Regulatory SNP rs5743417 impairs constitutive expression of human β-defensin 1 and has high frequency in Africans and Afro-Americans.
Luis Antonio Cruz DíazAbel Gutiérrez-OrtegaRocío Del Carmen Chávez ÁlvarezJesús Salvador Velarde-FelixErnesto Prado Montes de OcaPublished in: International journal of immunogenetics (2020)
The prediction of regulatory single nucleotide polymorphisms (rSNPs) in proximal promoters of disease-related genes could be a useful tool for personalized medicine in both patient stratification and customized therapy. Using our previously reported method of rSNPs prediction (currently a software called SNPClinic v.1.0) as well as with PredictSNP tool, we performed in silico prediction of regulatory SNPs in the antimicrobial peptide human β-defensin 1 gene in three human cell lines from 1,000 Genomes Project (1kGP), namely A549 (epithelial cell line), HL-60 (neutrophils) and TH 1 (lymphocytes). These predictions were run in a proximal pseudo-promoter comprising all common alleles on each polymorphic site according to the 1,000 Genomes Project data (1kGP: ALL). Plasmid vectors containing either the major or the minor allele of a putative rSNP rs5743417 (categorized as regulatory by SNPClinic and confirmed by PredictSNP) and a non-rSNP negative control were transfected to lung A549 human epithelial cell line. We assessed functionality of rSNPs by qPCR using the Pfaffl method. In A549 cells, minor allele of the SNP rs5743417 G→A showed a significant reduction in gene expression, diminishing DEFB1 transcription by 33% when compared with the G major allele (p-value = .03). SNP rs5743417 minor allele has high frequency in Gambians (8%, 1kGP population: GWD) and Afro-Americans (3.3%, 1kGP population: ASW). This SNP alters three transcription factors binding sites (TFBSs) comprising SREBP2 (sterols and haematopoietic pathways), CREB1 (cAMP, insulin and TNF pathways) and JUND (apoptosis, senescence and stress pathways) in the proximal promoter of DEFB1. Further in silico analysis reveals that this SNP also overlaps with GS1-24F4.2, a lincRNA gene complementary to the X Kell blood group related 5 (XKR5) mRNA. The potential clinical impact of the altered constitutive expression of DEFB1 caused by rSNP rs5743417 in DEFB1-associated diseases as tuberculosis, COPD, asthma, cystic fibrosis and cancer in African and Afro-American populations deserves further research.
Keyphrases
- high frequency
- genome wide
- transcription factor
- endothelial cells
- gene expression
- dna methylation
- transcranial magnetic stimulation
- induced pluripotent stem cells
- cystic fibrosis
- pluripotent stem cells
- cell cycle arrest
- chronic obstructive pulmonary disease
- poor prognosis
- emergency department
- oxidative stress
- high density
- escherichia coli
- stem cells
- mycobacterium tuberculosis
- binding protein
- cell death
- dna damage
- metabolic syndrome
- climate change
- genome wide identification
- case report
- machine learning
- genetic diversity
- mesenchymal stem cells
- electronic health record
- induced apoptosis
- weight loss
- skeletal muscle
- dna binding
- lymph node metastasis
- young adults
- glycemic control