April 2009
By David Lin

Connecting Genes and Heart Diseases

Dr. Houser*: “Good morning Mrs. Heart. So, what seems to be the problem?”

Mrs. Heart: “Well doctor… I’m not feeling well, I’m not sure if it’s because I’m stressed lately…I think I might be coming down with something…”

Dr. Houser: “Alright, let’s take a look”

Mrs. Heart: “Okay…So what do you think Doc? I don’t think it’s diet-related because I’ve been eating a well-balanced diet lately….do you think it’s genetic? Is it something I inherited? My father, HeartyHarHar Sr., has had problem with his muscles…Should I be worried?”

Dr. Houser: “I see. Yes…I remember your father well. Well, it doesn’t seem like you have the same problem as your father. What you are feeling could be stress-related. I’ll prescribe some medicine right now which should make you feel a bit better. We’ll also run some tests too, just to be sure. The result will be available in the next hour or two.”

Mrs. Heart: “Okay, thanks Doc.”

Dr. Houser: “No problem, see you in a bit.”

(cue corny fadeout music)

Sounds ludicrous? (That was a rhetorical question.)

But wouldn’t it be great if doctors could actually “communicate” with the heart and provide the necessary management at the time of, or better yet, BEFORE the injury (major problem) occurs?
Absolutely.

“But how?” you might ask.

Scientists are exploring, discovering, and using various biological molecules, traits and indicators, known as “biomarkers”, as a means of investigating the status and wellbeing of the organ and, consequently, the patient.

What exactly are biomarkers, anyway?
Think back to your last trip to the doctor’s office – did he/she listen to your breathing and heartbeat using the stethoscope? Well, an abnormally fast or slow breathing rate or heartbeat can also be considered a “biomarker”, albeit not a specific one (i.e. there can be many different causes which lead to fast or slow breathing and heartbeat). Another example, which you might be familiar with, is doctors measuring the glucose level in blood of patients who have been fasting to help diagnose whether the patient has diabetes.

According to Health Canada, biomarker is defined as “a measurable characteristic that is an indicator of normal biologic processes, pathogenic processes, and/or response to therapeutic or other interventions”. This means that a variety of things – heartbeats, breathing rate, specific proteins, metabolites (substances produced from your metabolism) or even unique traits and changes in your genes can all be potentially used as biomarkers for diagnosis or even prognosis of injury or diseases.

Whether it’s for the diagnosis of cancer or assessment of organ-specific damage and/or diseases like diabetes, a variety of biomarkers have been identified.

Genomic Biomarkers
If you have already read some of the articles available on Genome BC’s website regarding DNA, genes and chromosomes [2,3], you are probably aware of the complexity behind them.

To give a brief review, our DNA carries the instructions for most of the proteins and structures in our bodies.

So how might these DNA and genes act as biomarkers to help us with the following scenarios?

Prediction – “How likely are you going to develop a specific heart disease in the future?”

A type of genomic biomarker which may help assess a person’s risk level for developing particular heart disease in the future is called Single Nucleotide Polymorphisms (or SNPs; pronounced ‘snips’). SNPs are a one-nucleotide difference between people and some particular versions can be linked to an increased or decreased risk of specific cardiovascular diseases. In fact, scientists have conducted genome-wide association studies (GWAS; pronounced ‘gee-waas’) to detect these genetic biomarkers in various diseases. For example, studies by Dr. McPherson and others have found SNPs on certain parts of chromosome 9 that may be associated with increased risk for coronary heart disease [4], a type of heart disease which involves the narrowing of small blood vessels that supply blood and nutrient (e.g. oxygen) to the heart.

Diagnosis – “What heart disease do you have exactly?”

The use of microarrays has allowed researchers to analyze the changes in the amount of gene expression (how much it is turned on or produces). A common term used in microarray studies is “gene expression profile”. All this really means is a specific pattern of a combination of gene expression levels. There may a gene expression profile for a heart disease which includes tens, hundreds, or even thousands of genes. In one study, more than two hundred genes have been identified to have significantly different levels in patients with cardiomyopathies (i.e. heart muscle disease) as compared to those without [5]. As you can imagine, different gene expression profiles may be identified to help with the diagnosis of specific heart diseases.

Prognosis – “So we know what heart disease you have…but what’s outlook for you?”

Depending on how the researchers conducted their experiments and the various factors involved (e.g., which population of patients were included in the study? what’s the disease phenotype of interest?), any type of the genomic / genetic biomarkers mentioned above, whether it’d be SNPs, or gene expression profiles, can all potentially provide prognostic values. Studies have shown that genetic biomarkers derived from heart biopsy (i.e. tiny piece of heart muscle tissue doctors obtained for examination) of patients with new onset heart failure (when the heart is unable to pump normally to supply sufficient blood flow for the body) may help assess prognosis of patients (i.e. either good = event-free survival, or bad = death, or need for heart assist device implantation or transplantation) [6].

A hypothetical example: Clinical use of genomic biomarkers in the future

As a hypothetical example, a person might carry SNPs which have been associated with increased risk of development of coronary artery disease (CAD), a type of heart disease characterized by the build up of fatty material in the arteries/blood vessels which supply the heart muscle with oxygen and nutrients. Unfortunately, despite knowing he/she has these disease risk SNPs, the person continues to smoke, drink and eat high cholesterol food at an excessive rate (all factors which can contribute to development of CAD).

One day, the person feels intense pain in the chest and has to be sent to the emergency room. There, the doctor provides the proper supportive treatment and requests a combination of traditional clinical tests and gene expression profile test on the patient’s blood. Based on the test results and the gene expression profile, the patient is diagnosed with heart attack as a result of CAD. Worried about the future progression of CAD, the doctor requests another gene expression profile test. The test result comes back – it’s not good. This patient needs immediate intervention and therapies to prevent the particular CAD from progressing. The patient is given drugs and sent home He/she was also told to limit the smoking / drinking / cholesterol intake.

A few weeks later, patient comes back for check-up and monitoring. The physician runs a couple of tests to assess how well the heart is functioning and measures specific DNA markers to check for response to therapy. Luckily, all is well. The therapy seems to be working; the disease doesn’t seem to be worsening. The patient is going to be alright, after all.

Conclusion – The search continues
In the end, the different types of genomic biomarkers (SNPs, gene expression profiles, etc.) may be complementary to one another. Given our current understanding of cardiovascular diseases, the general consensus among the research community is that, instead of finding that single “miracle” marker for the heart disease of interest, a combination of biomarkers are going to be necessary to achieve the desired prognostic and diagnostic values [7, 8]. But just exactly which are most useful and relevant clinically? That’s the million-dollar question researchers are trying to answer. It is also possible that genomic biomarkers are just another piece of the puzzle, and that we might get better results using a combination of genomic and other biomarkers. Another likely scenario is that genomic biomarker tests are used in conjunction with regular clinical exams.

Regardless of the genomic biomarkers identified by the scientists, diagnoses for cardiac diseases will still require astute physicians’ clinical observations and the correct interpretation of test results. That said, the search for genomic cardiac biomarkers continues.

(We now return the regular programming)

Mrs. Heart: “Hey Doc, so…did the test results come back yet?”

Dr. Houser*: “Hi Mrs. Heart, yes, I just received the results….Let’s see…based on the SNP test, it doesn’t look like you have an increased risk of cardiomyopathy like your dad did. Other gene expression profile test results also came back normal.”

Mrs. Heart: “Phew, that’s great news”

Dr. Houser: “Yup, I think you are going to be just fine”

Mrs. Heart: “By the way, what did you mean by SNP…and genes and gene expression?”

Dr. Houser: “Excellent question. Let me give you the world-wide-web address to Genome BC’s genomics education website…”

(cue corny fadeout music)

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*no relation to Dr. Doogie Howser or Dr. Gregory House. In fact, he’s much older than Doogie and much nicer than Greg).


Did you know…
Genome BC and Genome Canada are also involved in (Genomic) biomarker studies?
Large-scale “biomarker-searching” projects, such as the one funded by Genome Canada (called “the Better Biomarkers of Acute and Chronic Allograft Rejection” project), are currently underway to identify genomic (as well as protein and metabolite) biomarkers which might help pave the way for future diagnosis and prognosis of organ rejection. Similarly, a not-for-profit society, called The PROOF Centre of Excellence (Prevention of Organ Failure), is also working hard to discover, develop, and implement genomic and other types of biomarkers which may provide substantial impact on health care in Canada.


References:

1. Heart disease statistics. 2008 [cited; Available from: http://www.heartandstroke.bc.ca/site/c.kpIPKXOyFmG/b.3644453/k.3454/Statistics.htm.
2. What is a Gene? 2004 [cited; Available from: http://www.genomicseducation.ca/informationArticles/genebasics/what_is_a_gene.asp.
3. Brown, E. The Link Between Chromosomes, DNA, and Genes 2007 [cited; Available from: http://www.genomicseducation.ca/informationArticles/genebasics/chromosomefundamentals.asp.
4. McPherson, R., et al., A common allele on chromosome 9 associated with coronary heart disease. Science, 2007. 316(5830): p. 1488-91.
5. Kittleson, M.M. and J.M. Hare, Molecular signature analysis: using the myocardial transcriptome as a biomarker in cardiovascular disease. Trends Cardiovasc Med, 2005. 15(4): p. 130-8.
6. Heidecker, B., et al., Transcriptomic biomarkers for individual risk assessment in new-onset heart failure. Circulation, 2008. 118(3): p. 238-46.
7. Maisel, A.S., V. Bhalla, and E. Braunwald, Cardiac biomarkers: a contemporary status report. Nat Clin Pract Cardiovasc Med, 2006. 3(1): p. 24-34.
8. Mehra, M.R., E. Feller, and S. Rosenberg, The promise of protein-based and gene-based clinical markers in heart transplantation: from bench to bedside. Nat Clin Pract Cardiovasc Med, 2006. 3(3): p. 136-43.