By David N. Leff
The death of Elvis Presley, his publicist is said to have said, "was a good career move."
In a similar unintentional posthumous vein, clinician David Altshuler told BioWorld Today, "A substantial fraction of people who have a heart attack die of that first heart attack, and that's their first warning that they have the disease."
Altshuler, a clinical endocrinologist at Harvard-affiliated Massachusetts General Hospital, is dedicated to the proposition that human gene mutations can provide timely early warnings of many common maladies, notably coronary artery disease, diabetes, colon cancer, even schizophrenia. Wearing his human geneticist hat, Altshuler is a Fellow at the Whitehead Institute/MIT Center for Genomic Research.
There, he and his colleagues are in full pursuit of a ubiquitous gene entity called SNP, pronounced "snip," and standing for "single nucleotide polymorphism." Altshuler explained: "If we look at how the DNA of two individuals might vary from one other, the differences can take the form of a single base being swapped for an alternative base - that is, a single nucleotide polymorphism. There are also deletions and insertions of one and many nucleotides in the human genome, and the reason that we focused on these SNPs, where one of the four DNA nucleotides - A, T, C and G - is switched for an alternate base, is simply because they make up the bulk of human mutations. About 90 percent or more of all the mutations in the human genome - which contains an estimated 60,000 to 100,000 genes - are in the form of these SNPs."
He added ,"We focus on just the cases where these SNPs occur at an appreciable frequency - greater than one percent - in the general population. Probably the best example of the relevance of one of these is the case of mutant APOE-4, a risk-factor molecule in Alzheimer's disease [AD] patients. The APOE-4 SNP involves a T-to-C base substitution. It's a polymorphism that exists in 15 to 20 percent of the general population, who have a three-fold higher risk of AD."
Two Papers With But A Single Base Theme
Altshuler is co-lead author of a progress report in the July 1999 issue of Nature Genetics, titled "Characterization of single-nucleotide polymorphisms in coding regions of human genes."
A back-to-back article in the same issue of the journal, submitted jointly with the Whitehead paper, is by scientists at Case Western University, in Cleveland. It's titled: "Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis."
"We screened 106 genes in a population of 61 people," Altshuler recounted, "and we chose those 61 individuals from multiple ethnic groups, to try and represent much of the human population diversity. From this diverse set of people," Altshuler continued, "we screened 106 genes for the polymorphisms that exist in the gene sequences - the open reading frames (ORFs) - that actually specify the protein they express. And we found 560 polymorphisms in those 106 genes. Because we didn't precisely focus on the ORFs, we got a little bit on the edges. About 395 of those SNPs were in the ORFs."
Altshuler's take-home message from this first result was that "395 polymorphisms in 106 genes in a population of 61 people is a small number of polymorphisms - four per gene. And half of those were known as silent or synonymous mutations that didn't affect the protein the gene was making. So they are likely not to affect function very often. Really only half of them, two per gene, were of the variety that would alter the protein, and presumably alter the function of whatever that gene does."
In screening that 106-gene population, the Whitehead researchers did not know what diseases, if any, those subjects may have had. "One of the ideas of this approach," Altshuler said, "is that we were looking for polymorphisms that exist at appreciable frequency in the population, with the idea that such mutations, because they're so common, and present in so many people, may play a role in common diseases. But, obviously, a complementary approach is to focus precisely on people with a given disease. We don't know yet to what particular disease, if any, the SNPs we discovered may be relevant. What we're really doing here is trying to find out, getting the lay of the land, how many polymorphisms are there? And then begin the process of cataloging them, and testing for them in disease. We chose these genes because we thought that they were particularly relevant to certain disease states.
"So, then, we would have a heightened interest to say that this SNP in a gene that's involved in making a hormone might play a role in diseases that hormone is involved in," Altshuler said. "But, of course, the proof of that logic will actually come only when we do these studies in diseased people. Which we're beginning to do right now."
Getting Down To SNP-Disease Correlation
In this new research phase, which began half a year ago, the co-authors "have in our lab," Altshuler said, "on the order of 5,000 DNAs from different clinical populations that we've obtained from hospital colleagues. And we're now systematically asking whether patients who have this disease had a different frequency of this mutation than do people who do not have the disease. We have some tantalizing results, but nothing that's absolutely confirmed yet."
Reverting to heart disease as an example, Altshuler described how SNPs might lower the death rate of this disease, still the number-one killer in industrialized nations.
"In coronary artery disease, there are very good preventative measures, such as taking an aspirin every day, taking cholesterol-lowering or blood-pressure-lowering drugs. The trouble is that not nearly enough people take these preventative measures, particularly before they know that they're sick. There's the conundrum: We have these wonderful measures, but often people won't take them until they've already had a damaging event.
"The hope of this SNP research," Altshuler concluded, "is that we'd be able to identify certain risk factors to add to the known risk factors of hypertension and smoking, high cholesterol, etc. That would allow us to say to someone: 'You may be at higher risk than the average person. But rather than that being bad news about which you can do nothing, it would be good news that could get you to say, 'Well I'm going to start taking a cholesterol-lowering drug.'"