EUROMEDICA  Hanover 6-7  Juni 2008	Advanced methods of diagnosis, treatment and prophylactics
	European Academy of Natural Sciences, Hanover European Scientific Society, Hanover Russian Academy of Natural Sciences, Moscow

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We have recently carried out a comprehensive genetic analysis of 25 polymorphic variants of 18 xenobioticmetabolizing enzymes (XME) genes in 429 individuals, including 215 asthmatics and 214 controls. This study was designed to test a hypothesis of systemic involvement of XME genes in the genetic basis of bronchial asthma. We have revealed statistically significant associations of 106 combinations of XME genotypes with asthma susceptibility (p<0.05) by conventional two-way analyses. However, because multiple disease loci presumably interact to produce a complex disease phenotype, such as asthma, it is difficult to assess disease susceptibility loci by conventional locus-by-locus parametric-statistical methods. It is recognized that the main issues confronted by conventional parametric methods, such as logistic regression, are insufficient power and flexibility to detect high-order gene-gene interactions underlying a susceptibility to complex disease. The central problem in modeling gene-gene interactions is the dimensionality of the data and the large sample sizes needed to detect effects with so many dimensions. Taken this issue into account, we used the multifactor-dimensionality reduction (MDR) method (the MDR software v.1.1.0 is available at http://www.epistasis.org/mdr.html) as alternative nonparametric statistical approach to investigate the high-order gene-gene interactions responsible for susceptibility to bronchial asthma. We have performed an exhaustive search of all possible two- to five-locus models among all 24 genetic polymorphisms of the XME genes. Among five n-locus models, one three-locus model had a minimum prediction error of 37.8% and a maximum cross-validation consistency of 100% that was significant at the empirical p-value 0.05, as determined by 1000 permutations with Monte-Carlo procedure. The interaction between EPHX1 Y113H, CYP1B1 V432L and CYP2D6 G1934A loci has showed the highest cross-validation consistency and the lowest prediction error among all gene-to-gene interactions models evaluated by the MDR. Importantly, two of three XME genes included in this model, such as EPHX1 and CYP1B1, showed significant associations with susceptibility to asthma in our previous study. Meanwhile, the CYP2D6 gene polymorphism did not show any associations with the disease when we performed the one- and two-way analyses. This finding indicates epistasis: the effect of one gene may not be disclosed if the effect of another gene is not considered. Obviously, such high-order gene-gene interactions could not be readily disclosed by conventional analytical methods. Interestingly, a strong independent interaction between CYP2D6 and EPHX1 genes has been obtained by the MDR analysis. In addition, a cluster technique implemented into MDR software has observed a high degree synergistic interaction between these loci suggesting that the gene-gene effect may be driven by a true interaction, rather than by the main effect from the EPHX1 gene. Notably, although all the three genes were included in the best MDR model, the CYP1B1 gene displayed independence from interaction of CYP2D6 and EPHX1 genes. Certainly, it is very difficult to interpret biologically gene-gene interactions obtained the MDR analysis. However, the gene-gene interaction found makes mechanistic sense, because these genes are involved in the same biological pathway. It is probable that the integrated function of EPHX1, CYP1B1 and CYP2D6 genes and their products promotes coordinated metabolism of common xenobiotics, such as PAH and heterocyclic compounds in lungs and airways where these genes are vitally expressed. The information gleaned from our study may reflect the systemic involvement of the XME genes in susceptibility to asthma; the results obtained for the first time, and, in turn, could be very useful in unraveling the true biological roles of xenobiotic-metabolizing enzymes in the pathogenesis of the disease. To the best of our knowledge, the present study is the first to show that a number of xenobiotic-metabolizing enzymes genes are systemically involved rather in aetiology than in pathogenesis of asthma.

This research was supported in part by grant of the President of Russian Federation (MD-3571.2008.7).