Assessment of key regulatory genes and identification of possible drug targets for Leprosy (Hansen's disease) using network-based approach.

Leprosy is a major health concern and continues to be a source of fear and stigma among people worldwide. Despite remarkable achievements in the treatment, understanding of pathogenesis and transmission, epidemiology of leprosy still remains inadequate. The prolonged incubation period, slow rates of occurrence in those exposed and deceptive clinical presentation pose challenges to develop reliable strategies to stop transmission. Hence, there is a need for improved diagnostics and therapies to prevent mortality caused by leprosy. The objectives of this study are to identify significant genes from protein-protein interactions (PPIs) network of leprosy and to choose the most effective therapeutic targets. Fifty genes related with leprosy were discovered by literature mining. These genes were used to construct a primary network. Leading Eigen Vector method was used to break down the primary network into various sub-networks or communities. It was found that the primary network was divided into many sub-networks at the 6 levels. Seed genes were traced at each level till key regulatory genes were identified. Three seed genes, namely, GNAI3, NOTCH1, and HIF1A, were able to make their way till the final motif stage. These genes along with their interacting partners were considered key regulators of the leprosy network. This study provides leprosy-associated key genes which can lead to improved diagnosis and therapies for leprosy patients.

[1]  E. Sarno,et al.  A new paradigm for leprosy diagnosis based on host gene expression , 2021, bioRxiv.

[2]  James E. Tomkins,et al.  Advances in protein-protein interaction network analysis for Parkinson's disease , 2021, Neurobiology of Disease.

[3]  Nadeem Ahmad,et al.  Identification of the Key Regulators of Spina Bifida Through Graph-Theoretical Approach , 2021, Frontiers in Genetics.

[4]  Nadezhda T. Doncheva,et al.  The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets , 2020, Nucleic Acids Res..

[5]  Chuan Wang,et al.  Massively Parallel Sequencing of the Filaggrin Gene Reveals an Association Between FLG Loss-of-function Mutations and Leprosy , 2020, Acta dermato-venereologica.

[6]  L. Abel,et al.  The complex pattern of genetic associations of leprosy with HLA class I and class II alleles can be reduced to four amino acid positions , 2020, PLoS pathogens.

[7]  N. Cardona-Castro,et al.  Notch Signaling Pathway Expression in the Skin of Leprosy Patients: Association With Skin and Neural Damage , 2020, Frontiers in Immunology.

[8]  Barry Demchak,et al.  Cytoscape Automation: empowering workflow-based network analysis , 2019, Genome Biology.

[9]  E. P. Ambrosio-Albuquerque,et al.  The impact of KIR/HLA genes on the risk of developing multibacillary leprosy , 2019, PLoS neglected tropical diseases.

[10]  M. Pellegrini,et al.  The cell fate regulator NUPR1 is induced by Mycobacterium leprae via type I interferon in human leprosy , 2019, PLoS neglected tropical diseases.

[11]  G. Lettre,et al.  Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson’s disease , 2019, Proceedings of the National Academy of Sciences.

[12]  Priscila Medeiros,et al.  Polymorphisms in the TGFB1 and IL2RA genes are associated with clinical forms of leprosy in Brazilian population , 2018, Memorias do Instituto Oswaldo Cruz.

[13]  V. Pathak,et al.  VDR polymorphism, gene expression and vitamin D levels in leprosy patients from North Indian population , 2018, PLoS neglected tropical diseases.

[14]  A. Alam,et al.  Assessment of the key regulatory genes and their Interologs for Turner Syndrome employing network approach , 2018, Scientific Reports.

[15]  G. M. Sperandio da Silva,et al.  Autophagy Impairment Is Associated With Increased Inflammasome Activation and Reversal Reaction Development in Multibacillary Leprosy , 2018, Front. Immunol..

[16]  Xiulu Yu,et al.  Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese. , 2018, American journal of human genetics.

[17]  A. C. Messias,et al.  miRNome Expression Analysis Reveals New Players on Leprosy Immune Physiopathology , 2018, Front. Immunol..

[18]  Y.Y. Li,et al.  A pleiotropic effect of the APOE gene: association of APOE polymorphisms with multibacillary leprosy in Han Chinese from Southwest China , 2018, The British journal of dermatology.

[19]  Z. Babaloo,et al.  Analysis of CTLA-4+49A/G gene polymorphism in cases with leprosy of Azerbaijan, Northwest Iran. , 2018, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[20]  Xiulu Yu,et al.  The mtDNA replication-related genes TFAM and POLG are associated with leprosy in Han Chinese from Southwest China. , 2017, Journal of dermatological science.

[21]  E. Sarno,et al.  Autophagy Is an Innate Mechanism Associated with Leprosy Polarization , 2017, PLoS pathogens.

[22]  R. Werneck,et al.  Association Analysis Suggests SOD2 as a Newly Identified Candidate Gene Associated With Leprosy Susceptibility. , 2016, The Journal of infectious diseases.

[23]  M. Moraes,et al.  The GATA3 gene is involved in leprosy susceptibility in Brazilian patients. , 2016, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[24]  C. Franco-Paredes,et al.  Delayed Diagnosis, Leprosy Reactions, and Nerve Injury Among Individuals With Hansen's Disease Seen at a United States Clinic , 2016, Open forum infectious diseases.

[25]  Yong-Gang Yao,et al.  Common variants of OPA1 conferring genetic susceptibility to leprosy in Han Chinese from Southwest China. , 2015, Journal of dermatological science.

[26]  E. V. Kulish,et al.  Genomic Study of Cardiovascular Continuum Comorbidity , 2015, Acta naturae.

[27]  S. Thiel,et al.  Leprosy Association with Low MASP-2 Levels Generated by MASP2 Haplotypes and Polymorphisms Flanking MAp19 Exon 5 , 2013, PloS one.

[28]  E. Sarno,et al.  Gene Expression Profiling Specifies Chemokine, Mitochondrial and Lipid Metabolism Signatures in Leprosy , 2013, PloS one.

[29]  A. Emili,et al.  Protein-protein interaction networks: probing disease mechanisms using model systems , 2013, Genome Medicine.

[30]  D. Malhotra,et al.  Genetic variations and interactions in anti-inflammatory cytokine pathway genes in the outcome of leprosy: a study conducted on a MassARRAY platform. , 2011, The Journal of infectious diseases.

[31]  G. Kaplan,et al.  Common polymorphisms in the NOD2 gene region are associated with leprosy and its reactive states. , 2010, The Journal of infectious diseases.

[32]  J. Bell,et al.  Variation in MICA and MICB genes and enhanced susceptibility to paucibacillary leprosy in South India. , 2006, Human molecular genetics.

[33]  D. Malhotra,et al.  Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population , 2006, European Journal of Human Genetics.

[34]  M. Hatta,et al.  Population survey to determine risk factors for Mycobacterium leprae transmission and infection. , 2004, International journal of epidemiology.

[35]  M. Shaw,et al.  Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes , 2001, Genes and Immunity.

[36]  G. Sachdeva,et al.  Association of polymorphism at COL3A and CTLA4 loci on chromosome 2q31-33 with the clinical phenotype and in-vitro CMI status in healthy and leprosy subjects: a preliminary study , 1997, Human Genetics.

[37]  N. Mehra,et al.  Transporter associated with antigen-processing (TAP) genes and susceptibility to tuberculoid leprosy and pulmonary tuberculosis. , 1997, Tissue antigens.

[38]  C. K. Job,et al.  Transmission of leprosy in nude mice. , 1985, The American journal of tropical medicine and hygiene.