目的:免疫应答途径中的细胞因子和相关分子在决定麻风病中不同极性形式的宿主-病原体相互作用的结果方面似乎很重要。我们研究了这些基因中重要和功能重要的单核苷酸多态性(SNP)的作用,独立于我们的研究小组出版,通过结合相互作用和对计算机网络结果的额外分析,了解这些如何影响对疾病的易感性,麻风病.
方法:本研究旨在评估显著相关的个体SNP的总体综合贡献,以反映疾病形式的上位性相互作用及其结果。麻风病.此外,采用计算机模拟方法进行PARK2与促炎/抗炎细胞因子之间的蛋白质-蛋白质相互作用研究。
方法:基于人口的病例对照研究涉及北印度的数据。蛋白质-蛋白质相互作用网络是使用cytosscape构建的。
方法:研究包括来自2305个北印度人样本(829名麻风病患者;1476名健康对照)的数据,由我们的研究小组产生。
方法:对于基因型相互作用分析,选择的SNP之间的所有可能的基因型组合被用作独立变量,使用二元逻辑回归和正向似然比方法,保持性别为协变量。
结果:PARK2与抗炎/促炎细胞因子基因的显著SNP之间的相互作用分析,在病例对照比较中包括跨越HLA(6p21.3)区域的BAT1至BTNL2-DR,联合分析表明:(1)PARK2、肿瘤坏死因子(TNF)、BTNL2-DR,白细胞介素(IL)-10,IL-6和TGFBR2增加了麻风病的风险(OR=2.54);(2)PARK2,BAT1,NFKBIL1,LTA,TNF-LTB,IL12B和IL10RB与其各自的贡献相比提供了增加的保护(OR=0.26)。
结论:涉及PARK2和细胞因子基因的表观SNP-SNP相互作用提供了麻风病易感性的附加风险。此外,PARK2和重要的促炎/抗炎分子的蛋白质-蛋白质相互作用表明PARK2是免疫调节的核心,调节感染时不同细胞因子的产生。
OBJECTIVE: 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.
METHODS: 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.
METHODS: Population-based case-control
study involved the data of North India. Protein-protein interaction networks were constructed using cytoscape.
METHODS: Study included the data available from 2305 Northern Indians samples (829 patients with leprosy; 1476 healthy controls), generated by our research group.
METHODS: 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/anti-inflammatory molecules indicate that PARK2 is central to immune regulation, regulating the production of different cytokines on infection.