Assembly of inflammation-related genes for pathway-focused genetic analysis

Abstract

Recent identifications of associations between novel variants in inflammation-related genes and several common diseases emphasize the need for systematic evaluations of these genes in disease susceptibility. Considering that many genes are involved in the complex inflammation responses and many genetic variants in these genes have the potential to alter the functions and expression of these genes, we assembled a list of key inflammation-related genes to facilitate the identification of genetic associations of diseases with an inflammation-related etiology. We first reviewed various phases of inflammation responses, including the development of immune cells, sensing of danger, influx of cells to sites of insult, activation and functional responses of immune and non-immune cells, and resolution of the immune response. Assisted by the Ingenuity Pathway Analysis, we then identified 17 functional sub-pathways that are involved in one or multiple phases. This organization would greatly increase the chance of detecting gene-gene interactions by hierarchical clustering of genes with their functional closeness in a pathway. Finally, as an example application, we have developed tagging single nucleotide polymorphism (tSNP) arrays for populations of European and African descent to capture all the common variants of these key inflammation-related genes. Assays of these tSNPs have been designed and assembled into two Affymetrix ParAllele customized chips, one each for European (12,011 SNPs) and African (21,542 SNPs) populations. These tSNPs have greater coverage for these inflammation-related genes compared to the existing genome-wide arrays, particularly in the African population. These tSNP arrays can facilitate systematic evaluation of inflammation pathways in disease susceptibility. For additional applications, other genotyping platforms could also be employed. For existing genome-wide association data, this list of key inflammation-related genes and associated subpathways can facilitate comprehensive inflammation pathway- focused association analyses.

Figure 1. Development of an immune response.

Depicted is a schematic representation of an immune response to a generic pathogenic insult. The phases of immune responses (described in Table 2) are shown in bold. Additional aspects not shown are the involvement of secondary lymphoid tissues for initial T cell and B cell activation by dendritic cells that migrate from the site of inflammation to lymph nodes and other secondary lymphoid structures. The resolution of immune responses, immunological memory, and homeostasis are also not depicted.

Figure 2. Inflammation subpathways involved in the response to danger signal.

The concerted action of multiple functional subpathways in the initial response of a macrophage to bacteria or virus is depicted. Solid arrows indicate signaling events and dashed arrows stimulated production of proteins and other inflammatory mediators (including autocrine/paracrine responses of the macrophage to the released molecules).