BioWorld International Correspondent

LONDON - Trawling for rare variants of genes thought to have a role in diseases might be the best way to identify people at risk of developing conditions such as heart disease, schizophrenia, Alzheimer's disease and Type II diabetes, a new study suggested.

The UK-based team of researchers who carried out the study showed that about one-quarter of people at high risk of developing colon cancer have rare variations in one of five candidate genes thought to predispose to cancer development. They predicted that a blood test could one day be used to identify those at high risk of colon cancer, who then could be monitored and given early treatment, if necessary.

Walter Bodmer, head of the Cancer Research UK Cancer and Immunogenetics Laboratory at the Weatherall Institute of Molecular Medicine in Oxford, UK, told BioWorld International that the study's findings support what is known as the "rare variant" hypothesis.

It proposes that rare variants of genes collectively explain many cases of disease in which there is known to be a link to inheritance - such as heart disease, manic depression, Alzheimer's disease and schizophrenia. The hypothesis, if proved, would explain why it has been difficult to find genetic mutations that account for those diseases: It simply is because the individual variants are so rare.

Bodmer said: "What we have shown is that an inherited tendency can be explained by the sum of the individual effects of changes in many different genes, rather than by a change in one gene, which is a relatively frequent variant. So, such inherited tendencies are not explained by common variants, which have a slight effect on the chance of getting the cancer, but by many different variants of much lower frequency, which may confer much higher susceptibility."

That conclusion, he added, has a significant impact on the way scientists should go about finding those sorts of inherited susceptibilities to cancer. "It will also lead to better understanding of the sorts of factors that give rise to disease susceptibility," he said.

The study is reported in the Nov. 9, 2004, issue of Proceedings of the National Academy of Sciences, in a paper titled "Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas."

Bodmer and his colleagues have worked for many years on the genetics of colon cancer. Conditions such as familial adenomatous polyposis (FAP), which is inherited in a straightforward Mendelian way, are thought to account for less than 4 percent of cases of colorectal cancer in a typical European population.

FAP causes hundreds or thousands of polyps in the colon, which can develop into cancers. However, some people have between three and 100 polyps, and researchers have speculated that those might be due to mutations that affect the function of a protein but less severely than in FAP. Similarly, people with such numbers of polyps are at reduced risk of developing colon cancers, with a risk of perhaps only two or three times that of the general population.

The Oxford team and their collaborators decided to screen the DNA of 124 people with multiple polyps numbering from three to 100, on the grounds that those people might be more likely to have genetic variations that increased their susceptibility to colon cancer. The researchers looked at the sequences of five genes that they thought might play a role in cancer development.

They looked for two known variants of the adenomatous polyposis coli gene (which is mutated in FAP). They also examined two DNA mismatch-repair genes, plus two others that play roles in pathways that lead to cancer. They carried out the same analysis on 483 random controls.

Bodmer said: "When we added up all the variants that we found, we discovered that they occurred in approximately 25 percent, compared to only about 12 percent of the controls - a highly statistically significant difference."

He predicted that different variants will be found in different populations. Next steps will include looking at a wider range of genes and at the function of some of the gene variants identified. "We will also search for variants in other groups, such as those who have first- or second-degree relatives with colon cancer, and those with early onset of colon cancer," Bodmer said.