Jeffrey S. Buguliskis Ph.D. Technical Editor Genetic Engineering & Biotechnology News

It’s Important to Examine the Associated Genetic Complexities

Since cardiovascular disease (CVD) still represents the leading cause of death in the United States, researchers are, if anything, only more determined to identify the triggers of disease and those who may be at greatest risk. Science has made considerable progress over the years identifying and even treating many of the risk factors that contribute considerably to CVD progression (e.g., hypertension, type 2 diabetes, cigarettes, and physical inactivity), resulting in an overall decline in mortality rates.

However, in the genomic age, researchers feel they can push the diagnostic testing boundaries even further by testing for subclinical disease through specific genetic biomarkers. This spirit animates a recent report published online ahead of print in Nature and discussed in GEN. It describes how a scientific team led by researchers at Massachusetts General Hospital discovered the first gene linked to mitral valve prolapse (MVP).

While it has been well documented that MVP is heritable and variably expressed in families, a specific genetic marker had not been previously identified. Although more work will need to be done with larger cohorts of MVP patients to determine the prevalence of the mutation in the DCHS1 gene, the identification of this genetic mechanism may hold potential for presurgical therapeutic intervention—an important discovery given that MVP affects nearly 1 in 40 people worldwide.  

Mendel’s Heart Was in the Right Place

To understand the impact that genetic testing has on the diagnosis and treatment of CVD, it’s important to have an appreciation for the genetic complexities surrounding different diseases of the heart. Prior to the rapid rise in genomics over the last few years, several genes associated with Mendelian forms of CVD—those that follow classic inheritance patterns—were identified. However, these diseases only represent a small percentage of CVD cases, albeit no less deleterious to those patients stricken with them. Some examples include aortic aneurysms, hypertrophic cardiomyopathy, long-QT syndrome, and premature myocardial infarction (occurring at or younger than 55 (men) or 65 (women). These diseases are often called simple, or monogenic, in that a single gene is sufficient to cause disease.

Additionally, there have been various recessive mutations identified that have been associated with familial forms of cardiovascular risk factors. Consequently, genetic studies led to the observation that mutations in the low-density lipoprotein receptor results in hypercholesterolemia and myocardial infarction—a Nobel winning discovery that eventually paved the way for the development of statin drugs.

The majority of CVDs, however, are not caused by a single gene mutation and are considered to be polygenic, having heritable and environmental contributions toward the disease phenotype. These multigenic defects have complicated diagnostic measures that are often employed to determine progression of the disease, as patient to patient variance makes it difficult to home in on the most important offending genes. Scientists realized a number of years ago that simple genetic analyses or even genetic linkage studies using several hundred DNA markers would not provide the requisite resolution to identify predisposing polygenic traits.

With the rise of next-generation sequencing technology, researchers have the power to analyze DNA sequences more epidemiologically, by rapidly deciphering mass quantities of genetic information from an array of patients in an extremely short period of time. These genome-wide association studies (GWAS) have allowed scientists to assemble catalogs of cardiovascular variants leading to the discovery of a large number of new genetic loci associated with CVD risk factors and subclinical indexes.

For instance, scientists from the China-Japan Friendship Hospital in Beijing recently reported in PLOS One on a GWAS using close to 5,000 type 2 diabetes patients, not currently taking lipid-lowering medications. The researchers found five single nucleotide polymorphisms (SNPs) that were significantly associated with increased triglyceride levels. Furthermore, the investigators found that one of the SNPs, TOMM40, was associated with increased LDL levels in study patients. These are important findings since it has been well documented previously that dyslipidemia is a strong risk factor for CVD.

Studies like this provide important insight into the molecular underpinnings that often initiate the progression toward CVD. Yet, GWAS are not the only tool accessible to genomic scientists. Many studies have looked at either specific mutations and/or SNPs, thought to have an association with various diseases of the heart, using NGS techniques such as whole-exome sequencing, which looks at only the coding regions of the genome. Alternatively, whole-genome sequencing, which deciphers the entire genome, can identify SNP’s within the noncoding regions of DNA that often play a role in gene regulation.

“Whole-exome sequencing techniques, particularly in those with “panel-negative” cases, have provided additional yield in single center experiences, as it relates to identifying novel genetic determinants of inherited cardiovascular diseases, but current costs and lack of reimbursement remained limiting factors,” explains W.H. Wilson Tang, M.D., Director of the Center for Clinical Genomics at the Cleveland Clinic. “Newer noncoding genetic and epigenetic markers (circulating or tissue-specific) are also emerging, but many are still in investigative stages. There is hope that whole-genome sequencing may someday unravel genetic regulation and complex interactions with noncoding regions (e.g. 9p21 polymorphism) that have long been linked to cardiovascular diseases, but via unknown mechanisms.” 

Cross My Heart and Hope to Thrive

As with all healthcare related research, the public and scientists alike tend to ask similar questions: how applicable is this to treating disease and when can we see it in use within a clinical setting? While NGS techniques have made some headway, converting from a pure laboratory method to a clinical diagnostic tool, obstacles still remain. Interestingly, the theme of reimbursement guidelines seems to be a common thread among the application of genomic methods in precision medicine—a “kink” that will need to be worked out sooner rather than later, if personalized medicine is to come to fruition.

“The lack of uniform reimbursement and guidance to treatment alterations in probands remain the single biggest limitation to widespread implementation of cardiac disease genetic testing. This is understandable at present because even with identified genetic mutations it may not be necessary to change treatment approaches, only to benefit from cascade testing for at-risk mutation carriers,” states Dr. Tang. “Furthermore, there is a lack of basic genomic medicine education in cardiovascular disease training, and the paucity of clinically relevant or treatment-related translational research in cardiovascular genomics also poses some challenges.”

Setting the bureaucratic complications aside, if the scientific strides made in CVD genomics and testing are any indication of its future, than we should be prepared for real meaningful cardiac therapies soon. Furthermore, the combination of fields like pharmacogenomics with cardiogenomics should help shape current drug regimens for CVD patients and aid in the rational design of new therapies.

“Specific therapeutic approaches targeting specific cardiovascular genetic diseases are in early-phase development, several of them provide opportunities to potentially prevent or delay onset of overt manifestations,” notes Dr. Tang. “Some of them, including various rare systemic diseases such as transthyretin amyloidosis or Duchenne’s muscular dystrophy, already have specific drug targets and have been in active clinical investigations.” 

Interestingly there may even be assistance to CVD testing coming from seemingly unrelated areas. As Dr. Tang points out, “there is increasing recognition of the contributory role of the gut microbiome in cardiometabolic disorders as well as cardiovascular disease pathogenesis—an area that is currently under active investigations.”

Dr. Tang goes on to add that CVD genomics has already made an impact on patient’s lives and that he is optimistic of a successful future. “The biggest yield so far in cardiovascular genetics has been the discovery of novel drug targets (like PCSK9) based on genomic analyses of rare variants that can identify disease mechanisms, and there is hope that more will come.” 

This article was originally published in the September 2015 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to

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