Exome-wide search and functional annotation of genes associated in patients with severe tick-borne encephalitis in a Russian population

Abstract

Background Tick-borne encephalitis (TBE) is a viral infectious disease caused by tick-borne encephalitis virus (TBEV). TBEV infection is responsible for a variety of clinical manifestations ranging from mild fever to severe neurological illness. Genetic factors involved in the host response to TBEV that may potentially play a role in the severity of the disease are still poorly understood. In this study, using whole-exome sequencing, we aimed to identify genetic variants and genes associated with severe forms of TBE as well as biological pathways through which the identified variants may influence the severity of the disease. Results Whole-exome sequencing data analysis was performed on 22 Russian patients with severe forms of TBE and 17 Russian individuals from the control group. We identified 2407 candidate genes harboring rare, potentially pathogenic variants in exomes of patients with TBE and not containing any rare, potentially pathogenic variants in exomes of individuals from the control group. According to DAVID tool, this set of 2407 genes was enriched with genes involved in extracellular matrix proteoglycans pathway and genes encoding proteins located at the cell periphery. A total of 154 genes/proteins from these functional groups have been shown to be involved in protein-protein interactions (PPIs) with the known candidate genes/proteins extracted from TBEVHostDB database. By ranking these genes according to the number of rare harmful minor alleles, we identified two genes ( MSR1 and LMO7), harboring five minor alleles, and three genes ( FLNA, PALLD, PKD1 ) harboring four minor alleles. When considering genes harboring genetic variants associated with severe forms of TBE at the suggestive P -value < 0.01, 46 genes containing harmful variants were identified. Out of these 46 genes, eight ( MAP4, WDFY4, ACTRT2, KLHL25, MAP2K3, MBD1, OR10J1, and OR2T34) were additionally found among genes containing rare pathogenic variants identified in patients with TBE; and five genes ( WDFY4 , ALK, MAP4, BNIPL, EPPK1 ) were found to encode proteins that are involved in PPIs with proteins encoded by genes from TBEVHostDB. Three genes out of five ( MAP4, EPPK1, ALK ) were found to encode proteins located at cell periphery. Conclusions Whole-exome sequencing followed by systems biology approach enabled to identify eight candidate genes ( MAP4, WDFY4, ACTRT2, KLHL25, MAP2K3, MBD1, OR10J1, and OR2T34 ) that can potentially determine predisposition to severe forms of TBE. Analyses of the genetic risk factors for severe forms of TBE revealed a significant enrichment with genes controlling extracellular matrix proteoglycans pathway as well...

Whole-Exome Sequencing Analysis of Human Semen Quality in Russian Multiethnic Population

“…This gene plays an important role in autophagic biological processes and may highly express in early and late spermatids 2 . Genetic variants in and around the WDFY4 gene were identified as associated with systemic lupus erythematosus (Yang et al, 2010) and with severe tick-borne encephalitis (Ignatieva et al, 2019). In our study, we found that the SNP marker rs12268007 of the WDFY4 gene had the same properties as the FAM71F1 gene.…”

Human plasmacytoid dendritic cells at the crossroad of type I interferon-regulated B cell differentiation and antiviral response to tick-borne encephalitis virus

“…The importance of this pathway for controlling flavivirus replication has been also addressed by Lindqvist et al in the CNS, where astrocytes mount a rapid IFN response to restrict viral spread [11]. In addition, several studies further sustained the relevance of the IFN pathway by showing that in different populations predisposition to severe forms of TBE and susceptibility to TBEV-induced disease are associated with single nucleotide polymorphism and intronic polymorphism in IFN and ISGs [12][13][14]. Notwithstanding, for TBEV, the antiviral type I IFN response is not well characterized in humans although this virus was used as model of infection in the first IFN studies [15].…”

Whole Genome Sequencing-based Characterization of Human Genome Variation and Mutation Burden in Botswana

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