A genetic variant that once seemed almost guaranteed to cause Crohn disease actually has negligible effects in the general population, a study of more than 43,000 Danish people shows.
The result could be a blow to personalized medicine, which seeks in part to estimate people’s risk of developing diseases by analyzing the genetic variants they carry. Previous studies comparing people with an inflammatory bowel disease called Crohn disease to healthy people have found that people with variations in a gene on chromosome 16 known as NOD2 or CARD15 had 17 times greater risk of developing the disease than people who did not carry the variants.
But the new study, published online April 6 in the Canadian Medical Association Journal, took a different approach. Instead of singling out people with Crohn disease ahead of time, it looked in a general population and found that people carrying a disease-associated variant on both copies of chromosome 16 had only three times greater risk of getting the disease than noncarriers — a rise that is not statistically significant.
“We expected that what we would find would be less in the general population, but not that it would be almost negligible,” says Børge Nordestgaard, a genetic epidemiologist at the University of Copenhagen and leader of the new study.
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The researchers analyzed three Crohn-associated variants in the NOD2/CARD15 gene of 43,596 Danish people. Most did not carry any variants associated with Crohn disease. But 11 percent had at least one risk-elevating copy of the gene, and 0.4 percent carried two copies.
Only 1.5 percent of people who had a disease-elevating copy of NOD2 on both chromosomes actually developed Crohn disease by the time they were 50, and 0.3 percent of people with one copy got Crohn disease. That result indicates that even a strong association between a gene variant and a disease doesn’t have very much influence on whether a person carrying the variant will get sick.
If a person is already sick, however, testing the NOD2/CARD15 variants may help doctors distinguish Crohn disease from a similar inflammatory bowel disease called ulcerative colitis, Norestgaard says. Changes in the gene are associated with Crohn disease but not with ulcerative colitis. The Danish study’s results indicate the problem with extrapolating the risk seen in patient groups to the rest of the population, says Katherine Siminovitch, who heads the genomic medicine at Mount Sinai Hospital in Toronto.
“When you study a patient population, they have not just one, but probably many genes that allow the disease to develop,” she says.
But in the general population, many healthy people are likely to carry one disease-linked version of a gene but no other genetic risk factors for the disease. And lifestyle and other environmental factors are also important in the development of diseases.
“That’s the complicated part of personalized medicine. We’re getting it in bits and pieces, but we don’t know how these things work together,” Siminovitch says. “There are a lot of gaps, and this study shows us what needs to be done to fill in those gaps.”