In a large-scale study conducted with 2,643 children, international researchers with the participation of the Department of Experimental Pneumology of Ruhr-University Bochum (RUB), Germany (Prof. Dr. Albrecht Bufe), have discovered a gene variant that contributes significantly to the risk of childhood asthma.
Comparisons of the entire genome of healthy children and those afflicted with asthma (genome wide screening) drew their attention to variants of a sequence in on Chromosome 17q21 which encodes the ORMDL3 protein group. Variants in this gene sequence are linked to a significantly higher risk of asthma. The researchers have reported on their findings in the current online issue of the science magazine, Nature.
Environmental factors are the trigger
Bronchial asthma is one of the most common chronic childhood lung diseases. Some 15% of German children between the age of 6 and 16 are victims of the disease, while up to 30% of children in Australia, England and the USA are affected. Asthma is an inflammatory reaction of the bronchial mucosa which leads to restriction of the respiratory passages resulting in shortness of breath, coughing, wheezing and a notable impairment to the quality of life coupled with chronic changes in the lung. Allergies to harmless environmental substances such as grass, tree pollen and house dust mites trigger asthma in 80% of children's cases. These allergies as well as infections and environmental conditions function in a way that is as yet not fully understood as triggering factors, leading to the outbreak of the disease.
Genes lay the foundation
One of the causes for the appearance of asthma is certain hereditary factors: 70 percent of children whose parents both suffer from asthma are also likely to get the disease. A child with healthy parents has only a five to 15-percent risk, depending on where it grows up. Genetic factors include variations in the complex regulation of the sensitisation to allergies, variations in the reaction of the innate immune system to innumerable microbial and other environmental factors and variations in genes responsible for inflammatory reactions in mucous membranes and the immune system. "Numerous gene variations in the broadest variety of genes are responsible for the emergence of allergies and allergic diseases such as neurodermatitis, hay fever and indeed asthma", explains Prof. Bufe. "However, an unambiguous clarification of this complex situation has only been partially possible up to now."
Searching for stars in the sky
To gain deeper insight, Bochum's Experimental Pneumology Dept. is participating in the "Multicentre Asthma Genetics in Childhood Study" (MAGICS, directed by the University of Munich Children's Hospital, PD Dr. M. Kabesch). This network is the source of most of the 2,643 children examined for the analysis published in NATURE (321 asthmatics and healthy children come from Bochum). "One reason for the special significance of this study is the very large number of children examined", says Prof. Bufe. "The other is that for the first time, the 'genome wide screening' method was applied to such a large group of patients." The process involves comparing all of the genetic information of all the test persons with that of the others. Variations in the genes - for instance, the exchange of individual bases, which occurs frequently and which by no means has to inevitably result in illness - are examined for whether they often appear together with a specific disease. "With some 40,000 human genes, this is like searching for stars in the sky", illustrates Prof. Bufe.
The function of the gene sequence remains unclear
The genome wide screening conducted within the framework of a European GABRIEL Consortium under the leadership of the Imperial College in London (Prof. Dr. W. Cookson) directed the attention of the researchers to the ORMDL3 gene complex in Chromosome 17q21. Variations in this sequence appeared with significantly greater frequency in children suffering from asthma and are therefore a clear risk factor. The function of the gene complex remains completely unknown. "We only know that ORMDL3 is expressed on the endoplasmatic reticulum, an organelle. This ORMDL3 expression is prominent in many cells and tissues, especially in immune cells", says Prof. Bufe. "Here we have found something that is completely unknown, completely new - this might open up a brand new perspective of our understanding of children's asthma", he hopes. The next step for the researchers is to try and find out the exact function of the ORMDL3 proteins affected by the variations in the gene complex.
Since asthma is not exclusively dependent on the genes, but is instead triggered by environmental stimuli, genetically predisposed children do not necessarily have to become ill: Training of the immune system in the first year of life reduces the risk of asthma, as research conducted by a German-Austrian-Swiss workgroup under the coordination of Munich University's Children's Clinic (Prof. Dr. E. von Mutius) with the participation of the Experimental Pneumology Dept. in Bochum has verified. Microbial and other environmental factors, such as those found in animal stables on traditional farms, activate the receptors of the innate immune system in the bronchial passages and in the gastrointestinal tract. The activation of these receptors appears to be linked with the maturation of the immature immune system. Genetic variations in these receptors (for example, Toll-like-Receptors 2 and 6) are associated with the risk of asthma in childhood.
Looking for the crucial environmental factors
Bochum's Experimental Pneumology Dept. researchers are searching for the environmental factors that stimulate the immune system in early childhood. They could demonstrate that the inhalation of extracts from animal stable dust as found on traditional farms - isolated and analysed together with the Division of Structural Biochemistry at the Research Centre Borstel in Schleswig-Holstein (Prof. Dr. O. Holst) - impedes allergic sensitisation and asthma in animal models. The long-term aim is the identification of the protective factors in the extracts and acquiring an understanding of the mechanisms that contribute in early childhood to the immune system's tolerance to allergies and asthma. "In this regard, the genetic variations apparently play an important role, as demonstrated in the current publication in NATURE", according to Prof. Bufe.
http://www.ruhr-uni-bochum.de/homeexpneu and http://www.gabriel-fp6.org/index.htm