PARK2 and proinflammatory/anti-inflammatory cytokine gene interactions contribute to the susceptibility to leprosy: a case–control study of North Indian population

Abstract

ObjectivesCytokines and related molecules in immune-response pathways seem important in deciding the outcome of the host–pathogen interactions towards different polar forms in leprosy. We studied the role of significant and functionally important single-nucleotide polymorphisms (SNPs) in these genes, published independently from our research group, through combined interaction with an additional analysis of the in silico network outcome, to understand how these impact the susceptibility towards the disease, leprosy.DesignThe study was designed to assess an overall combined contribution of significantly associated individual SNPs to reflect on epistatic interactions and their outcome in the form of the disease, leprosy. Furthermore, in silico approach was adopted to carry out protein–protein interaction study between PARK2 and proinflammatory/anti-inflammatory cytokines.SettingPopulation-based case–control study involved the data of North India. Protein–protein interaction networks were constructed using cytoscape.ParticipantsStudy included the data available from 2305 Northern Indians samples (829 patients with leprosy; 1476 healthy controls), generated by our research group.Primary and secondary outcome measuresFor genotype interaction analysis, all possible genotype combinations between selected SNPs were used as an independent variable, using binary logistic regression with the forward likelihood ratio method, keeping the gender as a covariate.ResultsInteraction analysis between PARK2 and significant SNPs of anti-inflammatory/proinflammatory cytokine genes, including BAT1 to BTNL2-DR spanning the HLA (6p21.3) region in a case–control comparison, showed that the combined analysis of: (1) PARK2, tumour necrosis factor (TNF), BTNL2-DR, interleukin (IL)-10, IL-6 and TGFBR2 increased the risk towards leprosy (OR=2.54); (2) PARK2, BAT1, NFKBIL1, LTA, TNF-LTB, IL12B and IL10RB provided increased protection (OR=0.26) in comparison with their individual contribution.ConclusionsEpistatic SNP–SNP interactions involving PARK2 and cytokine genes provide an additive risk towards leprosy susceptibility. Furthermore, in silico protein–protein interaction of PARK2 and important proinflammatory/anti-inflammatory molecules indicate that PARK2 is central to immune regulation, regulating the production of different cytokines on infection.

Common variants in the PARL and PINK1 genes increase the risk to leprosy in Han Chinese from South China

“…3). Note that PINK1 directly interacted with PARK2, which was identified as a leprosy risk gene in several populations424344. However, our NGS analysis for the PARK2 gene revealed no association of this gene with leprosy though we observed positive associations between PARL and leprosy or between PINK1 and leprosy in this relatively small sample.…”

PINK1/Parkin-Dependent Mitochondrial Surveillance: From Pleiotropy to Parkinson's Disease

“…Conversely, pathogens that perturb mitochondrial function trigger a protective UPR mt response. Together with strong emerging links between PINK1 and Parkin and the regulation of pathogen response pathways in C. elegans and mammals (Mira et al, 2004 ; Manzanillo et al, 2013 ; Chopra et al, 2014 ; Kirienko et al, 2015 ), these observations warrant a detailed analysis of the role of PINK1/Parkin-dependent mitochondrial quality control in cells of the immune system, particularly in the central nervous system, where their dysfunction may contribute to neurodegeneration.…”

“…Historically, PARK2 /Parkin was firstly associated with increased susceptibility to infection by mycobacteria, such as M. leprae and M. tuberculosis (Mira et al, 2004 ; Manzanillo et al, 2013 ; Chopra et al, 2014 ). Parkin modulates the host response to these pathogens by promoting their clearance via ubiquitin-mediated autophagy (Manzanillo et al, 2013 ).…”

Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20‐dependent negative feedback loop

“…Several studies have linked Parkin and PINK1 to innate immunity (Greene, Whitworth, Andrews, Parker, & Pallanck, 2005;Matheoud et al, 2016;Torres-Odio et al, 2017). A loss of PARK2 function increases susceptibility to mycobacterial infection and sensitivity to inflammation-related dopaminergic (DA) neuron degeneration (Chopra et al, 2014;Frank-Cannon et al, 2008;Lazarou, 2015;Manzanillo et al, 2013;Mira et al, 2004), while the expression of PARK2 and PINK1 is stimulated by hepatitis viruses (Khan, Syed, Kim, & Siddiqui, 2016). Parkin regulates the NF-jB-dependent inflammatory pathway (Henn et al, 2007), and Parkin deficiency enhances the production of cytokines, such as TNFa, IL-6 and monocyte chemoattractant protein-1 (MCP-1; de L es eleuc et al, 2013;Tran et al, 2011).…”