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Team Analyzes Quake Genome With An Eye Toward Clinical Utility

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Whole-genome sequence data can provide clinically useful information about disease risk and drug response, according to a paper appearing in the Lancet online today.

"Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients," senior author Russ Altman, a Stanford University bioengineering and genetics researcher, and his co-authors wrote.

Researchers from Stanford and Harvard Universities analyzed co-author Stephen Quake's genome, which was published last fall, looking for SNPs and copy number changes implicated in disease risk or drug response. They then integrated this information with Quake's medical and family history and his statistical disease risk to try to determine whether whole-genome sequence could uncover clinically useful information.

Quake, who is 40 years old and has a family history that includes coronary artery disease and sudden cardiac death, had no significant known medical problems prior to the study.

The researchers came up with an algorithm to assess Quake's risk for 55 different conditions based on his genome sequence and incorporated this data with information from Quake's family history, personal medical history, and additional medical screening results. Quake received genetic counseling as part of the study.

Of the roughly 2.6 million SNPs and 752 copy number changes evaluated in the genome, the researchers determined, among other things, that Quake is at elevated risk of myocardial infarction, type 2 diabetes, and certain cancers.

In particular, the team found, Quake carries rare variants in three genes — TMEM43, DSP, and MYBPC3 — that have been tied to sudden cardiac death.

And although a clinical examination did not reveal signs of cardiomyopathy, Quake does carry a mutation in an apolipoprotein precursor gene called LPA — and, as predicted from this mutation, also has somewhat increased lipoprotein levels.

When they turned their attention to variants believed to affect drug response, the team found changes in several genes linked to drug response, including five to 10 SNPs that hadn't been identified in the past.

"This is really exciting because we never would have found these if we'd just relied on our usual panel of SNPs," Altman, who leads Stanford University's Pharmacogenetics and Pharmacogenomics Knowledge Base, known as "PharmGKB," said in a statement.

For instance, Quake has a loss of function mutation in the CYP2C19 that's suspected of causing increased resistance to the anti-clotting drug clopidogrel, marketed as Plavix. Quake also has variants associated with enhanced response to statin treatment and low initial warfarin dose requirement.

At this stage, though, the team cautioned that the clinical utility of whole-genome information remains at the proof-of-principle stage. They also noted that more work is needed to catalog the mutations that can arise in the genome and their consequences. But Quake is optimistic about the long-term potential of genomics for improving medical care.

"Information like this will enable doctors to deliver personalized health care like never before," he said in a statement. "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."

Even so, Quake concedes that it's possible not everyone will be as open to having their genomic data scrutinized.

"[I]t's important to recognize that not everyone will want to know the intimate details of their genome, and it's entirely possible that this group will be the majority," he said. "There are many ethical, educational, and policy questions that need to be addressed going forward."

Indeed, in an accompanying comment article set to appear in the same issue Lancet, the University of Leicester's Nilesh Samani and co-authors highlighted such ethical issues as part of their discussion of the role of personalized genomics in medicine.

"Whereas these issues are familiar in genetic testing, the scale of the data contained within each personal genome, and the potential implication for so many different aspects of an individual's health (and the health of their relatives), mean that these issues will need to be even more carefully considered (and legislated on where necessary) to prevent misuse," they wrote.

Meanwhile, in an editorial set to appear in the same issue of the Lancet, Henry Greely, a Stanford University law professor and chair of Stanford's Center for Law and Biosciences, and his colleagues touched on the challenges of applying whole-genome sequencing in a clinical setting.

"We are optimistic about the value of whole-genome sequencing in medical practice, but implementation of such testing will be challenging," they wrote. "We need to begin thinking about when and how to offer full genome sequencing for clinical use. This preparation is essential to achieve maximum benefits from this technology, while keeping the harms to a minimum."