Using Genetic Mutations to Cure Heart Disease

Researchers from Stanford University School of Medicine and the Palo Alto Veteran Affairs Health Care System have established a section of genetic mutations which govern cholesterol levels in the body and may also guide the development and use of cardiovascular and diabetes drugs. This data was obtained from the DNA composition of about 300, 000 veterans.

The scientists were able to isolate about three mutations which cause disruption in how the respective genes function. Despite how bad it sounds, this isolation was actually beneficial to the veterans who took part in this research. They exhibited improvement in their blood’s cholesterol profiles and showed significantly reduced risks of experiencing heart disease, diabetes, or even abdominal aortic aneurysm. This was dependent on the specific gene mutation conducted.

Genetically Engineered Medication

Tim Assimes, MD, Ph. D. , an associate professor of cardiovascular medicine led the research. He pointed out that the idea of the research was to use genetic data which has been linked to electronic health records and obtained from a significantly large number of individuals in order to identify genetic variants which then improved lipid profiles and provided protection against cardiovascular diseases. Thus they were able to engineer targeted drugs for improvement.

Three main genes were pinpointed by the study- PDE3B, PCSK9, and ANGPTL4. One day, each of these could be targeted to treat either heart disease, abdominal aortic aneurysm or diabetes, in that order. The most intriguing mutation was however noted in PDE3B. Assimes took note of this due to the presence of a drug named cilostazol. This drug mimics the mutation in that gene which is beneficial hence putting the drug in a very strong position for use in the treatment of heart disease. The lead authorship of the study was shared with Derek Klarin, MD, who is a clinical fellow in surgery at Harvard, together with Scott Damrauer, MD, an assistant professor of surgery at the University of Pennsylvania and the Corporal Michael Crescenz VA Medical Center found in Philadelphia.

The Million Veteran Program

Klarin, Damrauer, and Assimes used the power of numbers to identify the molecular factors which hold an influence on the levels of cholesterol in the blood. They also used the national research initiative established at the Veterans Health Administration, named Million Veteran Program, whose aim is to discover the genetic determinants which result in health and disease among United States Veterans, to pool genetic information.

This was done through the use of cholesterol readouts from 297, 626 candidates. From this, they tried to find variants which had a role in cholesterol levels. The study was then able to underline 188 previously identified cholesterol genetic markers and was able to identify 118 previously undiscovered markers.

The researchers then decided to zero in on a narrow silver of rare genetic irregularities for further analysis. This was conducted through the use of a technique known as PheWAS, phenome-wide screen. It was already established that these gene mutations have an effect on cholesterol. However, their intention was to further establish whether these mutations could also affect the risk of development of other diseases. This technique is used to glean information on risk of disease from vast databases of genetic information which is linked to electronic health records.

The scientists noted that each of the mutations had a favorable sway on the veterans' cholesterol levels. However, the difference was in how it had an effect on their exposure to risk from other diseases. The PDE3B mutation resulted in increased protection against heart disease. The PCSK9 mutation both decreased the risk of heart disease as had been previously established, but also the risk of abdominal aortic aneurysm. The mutation of ANGPTL4 led to a dampening of the risk for Type 2 diabetes.

Loss-of-Function Variants

Each of these mutations works as 'loss-of-function' variants. This means they are used to either substantially reduce or completely halt the function of the gene. Thus, this establishes a good case for the development of drugs which mimic the functioning of these mutations. For instance, if the risk of heart disease is significantly reduced by having a faulty PDE3B gene, it becomes a promising pharmaceutical inspiration. The researchers in this study associated the PDE3B mutation with higher HDLs, lower triglycerides and a 20 percent less risk of heart disease.

Despite the efforts made by this research to identify new targets of curbing heart disease, the researchers advised caution against prescribing drugs simply for this purpose. The genetics simply suggest a reduction of triglycerides to reduce the risk of heart disease. However, this should be established after a randomized clinical trial, looking specifically at outcomes of heart disease.

The researchers pointed to how previous information has turned out to be misleading. Despite how good cholesterol profiles may appear, the main objective of the drug should be to bring out the intended outcome, which in this case is a heart attack. However, they hope that this will not be the case with cilostazol.