Transcript

Welcome to AACC’s Expert Access Live Online program

Our topic this month is Genetic Testing to Predict Hypertension and Salt Sensitivity

This month's expert is Robin A Felder, PhD. View the presentation and direct your questions to our experts.

AACC would like to thank Bayer HealthCare Diagnostics for making this program possible.

Is hypertension higher in minority communities...?
Washington, DC

Robin A Felder, PhD: The prevalence of hypertension is higher in African Americans and in other blacks. The latest figures I have is approximately 25% of whites have hypertension, while the incidence in blacks is approximately 36%. However, there is some confusion about "race" and "ethnicity" in the medical literature, so these figures may not be absolute at this time.

In your presentation you note that a substantial portion of essential hypertension may be heritable and suggest that a genetic test may be warranted. My question to you is whether or not the medical community is prepared to deal with all the ramifications of such a test. The genetic tests we currently have focus on relatively rare diseases such as cystic fibrosis (~1 in 35,000) and Huntington’s (1-15 per 100,000)—the exception being breast cancer—and we’re still not sure how best to interpret and use these tests. Is there any hope for effective use of these tests in a disease state that may affect as many as 1 in 4 adults?
Houston, TX

Robin A Felder, PhD: The most important use of a genetic test is to identify the root cause of disease so that we may effect a cure by the best measns possible. In many cases, medical conditions may be cured by allowing nature and healing to take its course (under appropriate medical supervision) and to encourage healthy lifestyles. Hypertension is a disease that can be delayed or prevented by healthy food consumption and exercise. The DASH (Dietary Approaches to Stop Hypertension) diet, developed with NIH funds, is an example of a low salt, low fat diet that can reduce blood pressure by 10%. 81% (Harris poll) of individuals will take a genetic test if there is something positive they can do to overcome their genetic destiny. We hope that polygenic tests for all the chronic diseases (hypertension, asthma, osteoarthritis, diabetes) will encourage individuals to adopt healthy lifestyles. The next diagnostic paradigm is to passively monitor the effect of adopting a healthy lifestyle so that one can remain encouraged to continue the healthy behavior. Passive in-home health monitoring is the subject of another funded program in the Medical Automation Research Center (http://marc.med.viginia.edu).

What is the name of the single nucleotide polymorphism identified in people from Ghana, Italy, and Japan who are known to be sodium sensitive and suffer from edema in the extremeties? Thank you.
Saranac Lake, NY

Robin A Felder, PhD: I am not aware of a specific SNP that is associated with edema in the extremeties. However, the SNPs that we have identified to be associated with salt sensitivity in Japanese and Caucasians (from Italy) all reside in G protein coupled kinase type 4. Unfortunately, we have not yet tested our Ghanaians subjects for salt sensitivity. The salt sensitivity test that is appropriate to use requires about 2 weeks to administer and involves an overnight stay in the hospital. Therefore, this test is not practical to use for the general community.

Hi Robin, I wasn't aware that HT was genetically identifiable! Surely, polymorphism precludes this type of approach?
Scunthorpe, UK

Robin A Felder, PhD: Hypertension is a phenotype measured as an increase in either systolic or diastolic blood pressure (or both). A panel of single nucelotide polymorphisms have been shown to be associated with the expression of the hypertensive phenotype. It would take many years to perform the study of identifying individuals positive for selected SNPs and to correlate their genotype with their increase in blood pressure. Using association studies it is possible to suggest with a relatively high degree of certainty that a certain genetic SNP profile would increase the odds of developing hypertension. On the other hand, salt sensitivity is something that can be identified using a diagnostic procedure. In this case we can show that individuals (Japanese)with three or more SNPs in the GRK4 gene are almost invariably salt sensitive. More work will need to be done to show the true predictive value of a SNP panel for hypertension or salt sensitive hypertension.

I read the PDF and found my answer, thanks anyway.
SARANAC LAKE, NY

Robin A Felder, PhD: You are welcome.

Thank you for an informative presentation, Dr. Felder. You note that 25%–50% of normotensive individuals also show some degree of salt sensitivity, raising the specter that some people could receive needless and potentially expensive treatment as a result of a "false-positive" genetic test. Has anyone suggested clinical tools or test algorithms to help identify this group?
Chicago, IL

Robin A Felder, PhD: Plasma renin activity has been used as a surrogate marker for intermediate phenotypes for hypertension, including salt sensitivity. However, this marker has less than a 50% predictive value. Right now, we feel that if one has 3 or more SNPs for GRK4, there is a relatively higher likelihood for being salt sensitive than salt resistant. We are currently running a 3,000 subject clinical trial funded by the National Heart Lung and Blood Institute in order to further determine the effect of GRK4 SNPs on blood pressure and salt sensitivity. Fortunately, the best and most effective treatment for salt sensitivity is a low salt diet. Unfortunately, many individuals need a positive diagnostic test as a catalyst to adopt healthy lifestyle habits. If you recall the impact that measuring blood lipids had on the fat consumption habits of Americans, one can see that there can be profound public health benefits of the right kind of test.

I'm 70 years of age and I feel quite young and active; it seems that I'm 15 years younger. However, I had hypertension since 1973 and it has been treated with antihypertensive pills. In 1993 I had a major stroke from which I did totally recovered. About 1 year ago, I was diagnosed with an aneurysm of the abdominal aorta (now is 4 cm. diameter). My question is: IS THERE AN ALTERNATIVE MEDICINE METHOD TO CONTROL HYPERTENSION AND TO CONTROL THE GROWTH OF THE ANEURYSM?
Laguna Niguel, CA 92677

Robin A Felder, PhD: As a clinical Ph.D., there is a limit to my medical knowledge. However, my understanding is that your genetic predisposition for elevated blood pressure is probably unrelated to the aneurysm. High blood pressure leads to stroke, renal failure, eye problems, and other pressure related end organ damage. Therefore, it is important to use any means available to maintain a blood pressure under 140mm Hg systolic and 90mm Hg diastolic. Therefore, exercise, maintaining a low body mass index, and staying on the pills are all great ideas. My best wishes for your future good health.

I'm a GP and not quite sure what additional information a positive genetic test would tell me. If some timely BP monitoring on either side of a sodium challenge indicated salt sensitivity, I'd suggest a low-sodium diet and more frequent check-ups. What other investigations would a positive genetic test trigger? Should it change my course of action w/ the patient, i.e. starting drug therapies?
Fargo, ND

Robin A Felder, PhD: I am pleased to get this question from a GP. We are anxious to improve the amount of useful information available to you in order to guide the advice you give your patients as well as the value of the diagnostic services you provide. Many patients are unaware of the harmful effects of elevated blood pressure and salt consumption. Unfortunately, timely monitoring of blood pressure after a high salt meal will not catch most cases of salt sensitivity. For more information on this topic see the following references. de la Sierra. J Hum Hypertens 2002;16(4):255-60 Weinberger. Hypertension 1991;18:67-71 Since subjects with salt sensitivity will have the same morbidity and mortality as subjects with hypertension, there is a need for a diagnostic test. However, the current protocols that are considered "diagnostic" cost over $2,000 to administer (the definitive test is described by de la Sierra, and the shorter version by Weinberger). Hopefully, a genetic panel would help you identify those at risk so that you could help them understand the benefits of a healthy life style. You could also encourage these individuals to visit your clinic more often for an accurate blood pressure determination. We are working on the correlation between selective SNPs for hypertension and/or salt sensitivity and the most likely drug regimen to administer.

I didn't notice anything in your presentation regarding risk of death in otherwise healthy salt-sensitive individuals (my apologies if I overlooked this). Do you know whether this kind of data is available?
Miami, FL

Robin A Felder, PhD: Dr. Weinberger has published a number of articles on this very issue. Basically he has written the that morbidity and mortality for salt sensitivity is similar to that of hypertension. Thus, this condition is truely the "stealth killer," since there is no simple or affordable test. Here is a reference for one of Weinberger's articles Weinberger. Hypertension 1991;18:67-71

Just wanted to remind participants that increased salt sensitivity coupled with decreased activity of the renin-angiotensin-aldosterone system has been shown to predict improved insulin sensitivity in patients with high-salt intake compared to those with low-salt intake, suggesting an interaction among salt intake, salt sensitivity, RAAS and insulin action. And since insulin resistance appears to be part of the pathology of the cluster of cardiovascular risk factors dubbed 'the metabolic syndrome', salt sensitivity testing would be an important factor in recommending dietary guidelines for persons at risk of both the metabolic syndrome and/or CVD.
Malmo, Sweden

Robin A Felder, PhD: Thank you for bringing up the constellation of related diseases which has been termed "the metabolic syndrome." We are studying the interaction of the renin angiotension aldosterone systems and that of the dopaminergic system, which is the basis of the inability for individuals with GRK4 SNPs to properly excrete a salt load. It will be interesting if there are common biochemical pathways that will be behind the links in the metabolic syndrome.

I believe NIH is still accepting grant applications for projects to develop non-invasive or minimally invasive diagnostic screening tests of salt sensitivity. At least that's what their web site indicates (http://grants.nih.gov/grants/guide/pa-files/PA-03-123.html).
Bethesda, MD

Robin A Felder, PhD: As a result of our publications on this topic, we have seen an increasing interest from the NHLBI to fund studies leading to better salt sensitivity tests. I encourage those with novel ideas in this area to seek SBIR or STTR funding. Since this is an RFA, the budget can be subtantially higher than the usual $100K.

Is risk stratification by age, BMI, race, and gender good enough for population-based screening, with additional testing performed on those in the highest-risk group?
Winston-Salem, NC

Robin A Felder, PhD: Since over 93 million Americans have either hypertension, salt sensitivity, or both, using the parameters in your question would be insufficient to pull out the highest risk group. Clearly those with higher BMI and elders are more likely to express the hypertensive phenotype. However, either hypertension and salt sensitivity affects almost one in every two individuals.

I gather that these genetic tests aren't yet available for clinical use, but once they are, how many genes do you think will be assayed on a "hypertension panel" and do you think payers will cover it? There's still great debate about these issues in cystic fibrosis testing.
Independence, MO

Robin A Felder, PhD: We have settled on a 10 SNP panel for now. However, we are constantly refining the SNP mix. Our studies to date and those of other investigators that are testing their available cohorts have shown that SNPs in GRK4 to be the most diagnostic, with further refinement of the predictive value with SNPs in alpha adducin and angiotensin converting enzyme (ACE). Since hypertension and salt sensitivity are diseases with prevalence that is higher than the top other 5 diseases combined, we expect significant interest from payers. Chronic disease consumes over 50% of the health care dollar. Therefore, any diagnostic test that will encourage the American consumer to adopt healthy lifestyles will be cost effective.

what are the tests available for genetic testing for hypertension and salt sensitivity?
philadelphia,pa

Robin A Felder, PhD: We have developed a panel of SNPs that are performed using the Serologicals Amplifluor(TM) technology. We selected this method since it was suitable for most clinical laboratories to perform. However, any molecular testing platform could probably be used. At this time, analyte specific reagents (ASR) are not available to assist laboratories with testing for this panel of SNPs.

The presentation lists several indications for the genetic test. If you know, has an insurer covered this test or a similar genetic test for any of the reasons listed in the presentation?
Sacramento California

Robin A Felder, PhD: We have not approached insurers with a request to cover this test, yet. I am not aware of any precedents for the use of diagnostic testing to encourage positive life style changes. However, the economics for this approach will be highly favorable.

What is the approximate cost of the SNP analysis for salt sensitivity identification?
Saranac Lake, NY

Robin A Felder, PhD: A price for this test has not been set.

Can you further elaborate on the sleep apnea connection with salt sensitivity.
Springfield, NJ

Robin A Felder, PhD: There is a connection between sleep apnea and hypertension that has been described in the literature. The connection between sleep and salt sensitivity is as follows; Normally, blood pressure drops when you are asleep. It quickly comes back to your resting state upon waking. However, salt sensitive subjects generally do not exhibit the dipping phenomenon. Thus, it has been proposed that ambulatory blood pressure monitoring at night could be diagnostic for salt sensitivity. Unfortunately, measuring blood pressure causes the tested subject to wake up. Thus, correlations have not been that strong between dipping and salt sensitivity. We are developing a matress pad that measures blood pressure passively (no cuffs) in order to test the correlation between salt sensitivity and dipping.

Regarding the concept of "low-renin hypertension" and "high renin hypertension" from many years ago, any relevance today, and does this concept have any significance for SNP analyses?
Brooklyn, NY

Robin A Felder, PhD: Several humoral/hormonal changes have been associated with salt sensitivity. For example, low plasma renin activity (PRA) levels are more commonly seen in salt sensitive than salt resistant subjects while normal PRA is more commonly found in SR than in SS subjects. However, salt sensitivity and low PRA do not correlate completely. Moreover, other studies have not found a difference in PRA levels between SS and SR subjects. Nevertheless, low PRA levels have been used as a surrogate marker for salt sensitivity. In such studies, variants of alpha-adducin, G-protein beta 3 subunit, CYP11B2 (aldosterone synthase), angiotensin converting enzyme (ACE), and GRK4 have been found to be associated with low renin and/or salt sensitive hypertension. Plasma plasminogen activator inhibitor-1 (PAI-1) levels have also been correlated with low renin hypertension. Because dopamine 1 receptors (D1R) increase renin secretion and because a D1R polymorphism has been associated with hypertension, it is also possible that low renin hypertension may be associated with D1R SNPs. However, PRA by itself has a relatively low predictive value.

Dear Prof. Thank you for this valuable presentationI am confused about the relation to the race: 1-African Americans have 36% rate. 2-people from Ghana, Italy, and Japan are known to be sodium sensitive.Please clarify.Thank you.Wadid Sadek (Ph.D.)
Wadid Sadek(Ph.D.)Burlington,VT

Robin A Felder, PhD: The rate of expression of the hypertensive phenotype is approximately 25% in Caucasions, 36% in blacks, and 28% in Japanese. I am sure that the expression of salt sensitivity is different in each group as well. However, I am not aware if these studies have been done (due to the difficulty with testing for salt sensitivity). Our data suggest that an intriguing pattern of genetic variation is present at the GRK4 locus. Combining association studies of these genes in large population of subjects from various ethnic groups promises to yield intriguing results that will shed further light on the genetic basis of hypertension and/or salt sensitivity.