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Background: Eosinophilic inflammation is considered to play an important role in the development as well as in the perpetuation of asthma. As eosinophil production and survival is under genetic control we investigated whether polymorphisms in eosinophil regulation pathway genes ( IL-3, IL-5, GM-CSF and their respective enhancers and receptors) may influence the development of atopic diseases. Methods: In two large study populations of children, the German part of the International Study of Asthma and Allergy in Childhood (ISAAC II) and the German Multicentre Atopy Study (MAS), 3099 and 824 children, seven polymorphisms previously associated with the development of atopic diseases were genotyped: two in and around the GM-CSF gene (Ile117Thr and T3085G), one in IL-3 (Pro27Ser), in IL-5 (C-746T), and in the IL-5 high affinity receptor chain IL-5R (G-80A) and two in the common receptor chain CSFR2b for IL-3, IL-5, and GM-CSF (Asp312Asn and Glu249Gln). Statistical analyses were performed using chi-squared tests and variance analyses. Gene by gene interactions were evaluated in logistic regression models. Results: The T allele at position −746 in the IL-5 gene was significantly protective for atopy in the ISAAC II population ( P = 0.006). Furthermore, the risk for atopic asthma was decreased in carriers of the T allele ( P = 0.036) and evidence for interaction with the enhancer polymorphism 3085 bp 3′ of GM-CSF was detected. Conclusions: IL-5 C-746T influenced atopic outcomes and showed evidence for gene by gene interaction. No significant associations were found with all other tested polymorphisms in the eosinophil regulation pathway after correction for multiple testing. [ABSTRACT FROM AUTHOR]