The two markers were described June 3 in a poster at the International Vascular Biology Meeting in Toronto, Canada. CD had previously disclosed four other new markers, and White says the company has confirmed associations for "scores" of other genes as well.
To find the markers, CD researchers pooled the DNA from groups of people with a history of heart attack, also known as myocardial infarction. They then compared them to control pools taken from similar people with no such history.
The researchers looked for differences in about 9,000 known single-nucleotide polymorphisms (SNPs) between the two groups. However, White says his company looks only at "putative functional" SNPs, "those that are likely to change the activity, amount, or stability of a particular protein." The databases of The SNP Consortium Ltd., of which CD is not a member, are "actually very thin for SNPs in genes." He says that CD has "twice as many of those kind of functional SNPs in our database."
With so many possible matches, however, it's easy to get a false association. "[Some] 98% of studies that announce a discovery aren't confirmed in a second or third sample set," White says. Thus, after identifying markers in people recruited by their collaborators at the University of California at San Francisco, the researchers checked how many of the markers were associated with heart attack for patients from the Cleveland Clinic Foundation, Cleveland.
Jürg Ott, PhD, professor and head of the Laboratory of Statistical Genetics, Rockefeller University, New York, says that it is difficult to assess whether the claimed significance of the associations is reliable. But "the authors went through several steps of replication and validation, which is more than most people do," says Ott.
White envisions a multiplexed amplification and detection strategy using "around 10 to 25 markers" to identify patients at risk of heart attack. The most useful markers would be independent of traditional risk factors such as smoking, weight, age, and gender. CD says it is working with Quest Diagnostics Inc., Teterboro, N.J., to evaluate the practical potential of the results.
In addition to the diagnostic applications, White says that the results allow "other entries into the biology of these complex diseases," because some of the genes don't mesh with current understanding. For example, he says some of their studies have identified "genes that are typically thought of as being inflammatory genes, but which clearly have a role" in heart-attack risk. This result supports the idea that infection often plays a role in heart disease.
The company applied for diagnostic patents on SNPs associated with heart attacks, White says, as well as for therapeutic patents on genes that might be treatable with drugs.
Celera Diagnostics was formed in 2001 as a joint venture of Celera Genomics and Applied Biosystems Group, which are in turn wholly owned subsidiaries of Applera Corp.