Some people are resistant to genetic disease

Some people can evade diseases even though they carry genetic mutations that cause serious problems for others.

Researchers found 13 of these genetic escape artists after examining DNA from nearly 600,000 people, the scientists report online April 11 in Nature Biotechnology. Learning how such people dodge genetic bullets may help move inherited-disease research from diagnosis to prevention.

Hundreds of mutations that lead to genetic diseases have been uncovered since the discovery of a disease-causing flaw in the “cystic fibrosis gene” in 1989. But, says study coauthor Stephen Friend, “finding the gene that causes the disease is not the same as finding a way to prevent the symptoms or manifestations of that disease.”
Clues to preventing genetic diseases could come from studying people who should have gotten sick but didn’t, suggest Friend, of the Icahn School of Medicine at Mount Sinai in New York City, and colleagues. Finding people like that is a challenge, though, because they don’t have symptoms.

To find such people, the team assembled existing genetic data from 589,306 adults who had their DNA tested as part of 12 ongoing or past studies. The researchers then searched for mutations known to cause genetic diseases in childhood. Since study participants were adults, they should already have developed symptoms.

Initially, the researchers found more than 15,000 potential escape artists. Further analysis whittled the field to 42. Of those, medical records indicated that 14 had symptoms of their genetic disease after all. Another 15 were ruled out because a closer examination found that each person had only one copy of a mutated gene. The other copy was normal, so could compensate for the debilitated copy.

The remaining 13 people carried mutations associated with one of eight different diseases, but somehow had not developed symptoms. The study suggests that it is possible to find people who are resistant to getting genetic diseases.

But some resilient people may have been missed because the study included only a fraction of known disease-causing mutations, says Daniel MacArthur, a geneticist at Massachusetts General Hospital in Boston. More troubling is that the researchers could not confirm that resistant people were disease-free or verify that they really have mutations. That’s because consent forms signed when participants agreed to share their genetic information did not contain provisions for researchers to contact volunteers later for retesting. “Some of their resilient cases may be mirages,” MacArthur wrote in a commentary, also in Nature Biotechnology.
Garry Cutting, a medical geneticist at Johns Hopkins School of Medicine, is also concerned that some of the lucky 13 may not be true escape artists. Cutting studies genes and environmental factors that determine the severity of cystic fibrosis, a disease in which thick mucus builds up in the lungs, pancreas and other organs. People develop the disease when they inherit two defective copies of the CFTR gene. More than 1,800 mutations in that gene can cause the disease if inherited in double copies or in combinations of mutations.

Of the 13 resilient people in the study, three carry dual copies of a very rare mutation in the CFTR gene, but don’t have cystic fibrosis.

Only one person in a database of 88,000 cystic fibrosis patients carries two copies of the rare mutation. So finding three people with double copies of the mutation is extraordinary, Cutting says. “It’s so exceptional that I believe it requires more extensive verification.”

He says he would be “delighted” if the people really turn out to be resistant to getting cystic fibrosis, but he’s puzzled why that mutation alone allows escape. It could be that a variant in another gene counteracts that specific mutation in the CFTR gene. Or a second mutation in the mutant CFTR gene may reverse the effect of the disease-causing one. However, it is possible that the three people avoided cystic fibrosis because they have only one copy of the mutated gene and one healthy copy that the researchers missed with the methods they used, Cutting says.

MacArthur points out another potential drawback to the study: Even if the researchers expand the study to 1 million or more people, they may not discover enough “genetic superheroes” to create a sample size large enough to detect protective genes. Such an effort may require participation from hundreds of millions of people and researchers willing to share data on a global scale.