Study of the functional significance of polymorphic loci of the LOXL1 gene associated with glaucoma according to genome-wide studies (in silico analysis)

Abstract

Using the catalog of genome-wide studies (GWAS) of the National Human Genome Research Institute (https://www.genome.gov/gwastudies/), three polymorphic loci of the LOXL1 gene (rs2165241, rs4886776, rs893818) associated with glaucoma (pseudoexfoliation glaucoma/syndrome) were chosen for the study. Using modern databases on functional genomics (SIFT, PolyPhen-2, HaploReg, GTExportal), the functional significance of these polymorphic loci was assessed (nonsynonymous substitutions, epigenetic effects, association with gene expression, associations with alternative splicing of gene transcripts). The work establishes the important functional significance of the rs2165241, rs4886776 and rs893818 polymorphic loci of the LOXL1 gene. They demonstrate significant epigenetic effects (affect the affinity to five transcription factors, are located in the region of promoters and enhancers, in the region of hypersensitivity to DNase-1), are associated with the expression and alternative splicing of three genes (LOXL1, LOXL1-AS1, RP11-24D15.1) in cell cultures, organs and tissues pathogenetically significant for development of glaucoma, are strongly linked to the rs1048661 polymorphism, which causes the replacement of the Arg141Leu amino acid in the LOXL1 polypeptide. Polymorphic loci of the LOXL1 gene (rs2165241, rs4886776, and rs893818) are of great functional importance (epigenetic, eQTL, and sQTL), which may be the biomedical basis of their associations with glaucoma.