Hearing a small and quiet chorus in a vast and raucous crowd

(Another new science article that I wrote for the homepage of my institute, the MDC. See the archive there for more stories from MDC research.)

The labs of Young-Ae Lee and Norbert Hübner help identify new genetic risk factors for atopic dermatitis

If you suffer from atopic dermatitis, you surely know it. Infants develop rashes and a susceptibility to allergies that usually persists their whole lives. For years researchers have known that most cases have a hereditary basis, and a few culprit sites have been identified in the human genome. But others have been very difficult to detect. The laboratories of Young-Ae Lee and Norbert Hübner at the MDC, collaborating with other groups from Germany, the U.S., Ireland, China, and Japan, have now identified four new sites associated with atopic dermatitis. Some of these loci are involved in other diseases as well. The work draws on recently developed methods of correlating genetic factors to disease risks and huge cohorts of patients, nonaffected family members, and controls from several countries. The study appears in the July edition ofNature Genetics.

Finding the genetic causes of diseases like atopic dermatitis, which may involve multiple, subtle defects in DNA and environmental factors, has been one of the greatest challenges in disease research. Whether someone is affected or not might depend on a combination of single “letters” in the 3 billion nucleotides that make up a person’s DNA, and even very close relatives exhibit many “spelling” differences. Adding more distant relatives and others introduce a great deal more “noise”, making it extremely difficult to detect a specific site related to a disease.

A second hurdle has been the need to involve very large groups of patients, family members, and control individuals – preferably several such cohorts from different countries. That has to be done to distinguish sequences that cause a disease from those that originated in common ancestors, long ago, and have spread through any intermingling population. Young-Ae and her colleagues could draw on years of work by Germany and other countries to assemble cohorts of families affected by atopic dermatitis and a number of other diseases, and that work continues.

This type of research is considerably easier if a disease can be linked to changes in a single gene or DNA sequence; here, several sites in the genome are involved, and the environment seems to play a role as well. These factors combine to make the task incredibly complex. Imagine recording every conversation on Earth for a year, in hopes of finding a few people who are somehow similar, saying the same thing at the same time – without knowing in advance what topic or type of person you’re looking for. Multiply that problem by a factor of a few million and you get the idea. Even the best eavesdropping software would grind to a halt.

Over the past few years researchers have developed a methodological solution called genome-wide association studies (GWAS) that hammers at the problem statistically, using sophisticated analytical algorithms. The method is applied to the genome of every individual in the study. It establishes the statistical likelihood that certain regions of DNA are involved in a particular disease such as atopic dermatitis. Such studies give researchers “hot spots” for further investigation, in hopes of identifying exactly what sorts of genetic variants bring along increased risk, and why.

“If you compare the genetic code of different individuals, you’ll find differences such as single nucleotide polymorphisms, or SNPs, where the ‘spelling’ of a single nucleotide is swapped for another,” Young-Ae says. “Some of these SNPs confer a higher disease risk for individuals. In the current study we looked at every region of the genome that was somehow linked to processes of chronic inflammation, because past work has shown a link between these factors and atopic dermatitis.”

Young-Ae and her colleagues used a “DNA chip” that contained every SNP found so far in humans for these regions. Now they scanned the DNA of 2,425 German individuals with atopic dermatitis and 5,449 controls, looking for single letters of the code that conferred higher risk. This produced a list of “hits” that seemed to be significant; then the group expanded the study to 7,196 patients and 15,480 controls from Germany, Ireland, Japan and China, hoping to replicate the findings.

Young-Ae and her team confirmed earlier reports by other groups linking several SNPs to the disease; more importantly, they found four new ones. These sequences also corresponded to a person’s likelihood of having other chronic inflammatory conditions as well. Atopic dermatitis is associated with defects in the differentiation of skin cells called keratinocytes as well as problems with the immune system. Answering this question might show that multiple diseases could be traced back to a common biological mechanism.

For example, researchers have known that immune cells called T helper type 2 cells, which cluster at the skin during inflammations, are somehow involved. One of the genes confirmed in the study is the used to produce a protein called DcR3 that is found in abnormally high amounts during the inflammation associated with atopic dermatitis. New genes identified in the study include IL2-IL21, PRR5L, CLEC16A-DEXI, and ZNF652. CLEC16A, which is highly expressed in immune system cells such as B-lymphocytes, seems a particularly interesting candidate for further investigation, Young-Ae says.

Combining the new findings with those made previously now brings the total number of culprits to 11. “We estimate that this now accounts for about 14.4 percent of the hereditary factors involved in atopic dermatitis,” Young-Ae says. “Increasing that number will probably require expanding the study to new and larger cohorts, as well as developing new methods to find even more subtle associations between DNA, the disease, and environmental factors that might play a role.”

–       Russ Hodge

Highlight Reference:

Ellinghaus D, Baurecht H, Esparza-Gordillo J, Rodríguez E, Matanovic A, Marenholz I, Hübner N, Schaarschmidt H, Novak N, Michel S, Maintz L, Werfel T, Meyer-Hoffert U, Hotze M, Prokisch H, Heim K, Herder C, Hirota T, Tamari M, Kubo M, Takahashi A, Nakamura Y, Tsoi LC, Stuart P, Elder JT, Sun L, Zuo X, Yang S, Zhang X, Hoffmann P, Nöthen MM, Fölster-Holst R, Winkelmann J, Illig T, Boehm BO, Duerr RH, Büning C, Brand S, Glas J, McAleer MA, Fahy CM, Kabesch M, Brown S, McLean WH, Irvine AD, Schreiber S, Lee YA, Franke A, Weidinger S. High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat Genet. 2013 Jul;45(7):808-12

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