Inherited variation in immune genes and pathways and glioblastoma risk

Abstract

To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel-Haenzel P values = 1 × 10⁻⁵ to 4 × 10⁻³), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk.

Fig. 1.

Scatter plot of minP values of allergy- and inflammation-related genes (893) present in both UCSF Adult Glioma Study and MDA Study data sets. Each gene from each study site is assigned a minP value, which represents the results of a test of the association of that gene with glioblastoma. The minP is adjusted for multiple testing and number of SNPs per gene.

Fig. 2.

(a and b) Scatter plots of minP of genes by pathway from UCSF Adult Glioma Study and MDA Study data sets. Each gene from each study site is assigned a minP value, which represents the results of a test of the association of that gene with glioblastoma. The minP is adjusted for multiple testing and number of SNPs per gene.