KYOTO, JAPAN Children heterozygous for a filaggrin gene loss-of-function mutation are at an 8.2-fold increased risk for moderate to severe atopic dermatitis, while those who are homozygous for the defect carry a staggering 169-fold elevated risk, according to a case-control study.
This Irish study of mutations in the gene expressing filaggrin, a key skin barrier function protein, involved 262 children with dermatologist-diagnosed moderate to severe atopic dermatitis and 736 matched controls. As in other studies of people of Northern European ancestry, almost one-half of the atopic dermatitis patients possessed a filaggrin mutation, Dr. Gráinne M. O'Regan reported at an international investigative dermatology meeting.
The study also turned up three previously unknown filaggrin mutations, noted Dr. O'Regan of Our Lady's Children's Hospital, Dublin.
Her coinvestigator, W.H. Irwin McLean, Ph.D., noted that this brings the total number of filaggrin loss-of-function or null mutations identified to 39, mostly in the European and Far Eastern populations where studies thus far have been concentrated.
"The mutations are completely ethnic specific. The mutations you find in white people are not found in Japan, for example, with very, very few exceptions," he explained in his René Touraine Lecture at the meeting of the European Society for Dermatological Research, the Japanese Society for Investigative Dermatology, and the Society for Investigative Dermatology.
There is little doubt that other skin barrier genes just as replicable as filaggrin will emerge in the future. And additional filaggrin mutations await discovery, added Dr. McLean, professor of human genetics at the University of Dundee (Scotland).
"We don't know much yet about filaggrin mutations in black populations," he noted. "It's very difficult to analyze populations. It takes probably a year to do each ethnic group."
Heterozygotes for a filaggrin null mutation make half the normal amount of filaggrin. Homozygotes make none. In heterozygotes the penetrance is 40%, meaning 40% of bearers of one mutant allele have atopic dermatitis. The penetrance in homozygotes is 90% or more, and they tend to have the most severe skin disease.
The newest data on the prevalence of filaggrin null mutations in the general population come from an epidemiologic study in the north of England, where 1 in 7 individuals was found to carry one mutation and 1 in 90 carried two.
Two years ago, Dr. McLean and his coworkers shook up the dermatology world with their landmark discovery that filaggrin mutations strongly predispose to atopic dermatitis.
Their report brought forth a new appreciation of impaired skin barrier function as a driving force in the pathophysiology of this common inflammatory skin disease.
Since then, Dr. McLean said, one of the most common questions physicians ask him is this: Is atopic dermatitis fundamentally a skin barrier problem or an immunologic disorder?
"I think that's too simple a question," he added. Instead, the Irishman drew an analogy between atopic dermatitis and the St. Patrick's three-leafed shamrock. The "leaves" of atopic dermatitis are the skin barrier, the immune system, and the environment.
"If you have no barrier, every environmental trigger is going to cause eczema. And you can have some people who have a good barrier and a very, very sensitive immune system, so the environmental trigger gets through. But I think a lot of people will fall in the middle, where there's a barrier defect, there's something going on with the immune system, and there's an environmental trigger. The incidence of atopic dermatitis has increased over the years, and that's due to the changed environment. The genes controlling these two other things have stayed the same," Dr. McLean said.
His filaggrin research is funded by the British Skin Foundation, the National Eczema Society, and the Medical Research Council.