Abstract
Almost 90 % of disease-associated genetic variants found using genome wide association studies (GWAS) are located in non-coding regions of the genome. Such variants can affect phenotype by altering important regulatory elements such as promoters, enhancers or repressors, leading to changes in gene expression and consequently disease, such as thyroid cancer and allergic diseases. A number of allergy and atopy related diseases such as asthma and atopic dermatitis are related to histamine receptors; however, these diseases are not fully characterized at the molecular level. Moreover, candidate gene based studies of common variants known as single nucleotide polymorphism (SNPs) located in the coding regions of these receptors have given mixed results. It is important to complement these approaches by identifying and characterising non-coding variants in order to further elucidate the role of these receptors in disease. Here we present an analysis of histamine receptor genes using the tool AnNCR-SNP to characterise variants in non-coding genomic regions. AnNCR-SNP combines bioinformatics and experimental data sets from various sources to predict the effects of genetic variation on gene expression regulation. We find many SNPs located in areas of open chromatin, overlapping with transcription factor binding sites and associated with changes in gene expression in expression quantitative trait loci (eQTL) experiments. Here we present the results as a catalogue of non-coding variation in histamine receptor genes to aid histamine researchers in identifying putative functional SNPs found in GWAS for further validation, and to help select variants for candidate gene studies.
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Acknowledgments
This work was supported by the European Commission, EU-FP7-Systems Microscopy Network of Excellence [258068], Institute of Health “Carlos III” of the Ministry of Economy and Competitiveness (grants cofounded by European Regional Development Fund (ERDF): PI12/00900, PI12/02247, PI12/02481, PI12/02529, Red de Reacciones Adversas a Alérgenos y Fármacos RD12/0013/0001) and the Andalusian Government with European Regional Development Fund [CTS-486]. The CIBERER is an initiative from the Institute of Health Carlos III. Elena Rojano is a researcher from the Plan de Formación de Personal Investigador (FPI) supported by the Andalusian Government. James Richard Perkins is a researcher from the Sara Borrell Program (Ref CD14/00242) of the Carlos III National Health Institute, Spanish Ministry of Economy and Competitiveness (grants cofounded by European Social Fund (ESF): CP14/00034 and CP15/00103 respectively). The authors thank the Supercomputing and Bioinnovation Center (SCBI) of the Universidad de Málaga for their provision of computational resources and technical support (http://www.scbi.uma.es/site). The authors would like to acknowledge Pedro Seoane from SCBI for his help in the development of the AnNCR-SNP software.
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Elena Rojano, Juan A. Ranea and James Richard Perkins are involved in the development of the AnNCR-SNP software. The authors declare no other conflicts of interest.
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Supplementary tables 1-4. SNPs overlapping with a genomic element from at least one data source included in AnNCR-SNP. Each row represents a SNP located in the non-coding regions of the Histamine receptor genes specified in Table 1. The first five columns give further details on each SNP, the remaining columns each represents a genomic regulatory element.
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Rojano, E., Ranea, J.A. & Perkins, J.R. Characterisation of non-coding genetic variation in histamine receptors using AnNCR-SNP. Amino Acids 48, 2433–2442 (2016). https://doi.org/10.1007/s00726-016-2265-5
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DOI: https://doi.org/10.1007/s00726-016-2265-5