For the first time, researchers have used a healthy person's complete genome sequence to predict his risk for dozens of diseases and how he will respond to several common medications. The risk analysis, from the Stanford University School of Medicine, also incorporates more-traditional information such as a patient's age and gender and other clinical measurements. The resulting, easy-to-use, cumulative risk report will likely catapult the use of such data out of the lab and into the waiting room of average physicians within the next decade, say the scientists.
“This is really exciting because we never would have found these if we'd just relied on our usual panel of suspects”
"The $1,000 genome is coming fast," said cardiologist Euan Ashley, MD, assistant professor of medicine, referring to the cost of sequencing all of an individual's DNA. "The challenge lies in knowing what to do with all that information. We've focused on establishing priorities that will be most helpful when a patient and a physician are sitting together looking at the computer screen."
Priorities that include whether a certain medication is likely to work for that particular patient, or if it's likely to have adverse side effects. Priorities that include ascertaining how a patient's obesity or smoking combine with his or her inherent genetic risk for — or protection against — heart attack or diabetes. In short, priorities that result in concrete clinical recommendations for patients based on a degree of data that has never existed before.
"We're at the dawn of a new age in genomics," said Stephen Quake, PhD, who is the Lee Otterson Professor of Bioengineering. "Information like this will enable doctors to deliver personalized health care like never before. Patients at risk for certain diseases will be able to receive closer monitoring and more frequent testing, while those who are at lower risk will be spared unnecessary tests. This will have important economic benefits as well, because it improves the efficiency of medicine."
But it may also tell patients things they don't want to know.
Quake made national headlines last August when he used a technology he helped invent to sequence and publish his own genome for less than $50,000, and it is his genome that the researchers analyzed in this newest study. Ashley is the lead author of the research, which will be published in the May 1 issue of the Lancet.
An accompanying article about the ethical and practical challenges of such research, authored by a subset of the researchers involved in the first study, will appear in the online-only version of the Lancet on the same day. Hank Greely, JD, professor and director of Stanford's Center for Law and the Biosciences, is the senior author of the online piece.
"Patients, doctors and geneticists are about to hit by a tsunami of genome sequence data. The experience with Steve Quake's genome shows we need to start thinking — hard and soon — about how we can deal with that information," said Greely.
"When combined with other sources of information, genomics has the power to predict the diseases a person is most likely to develop and how he or she might respond to certain medicines," said Jeremy Berg, PhD, director of the NIH's National Institute of General Medical Sciences, which funded a portion of the work. "This work provides a glimpse of how genomics can play a role in personalizing the medical care of individual patients."
The study began when the 40-year-old, seemingly healthy Quake asked Ashley's opinion about a particular snippet in his genome associated with an inherited disease called hypertrophic cardiomyopathy. People with the condition have enlarged hearts that don't beat effectively and are at risk for sudden cardiac death. Quake was interested because a distant relative had died unexpectedly in his sleep at the age of 19 — presumably from some type of heart problem. Ashley, who runs Stanford's Hypertrophic Cardiomyopathy Center, was alarmed.
"Given his family history and the particular genetic variation Steve has, I recommended that he be screened for the condition," said Ashley. Quake agreed, but the conversation got the two thinking about how to analyze the information in Quake's genome on a more global level.
"Several of us had already been thinking about how you would take someone's genomic profile, and translate what's in the billions of base pairs in that DNA to something that's clinically useful," said Ashley, who headed the group of geneticists, physicians, bioinformaticians and ethicists involved in the study. "Then we realized, 'Hey, we already have someone's genome.'"
What's more, Atul Butte, MD, PhD, assistant professor in bioinformatics, and his lab members had already done a lot of the necessary leg work: They'd spent the previous 18 months meticulously cataloguing publications that associated particular genetic changes called SNPs (for single nucleotide polymorphisms) with effects on specific diseases. It was the first time anyone had compiled all the information in one database.
"We read thousands of publications," said Butte, "and we made a list of every single spot in the genome where we know that, for example, the letter A raises the risk of a particular disease, or the letter T confers protection. And then came Steve with his genome, and we were ready."
Together the researchers designed an algorithm to overlay the genetic data upon what was already known about Quake's inherent risk — based on his age and gender — for 55 conditions, ranging from obesity and diabetes to schizophrenia and gum disease. For example, as a 40-year-old white male, Quake entered the study with a 16 percent chance of developing prostate cancer in his lifetime. But as the computer, based on Quake's genomic sequence, began to incorporate the data of study after study, his risk scooched first lower, and then higher. (The researchers weighted the contribution of each variant according to the number, and sample size, of published studies confirming the association.)
In the end, after incorporating information about 18 separate variants from 54 studies, they determined Quake's risk of prostate cancer is actually about 23 percent. The opposite is true for his risk of Alzheimer's disease, which began at 9 percent and ended — due to the presence of several protective variants — at about 1.4 percent. The scariest monsters in the closet, however, were obesity, type-2 diabetes and coronary artery disease, each of which Quake has a more than 50 percent chance of developing, and each of which can affect the development of the other.
Was it alarming?