Abstract
The aim of our pilot study was to evaluate the contribution of genes for xenobiotic-metabolizing enzymes (XMEs) for the development of bronchial asthma. We have genotyped 25 polymorphic variants of 18 key XME genes in 429 Russians, including 215 asthmatics and 214 healthy controls by a polymerase chain reaction, followed by restriction fragment length polymorphism analyses. We found for the first time significant associations of CYP1B1 V432L (P=0.045), PON1 Q192R (P=0.039) and UGT1A6 T181A (P=0.025) gene polymorphisms with asthma susceptibility. Significant P-values were evaluated through Monte-Carlo simulations. The multifactor-dimensionality reduction method has obtained the best three-locus model for gene–gene interactions between three loci, EPHX1 Y113H, CYP1B1 V432L and CYP2D6 G1934A, in asthma at a maximum cross-validation consistency of 100% (P=0.05) and a minimum prediction error of 37.8%. We revealed statistically significant gene–environment interactions (XME genotypes–smoking interactions) responsible for asthma susceptibility for seven XME genes. A specific pattern of gametic correlations between alleles of XME genes was found in asthmatics in comparison with healthy individuals. The study results point to the potential relevance of toxicogenomic mechanisms of bronchial asthma in the modern world, and may thereby provide a novel direction in the genetic research of the respiratory disease in the future.
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Acknowledgements
This research was supported in part by a grant from the President of Russian Federation (MD-3571.2008.7). We thank Drs Mikhail Kozhuhov and Valery Panfilov from the Kursk Regional Clinical Hospital for their assistance in assembling patients with asthma, as well as for their help in diagnosis of the disease. We thank Professor Jason H Moore from Dartmouth Medical School and Dartmouth College (USA) for his expert assistance in the MDR statistical analysis and for helpful comments on interpretation of the MDR data.
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Polonikov, A., Ivanov, V. & Solodilova, M. Genetic variation of genes for xenobiotic-metabolizing enzymes and risk of bronchial asthma: the importance of gene–gene and gene–environment interactions for disease susceptibility. J Hum Genet 54, 440–449 (2009). https://doi.org/10.1038/jhg.2009.58
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DOI: https://doi.org/10.1038/jhg.2009.58
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