title: Predicting functional regulatory SNPs in the human antimicrobial peptide genes DEFB1 and CAMP in tuberculosis and HIV/AIDS.
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.
authors.affiliation: Personalized Medicine Laboratory (LAMPER), Medical and Pharmaceutical Biotechnology, Guadalajara Unit, Research Center of Technology and Design Assistance of Jalisco State, National Council of Science and Technology (CIATEJ AC, CONACYT), Av. Normalistas 800, Col. Colinas de la Normal, CP 44270 Guadalajara, Jalisco, Mexico. Electronic address: adolfo.flores.saiffe@gmail.com.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Flores Saiffe Farías
authors.affiliation: Industrial Biotechnology, CIATEJ AC, Zapopan Unit, CONACYT, Camino Arenero 1227, Col. El Bajío del Arenal, CP 45019 Zapopan, Jalisco, Mexico. Electronic address: eherrera@ciatej.mx.
authors.forename: Enrique
authors.initials: E
authors.lastname: Jaime Herrera López
authors.affiliation: Personalized Medicine Laboratory (LAMPER), Medical and Pharmaceutical Biotechnology, Guadalajara Unit, Research Center of Technology and Design Assistance of Jalisco State, National Council of Science and Technology (CIATEJ AC, CONACYT), Av. Normalistas 800, Col. Colinas de la Normal, CP 44270 Guadalajara, Jalisco, Mexico. Electronic address: ing_cjmv@hotmail.com.
authors.forename: Cristopher Jorge
authors.initials: CJ
authors.lastname: Moreno Vázquez
authors.affiliation: The Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, 350 Community Dr. Manhasset, NY 11030, USA. Electronic address: wtli2012@gmail.com.
authors.forename: Wentian
authors.initials: W
authors.lastname: Li
authors.affiliation: Personalized Medicine Laboratory (LAMPER), Medical and Pharmaceutical Biotechnology, Guadalajara Unit, Research Center of Technology and Design Assistance of Jalisco State, National Council of Science and Technology (CIATEJ AC, CONACYT), Av. Normalistas 800, Col. Colinas de la Normal, CP 44270 Guadalajara, Jalisco, Mexico; Molecular Biology Laboratory, Biosafety Area, Medical and Pharmaceutical Biotechnology, Guadalajara Unit, CIATEJ AC, CONACYT, Av. Normalistas 800, Col. Colinas de la Normal, CP 44270 Guadalajara, Jalisco, Mexico. Electronic address: eprado@ciatej.mx.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Prado Montes de Oca
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics*; D000465:Algorithms; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins / Q000235:genetics*; D030541:Databases, Genetic; D015658:HIV Infections / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014376:Tuberculosis / Q000235:genetics*; D023083:beta-Defensins / Q000235:genetics*
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; C406407:DEFB1 protein, human; D023083:beta-Defensins
keywords: Antimicrobial peptide; Cathelicidin LL-37; Defensins; HIV/AIDS; Regulatory single nucleotide polymorphisms (rSNP); Tuberculosis