PARK2 and proinflammatory/anti-in flammatory cytokine gene interactions contribute to the susceptibility to leprosy: A case-control study of North Indian population

Abstract

Objectives: Cytokines 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. Design: The 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. Setting: Population-based case-control study involved the data of North India. Protein-protein interaction networks were constructed using cytoscape. Participants: Study 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 measures: For 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. Results: Interaction 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. Conclusions: Epistatic 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/antiinflammatory molecules indicate that PARK2 is central to immune regulation, regulating the production of different cytokines on infection.