Predicting functional regulatory SNPs in the human antimicrobial peptide genes DEFB1 and CAMP in tuberculosis and HIV/AIDS. (December 2015)

• Record Type: Journal Article
• Authors: Flores Saiffe Farías, Adolfo; Jaime Herrera López, Enrique; Moreno Vázquez, Cristopher Jorge; Li, Wentian; Prado Montes de Oca, Ernesto
• Is Part Of: Computational biology and chemistry. Volume 59:Part A(2015)
• Page Start: 117
• Page End: 125
• Publication Date: 2015-12
• Subjects: Regulatory single nucleotide polymorphisms (rSNP) -- Tuberculosis -- HIV/AIDS -- Antimicrobial peptide -- Defensins -- Cathelicidin LL-37; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2015.09.002
• Languages: English
• ISSNs: 1476-9271

Abstract

Graphical abstract: Highlights: 10 SNPs in DEFB1 and CAMP modify the TFBS for 24 TFs related to HIV/AIDS and TB. We introduce the homotypic redundancy weight factor (HWF) to assess rSNP impacts. Our algorithm has 53% sensitivity and 84.6% specificity to detect functional rSNPs. Future ENCODE and 1000 genomes project releases will improve the proposed algorithm. This algorithm could be useful to probe design and personalized medicine. Abstract: Single nucleotide polymorphisms (SNPs) in transcription factor binding sites (TFBSs) within gene promoter region or enhancers can modify the transcription rate of genes related to complex diseases. These SNPs can be called regulatory SNPs (rSNPs). Data compiled from recent projects, such as the 1000 Genomes Project and ENCODE, has revealed essential information used to perform in silico prediction of the molecular and biological repercussions of SNPs within TFBS. However, most of these studies are very limited, as they only analyze SNPs in coding regions or when applied to promoters, and do not integrate essential biological data like TFBSs, expression profiles, pathway analysis, homotypic redundancy (number of TFBSs for the same TF in a region), chromatin accessibility and others, which could lead to a more accurate prediction. Our aim was to integrate different data in a biologically coherent method to analyze the proximal promoter regions of two antimicrobial peptide genes, DEFB1 and CAMP, that are associated with tuberculosis (TB) and HIV/AIDS. We predicted SNPs within the promoter regions that are more likely to interact with transcription factors (TFs). We also assessed the impact of homotypic redundancy using a novel approach called the homotypic redundancy weight factor (HWF). Our results identified 10 SNPs, which putatively modify the binding affinity of 24 TFs previously identified as related to TB and HIV/AIDS expression profiles (e.g. KLF5, CEBPA and NFKB1 for TB; FOXP2, BRCA1, CEBPB, CREB1, EBF1 and ZNF354C for HIV/AIDS; and RUNX2, HIF1A, JUN/AP-1, NR4A2, EGR1 for both diseases). Validating with the OregAnno database and cell-specific functional/non functional SNPs from additional 13 genes, our algorithm performed 53% sensitivity and 84.6% specificity to detect functional rSNPs using the DNAseI-HUP database. We are proposing our algorithm as a novel in silico method to detect true functional rSNPs in antimicrobial peptide genes. With further improvement, this novel method could be applied to other promoters in order to design probes and to discover new drug targets for complex diseases.