Stephen Turner, M.D.

The impact of hypertension on our health system is easy to grasp once you know that it is the most common reason an adult seeks health care. It is enormous—and it's expanding along with our national girth. One of every three Americans has hypertension, but 30 percent of them don't know it. That's why it's called the silent killer—many people don't know they have it until it's too late. It's the single most important risk factor for stroke, the most common risk factor for heart disease and a leading cause of kidney disease.

Two decades ago Stephen Turner, M.D., was frustrated by the inability to predict who was going to get or experience its complications, and by not being able to prescribe the most effective medication for patients once they were diagnosed. When early clinical studies showed that inheritance plays a role in the quagmire of causes, Dr. Turner dedicated his career to understanding the genetic basis of essential hypertension (high blood pressure with no identifiable cause). He is now an internationally recognized expert in a field that includes nephrologists, cardiologists, endocrinologists, radiologists, geneticists and epidemiologists.

An Early and Enduring Endeavor in Clinical Research

In 1983, Dr. Turner, along with other Mayo Clinic investigators launched a multidisciplinary research collaboration between the University of Michigan and Mayo Clinic, called the Rochester Family Heart Study, which continues to this day.

The following year, Dr. Turner was awarded one of the first grants to examine the relationship between genetic variation and common disease. The study investigated the genetic basis of abnormalities in sodium transport in humans in an effort to uncover their role in the development and persistence of high blood pressure — a relevant study in light of the high salt diet common to modern societies. Resulting publications established that knowledge about the genetic effects on the ability of red cells to transport sodium holds one of the keys to predicting the probability of having hypertension, independent of the effects of gender, age and body weight.

Under the Rochester Family Heart Study, Dr. Turner and colleagues studied 600 families who had children in Rochester schools.

Bruce Johnson, Ph.D.

"We discovered that blood pressure was more similar between people who share genes than those who do not," says Dr. Turner. "All of our work at that time was based on clinical similarities and differences. The next step was to sort out how much of the similarities were due to genetics, and how much to living together in similar environments. However, the technology was not yet available to measure DNA variation in large groups of subjects."

Fortunately, the group had the foresight to save the blood samples from the studies. With today's biotechnology, the whole genomes from the 4,000 study participants can be amplified to produce large amounts of genetic material, much of it from multiple generations. The genetic data is now being correlated with 20 years of blood pressure and other clinical and laboratory measurements—a unique and valuable resource for follow-up studies in genetic variation.

Dr. Turner's mentorship has led to many studies including those by physiologist Bruce Johnson, Ph.D. and his colleagues Michael Joyner, M.D., Niki Dietz, M.D., Eric Snyder, M.D., and Thomas Olson, M.D. Dr. Johnson's group examined cardiovascular responses to exercise in a group of young adults selected from the Rochester Family Heart Study.

"We had the participants exercise at two work intensities—a low level of exercise where no catecholamines are released, and heavy exercise where substantial amounts of epinephrine and norepinephrine are released," says Dr. Johnson. "Catecholamines stimulate adrenergic receptors which play a role in the cardiovascular adaptations to exercise, including the regulation of blood pressure."

Previous work by Dr. Turner and colleagues has found common variations in the genes that encode for the adrenergic receptors. In addition, this genetic variation caused some receptors to become less sensitive to catecholamine stimulation.

"This may help explain the range of cardiovascular responses observed in healthy adults," says Dr. Johnson. "And it may also provide insight into which patients may benefit from exercise training as an intervention to treat hypertension."

Gary Schwartz, M.D.

Another study that is putting the data to good use is an investigation into the genetics of low-renin hypertension initiated by Mayo nephrologist and hypertension specialist, Gary Schwartz, M.D., in 2003. It is the first study to identify a subset of people whose high blood pressure is based on the responsiveness of an important physiological system. The renin angiotensin system is a hormonal system involved in kidney function and blood pressure regulation. Blood pressure in people who have low activity of that hormonal system changes in response to salt in the diet.

"About 25 percent of people with essential hypertension have low-renin hypertension," explains Dr. Schwartz. "We are identifying this subgroup of people in the Rochester Family Heart Study to investigate their genetic factors. That may help us identify those who will respond to dietary salt restriction or particular drugs. We hope that by studying a smaller, more homogenous subgroup, the genetic signal will be easier to find."

Casting a Wider Net

Although Mayo Clinic initiated the low-renin study, the investigators were happy to share their protocol with long-time collaborators at Emory University , Atlanta , Ga. , and pool results. As researchers delve into the complex mechanisms that regulate blood pressure, even within one individual, they are beginning to understand just how diverse the set of causes are for hypertension. For example, Dr. Schwartz has published studies demonstrating that a person's blood pressure fluctuates considerably with time and activity. Given surprising new findings, such as that some people have a rise in blood pressure during sleep, the task of the researchers, the degree of collaboration, and the size of study samples needed to identify genetic influence, are all daunting.

To address the need, the National Institutes of Health initiated an extensive, collaborative program to identify genes that contribute to hypertension by studying family patterns. The Family Blood Pressure Program (FBPP) (http://www.sph.uth.tmc.edu/hgc/fbpp/) has been continually funded since 1995 and is now providing a publicly available resource to facilitate research into hypertension, its complications and responses to treatment.

FBPP incorporates four networks throughout the United States , including Hawaii . Each network includes multiple research sites and each site includes investigators from multiple disciplines. About 60,000 people, including multiple ethnic and racial groups, including Whites, Blacks, Hispanics, Asians and Pacific Islanders, are enrolled in a variety of FBPP studies.

"A high degree of collaboration is critical to enroll the huge numbers and variety of ethnic and racial groups necessary to characterize the genes that contribute to hypertension," says Dr. Turner. "Blacks, for example, have severe high blood pressure three times as often as whites, get complications more often, and have different responses to drugs. We want to know if that is a result of genetic variation as we see in some other diseases."

Mayo Clinic plays a critical role in the network to which it belongs—the Genetic Epidemiology Network of Arteriopathy (GENOA). In addition to recruiting 5,000 study participants, Mayo provides the network's biochemistry laboratory. Dr. Turner is the primary investigator for GENOA at Mayo.

GENOA has completed sampling and extensive genetic typing on thousands of sibling pairs, including Blacks from Jackson, Miss., Hispanics from Starr County, Tex. and Whites from Rochester, Minn. In 1999, Dr. Turner was one of the GENOA investigators who published the first genome-wide scan for genes influencing blood pressure in the Rochester Family Heart Study and one of the first follow-up studies, which identified chromosome 2.

Heart, Brain and Kidney Complications: Who's at Risk?

Iftikhar Kullo, M.D.

It is important to identify who, among those who have high blood pressure, are at risk of complications that cause heart, brain or kidney disease. The NIH is funding ancillary studies to map the genes that affect whether or not a person gets these complications.

With many DNA samples already measured, Dr. Turner's group now uses an analytical pattern, called linkage analysis, to hunt down the genes by tracing patterns of heredity in families who have these various complications. This effort was buoyed, in 1998, by the addition of cardiologist Iftikhar Kullo, M.D., to the group. Dr. Kullo investigates novel methods of predicting cardiovascular disease, including genetic factors.

A 2001 GENOA study using genome-wide linkage analysis turned up evidence that there are multiple regions that influence variation in specific lipid levels that are associated with coronary heart disease (Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:971.)

"We looked at coronary arteries of study participants, did genome-wide linkage analyses of 11 lipid traits and compared results," says Dr. Turner. "Mayo is a leader in the measurement of coronary artery calcification. We can now get high resolution CT scans to objectively quantify calcification in the heart. We hope that identification of genes that influence lipid metabolism will lead to a better understanding of what causes coronary artery disease and lead to the development of new therapies for the treatment and prevention of disease."

Dr. Kullo was first author on a recently published linkage analysis study that identified a genomic region on chromosome 1, which exhibits pleiotropic (shared) genetic effects on several lipid traits (HDL cholesterol, triglycerides, and LDL particle size) in related people who have high blood pressure (Am J Hypertension 2005 Aug; 18(8):1084-90).

"How this genetic region influences the correlation of these lipid traits may influence the susceptibility of people who have high blood pressure to develop chronic heart disease," says Dr. Kullo. "It is one more piece of this very large puzzle of trying to predict who is going to get the complication of cardiovascular disease from hypertension."

Magnetic Resonance Imaging (MRI) is an important tool in a separate NIH-funded collaborative study that the Turner group is participating in called Genetics of Microangiopathic Brain Injury (GMBI). The study is revealing a remarkably strong genetic risk for cognitive impairment caused by damage of tiny vessels in the brain.

"We are looking at the genetics of leukoaraiosis, a condition that leads to changes in the subcortical white matter of the brain," says Dr. Turner. "The white matter is supplied by arteries that penetrate deep into the brain. They have little collateral circulation and are particularly sensitive to small blood vessel damage. We're using MRI to measure this brain shrinkage and what we found is that the heritability of brain shrinkage due to white matter change is remarkably strong. Heritability is measured on a scale of zero to one, one being totally genetic and its heritability is 0.7. The reason it's clinically important is an increasing appreciation of the role of vascular disease in cognitive loss."

The influence of Genomics on Hypertension

The kidneys are another target organ for complications from hypertension and one of the biggest problems for patients with the condition is ending up on dialysis. The NIH recently funded a new study to investigate chronic kidney disease and the Turner group is gearing up to lead the effort in Rochester and Jackson, MS.

Taking the Trial and Error out of Drug Therapies

Dr. Turner's group is one of the first to study inheritance and drug response in the treatment of hypertension. Their research responds to the frustration of patients and their physicians in trying to identify the drug that is most likely to produce the best response in each patient. The field of pharmacogenomics tries to identify the genetic basis for why some people respond better to a given drug therapy than others.

"More than a half dozen drugs are available to treat high blood pressure but we have no clue how the drug will affect the patient until we try it," says Dr. Turner. "The aim of genetic research is to replace the trial and error process with genetic tests that can identify predictors of response so that we can choose the best drug for a given patient."

Dr. Turner's group has undertaken two large studies in pharmacogenetics, both in collaboration with Emory University in order to conduct parallel studies in Blacks. They come under the umbrella of The Genetic Epidemiology of Responses to Anti-Hypertensives (GERA) study, a separate NIH-funded study.

The studies involved carefully monitoring the blood pressure of study participants who were taken off their usual medication and all given the same drug. The investigators searched for frequency in particular genes by screening participants for 50 candidate genes thought to affect blood pressure, and comparing results with the phenotype—the way they responded to the drug.

Publications resulting from the study of the diuretic drug hydrochlorothiazide, have shown that polymorphisms in six genes—the beta-3 subunit of G-proteins, angiotensin converting enzyme (ACE), angiotensinogen, angiotensin II receptor, endothelial nitric oxide synthase, and a protein kinese regulator of sodium transport by the kidney—all make contributions to blood pressure response as a result of treatment with the drug.

Polymorphisms are common sequence variations, which are present in the population at a frequency of greater than one percent. They are the result of insertion or deletion of one, two or several bases. (There are four bases: adenine (A), thymine (T), cytosine (C) and guanine (G), which are the building blocks of DNA.) A set of these tiny variations help to create your unique DNA pattern. Polymorphisms are important because they can alter the structure and function of the gene product, which can lead to disease or affect response to a drug. By conducting genome-wide association studies using polymorphisms, geneticists further the understanding of disease processes. The goal is to use the knowledge to develop genetic-based diagnostics and therapies.

In another study, Dr. Turner's group found evidence of a gender specific effect on the blood pressure responses to the drug hydrochlorothiazide from a polymorphism in the gene that encodes angiotensin converting enzyme (ACE).

"Disease genes are logical candidates to influence the pharmacodynamics of antihypertensive drug response, and drug response genes are logical candidates to influence the development and progression of hypertension," explains Dr. Turner. "Each of these studies helps us to better understand the genetic basis for drug response to hypertension."

The Sobering Conclusion

There are many causes of essential hypertension. We know that obesity, diabetes, high cholesterol, inactivity and tobacco use are contributing factors. But how your body reacts to these environmental influences depends on the unique pattern of your genome. There is no single gene that is responsible for hypertension. The sobering conclusion of the last decade of research in this field is that it is a minefield of perplexing variations that has made identification of specific genes involved in hypertension causation a laborious and challenging task.

"Everyone is genetically unique so, to find these differences among people, the sample sizes need to be enormous," says Dr. Schwartz. "The genetic contribution is made by multiple genes with each of them having a very small effect. The interaction with gene environment and gene-to-gene interaction makes it much more difficult to ferret out gene variation than we originally thought."

It is becoming untenable for one institution to conduct meaningful genetics research into common conditions such as hypertension. Instead, broad, collaborative networks across multiple disciplines and institutions, such as FBPP, are the new paradigm for genetics research.

The good news is that you only have to collect DNA from a study participant once—their genetic data will be available for researchers indefinitely. Subsequent studies involving only clinical follow-up to determine the development of complications, such as heart attack or stroke, and to monitor the blood pressure and treatment changes, hold the promise of substantially increasing our understanding of the mechanisms that control blood pressure.

"We will be able to predict a predisposition to early death in the group of people that we have studied," says Dr. Turner. "Moreover, in the coming years, as investigators collect and analyze large amounts of genetic information, we have the potential to revolutionize approaches to the prevention, evaluation, and treatment of hypertension and its associated target organ diseases."