Molecular Relationships between Bronchial Asthma and Hypertension as Comorbid Diseases.

Comorbidity, a co-incidence of several disorders in an individual, is a common phenomenon. Their development is governed by multiple factors, including genetic variation. The current study was set up to look at associations between isolated and comorbid diseases of bronchial asthma and hypertension, on one hand, and single nucleotide polymorphisms associated with regulation of gene expression (eQTL), on the other hand. A total of 96 eQTL SNPs were genotyped in 587 Russian individuals. Bronchial asthma alone was found to be associated with rs1927914 (TLR4), rs1928298 (intergenic variant), and rs1980616 (SERPINA1); hypertension alone was found to be associated with rs11065987 (intergenic variant); rs2284033 (IL2RB), rs11191582 (NT5C2), and rs11669386 (CARD8); comorbidity between asthma and hypertension was found to be associated with rs1010461 (ANG/RNASE4), rs7038716, rs7026297 (LOC105376244), rs7025144 (intergenic variant), and rs2022318 (intergenic variant). The results suggest that genetic background of comorbidity of asthma and hypertension is different from genetic backgrounds of both diseases manifesting isolated.

Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks.

BACKGROUND: Hypertension and bronchial asthma are a major issue for people's health. As of 2014, approximately one billion adults, or ~ 22% of the world population, have had hypertension. As of 2011, 235-330 million people globally have been affected by asthma and approximately 250,000-345,000 people have died each year from the disease. The development of the effective treatment therapies against these diseases is complicated by their comorbidity features. This is often a major problem in diagnosis and their treatment. Hence, in this study the bioinformatical methodology for the analysis of the comorbidity of these two diseases have been developed. As such, the search for candidate genes related to the comorbid conditions of asthma and hypertension can help in elucidating the molecular mechanisms underlying the comorbid condition of these two diseases, and can also be useful for genotyping and identifying new drug targets. RESULTS: Using ANDSystem, the reconstruction and analysis of gene networks associated with asthma and hypertension was carried out. The gene network of asthma included 755 genes/proteins and 62,603 interactions, while the gene network of hypertension - 713 genes/proteins and 45,479 interactions. Two hundred and five genes/proteins and 9638 interactions were shared between asthma and hypertension. An approach for ranking genes implicated in the comorbid condition of two diseases was proposed. The approach is based on nine criteria for ranking genes by their importance, including standard methods of gene prioritization (Endeavor, ToppGene) as well as original criteria that take into account the characteristics of an associative gene network and the presence of known polymorphisms in the analysed genes. According to the proposed approach, the genes IL10, TLR4, and CAT had the highest priority in the development of comorbidity of these two diseases. Additionally, it was revealed that the list of top genes is enriched with apoptotic genes and genes involved in biological processes related to the functioning of central nervous system. CONCLUSIONS: The application of methods of reconstruction and analysis of gene networks is a productive tool for studying the molecular mechanisms of comorbid conditions. The method put forth to rank genes by their importance to the comorbid condition of asthma and hypertension was employed that resulted in prediction of 10 genes, playing the key role in the development of the comorbid condition. The results can be utilised to plan experiments for identification of novel candidate genes along with searching for novel pharmacological targets.

Search for New Candidate Genes Involved in the Comorbidity of Asthma and Hypertension Based on Automatic Analysis of Scientific Literature.

Comorbid states of diseases significantly complicate diagnosis and treatment. Molecular mechanisms of comorbid states of asthma and hypertension are still poorly understood. Prioritization is a way for identifying genes involved in complex phenotypic traits. Existing methods of prioritization consider genetic, expression and evolutionary data, molecular-genetic networks and other. In the case of molecular-genetic networks, as a rule, protein-protein interactions and KEGG networks are used. ANDSystem allows reconstructing associative gene networks, which include more than 20 types of interactions, including protein-protein interactions, expression regulation, transport, catalysis, etc. In this work, a set of genes has been prioritized to find genes potentially involved in asthma and hypertension comorbidity. The prioritization was carried out using well-known methods (ToppGene and Endeavor) and a cross-talk centrality criterion, calculated by analysis of associative gene networks from ANDSystem. The identified genes, including IL1A, CD40LG, STAT3, IL15, FAS, APP, TLR2, C3, IL13 and CXCL10, may be involved in the molecular mechanisms of comorbid asthma/hypertension. An analysis of the dynamics of the frequency of mentioning the most priority genes in scientific publications revealed that the top 100 priority genes are significantly enriched with genes with increased positive dynamics, which may be a positive sign for further studies of these genes.

Robotic QM/MM-driven maturation of antibody combining sites.

In vitro selection of antibodies from large repertoires of immunoglobulin (Ig) combining sites using combinatorial libraries is a powerful tool, with great potential for generating in vivo scavengers for toxins. However, addition of a maturation function is necessary to enable these selected antibodies to more closely mimic the full mammalian immune response. We approached this goal using quantum mechanics/molecular mechanics (QM/MM) calculations to achieve maturation in silico. We preselected A17, an Ig template, from a naïve library for its ability to disarm a toxic pesticide related to organophosphorus nerve agents. Virtual screening of 167,538 robotically generated mutants identified an optimum single point mutation, which experimentally boosted wild-type Ig scavenger performance by 170-fold. We validated the QM/MM predictions via kinetic analysis and crystal structures of mutant apo-A17 and covalently modified Ig, thereby identifying the displacement of one water molecule by an arginine as delivering this catalysis.