 9p21 were associated with the gene STAT1 (signal transducer and activator of transcription 1), which is a member of the signal transducers and activators of transcription family. STAT1 is involved in upregulating genes due to a signal by either type I, type II, or type III interferons.

"This was an extraordinary hunt to find how the risk DNA variant was exerting its effect, and it turned out to be quite remote through a gene known as STAT-1, a vital mediator of inflammation,” said contributing author Dr. Eric J. Topol, professor of cardiology at the Scripps Research Institute. "The hope is that in the future we can find better ways to control inflammation for patients carrying these sequence variants, which may ultimately reduce their risks of heart attacks.”

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