Getting under the skin of allergies

MDC scientists working with colleagues at institutions around the world have published a study in Nature Communications that sheds light on the atopic march, an especially severe form of allergic disease progression. The researchers identified seven genetic risk loci for the atopic march.

Prof. Young-Ae Lee wears two hats. As a pediatrician, she offers special consultation hours during which she mainly helps young patients that suffer from allergic conditions such as atopic dermatitis or food allergies. As a researcher, she works with her group at the MDC to investigate which genes play a role in such conditions and how this knowledge can be put to use as quickly as possible in the form of therapies or prevention. She recently headed a study that has now been published in Nature Communications and sheds light on the atopic march, a severe form of allergic disease progression.

Allergies are chronic inflammatory conditions in which the immune system forms antibodies against environmental allergens that it should recognize as harmless, like the pollen of grass or substances in specific foods. In some cases, patients experience a life-long progression of allergic diseases that begins in the first year of life with itchy, inflamed skin (atopic dermatitis) and is followed many years later by asthma and hay fever.

In a genome-wide association study (GWAS), the researchers identified seven genetic risk loci for the atopic march. Two of the seven loci were previously unknown and relate specifically to the connection between atopic dermatitis and asthma. The study indicates that the genetic loci that play a role in atopic dermatitis are associated particularly with an increased risk of developing other allergies. The meta-analysis included almost 20,000 individuals from twelve studies.

The study’s first author is Ingo Marenholz, a postdoc in Prof. Lee’s working group. The first thing a visitor notices upon entering Marenholz’s office is a computer screen that stands vertically. Why has he turned it sideways? “I can simply get a better overview of the tables that way,” he says. Marenholz clicks a few times inside a multi-branched directory on his hard drive, and the screen fills up with columns of numbers: hundreds and thousands of data points from genome-wide association studies that show genetic variants – “single nucleotide polymorphisms” (SNPs). In a genome-wide association study, chromosomes from every subject are examined in hopes of finding changes that are more frequent in affected individuals than in healthy ones. The meta-analysis required that the group’s members "sort" several million SNPs. Only changes that cleanly divided between the groups above a certain level of statistical significance were examined more closely. “You need as many cases as possible for such studies,” explains Marenholz.

So the scientists in Berlin wrote to their partners around the world who they knew had well-characterized allergy cohorts with long observation periods and asked them to investigate all the cases where asthma had developed after early-childhood atopic dermatitis. In this way, around 1,900 additional children in Europe, Australia and the United States with this clinical phenotype were added to the cohort of 500 cases created by Young-Ae Lee’s group. In all, this gave the scientists data from 2,428 patients to contrast with data from 17,034 people who showed no signs of the allergies. All the studies were genome-wide association studies.

The first phase (“discovery phase”) of statistical analysis already found one match, known to the scientists in Berlin from earlier GWASs. There were also several genetic loci that seemed worthy a closer look at the SNPs. In the subsequent, second phase of analysis (“replication phase”), seven hits emerged from the candidate loci: these were the genetic loci that influence the atopic march. “From our point of view, the prominent role of atopic dermatitis genes in the subsequent development of asthma was especially interesting,” says Lee. In addition to her MDC research group, Lee also leads the university’s outpatient clinic for pediatric allergy and atopic dermatitis at the Berlin-Buch campus. The results of her most recent study suggest that atopic dermatitis itself represents a risk factor for asthma.

Marenholz explains how the condition could progress. He notes that “could” is the operative word here, since “what we find is not a single explanation but rather a piece of a larger puzzle.”

This would mean that certain people are born with a higher risk of developing atopic dermatitis. Once children’s skin has been damaged by that disease, it is no longer able to keep other allergy-triggering substances away from the body. “Systemic sensitization to allergens occurs through the skin,” says Marenholz. It means that an organism is exposed to greater allergenic “stress” and thus forms antibodies. Later, antigens that the immune system cannot cope with are taken in through the lungs – which can lead to asthma. This is consistent with the group's findings that the main genetic risk factors for the atopic march were found among genes linked to atopic dermatitis.

In the future, this knowledge will help medical specialists identify high-risk patients. But it may also have a more direct benefit: “Our discovery suggests that prevention or systematic treatment of early childhood atopic dermatitis may enable us to interrupt the progression of the atopic march toward asthma,” says Prof. Lee.

This is a study featured as "MDC Research Highlight". Selected by a committee of MDC group leaders, these Highlights showcase examples of our best science.

Highlights Reference:

Meta-analysis identifies seven susceptibility loci involved in the atopic march (Nature Communications; DOI: 10.1038/ncomms9804)

Ingo Marenholz, Jorge Esparza-Gordillo, Franz Rüschendorf, Anja Bauerfeind, David P. Strachan, Ben D. Spycher, Hansjörg Baurecht, Patricia Margaritte-Jeannin, Annika Sääf, Marjan Kerkhof, Markus Ege, Svetlana Baltic, Melanie C. Matheson, Jin Li, Sven Michel, Wei Q. Ang, Wendy McArdle, Andreas Arnold, Georg Homuth, Florence Demenais, Emmanuelle Bouzigon, Cilla Söderhäll, Göran Pershagen, Johan C. de Jongste, Dirkje S. Postma, Charlotte Braun-Fahrländer, Elisabeth Horak, Ludmila M. Ogorodova, Valery P. Puzyrev, Elena Yu Bragina, Thomas J. Hudson, Charles Morin, David L. Duffy, Guy B. Marks, Colin F. Robertson, Grant W. Montgomery, Bill Musk, Philip J. Thompson, Nicholas G. Martin, Alan James, Patrick Sleiman, Elina Toskala, Elke Rodriguez, Regina Fölster-Holst, Andre Franke, Wolfgang Lieb, Christian Gieger, Andrea Heinzmann, Ernst Rietschel, Thomas Keil, Sven Cichon, Markus M. Nöthen, Craig E. Pennell, Peter D. Sly, Carsten O. Schmidt, Anja Matanovic, Valentin Schneider, Matthias Heinig, Norbert Hübner, Patrick G. Holt, Susanne Lau, Michael Kabesch, Stefan Weidinger, Hakon Hakonarson, Manuel A. R. Ferreira, Catherine Laprise, Maxim B. Freidin, Jon Genuneit, Gerard H. Koppelman, Erik Melén, Marie- Hélène Dizier, A John Henderson & Young Ae Lee

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