Potentially functional genetic variants in the complement‐related immunity gene‐set are associated with non‐small cell lung cancer survival

Abstract

The complement system plays an important role in the innate and adaptive immunity, complement components mediate tumor cytolysis of antibody‐based immunotherapy, and complement activation in the tumor microenvironment may promote tumor progression or inhibition, depending on the mechanism of action. In the present study, we conducted a two‐phase analysis of two independently published genome‐wide association studies (GWASs) for associations between genetic variants in a complement‐related immunity gene‐set and overall survival of non‐small cell lung cancer (NSCLC). The GWAS dataset from Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was used as the discovery, and multivariate Cox proportional hazards regression with false‐positive report probability for multiple test corrections were performed to evaluate associations between 14,699 single‐nucleotide polymorphisms (SNPs) in 111 genes and survival of 1,185 NSCLC patients. The identified significant SNPs in a single‐locus analysis were further validated with 984 NSCLC patients in the GWAS dataset from the Harvard Lung Cancer Susceptibility (HLCS) Study. The results showed that two independent, potentially functional SNPs in two genes (VWF rs73049469 and ITGB2 rs3788142) were significantly associated with NSCLC survival, with a combined hazards ratio (HR) of 1.22 [95% confidence interval (CI) = 1.07–1.40, P = 0.002] and 1.16 (1.07–1.27, 6.45 × 10−4), respectively. Finally, we performed expression quantitative trait loci (eQTL) analysis and found that survival‐associated genotypes of VWF rs73049469 were also significantly associated with mRNA expression levels of the gene. These results indicated that genetic variants of the complement‐related immunity genes might be predictors of NSCLC survival, particularly for the short‐term survival, possibly by modulating the expression of genes involved in the host immunity.

Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls

“…The “complement” gene‐set which formed the basis of this study was curated by Birnbaum, based on multiple independent publicly available databases (GO, KEGG, IMPORT, IPA, and IMMUNOME) combined with a complement gene‐set curated by Qian et al While this list is an empirically well validated, as with any list, some gene inclusions/exclusions will make it imperfect. For example, CSMD1, a regulator of C4 and a multiple‐domain regulator of the complement system was not included in this gene‐set .…”

“…The Birnbaum paper provided a gene‐set related to complement in SZ by collating information from neuroimmunology and general immunology literature, as well as pathway annotation programs, cross‐referenced with multiple gene expression databases (eg, GO, KEGG, IMPORT, IPA, and IMMUNOME) to assemble 34 complement‐related genes . The second publication included 32 of the original 34 genes with additional gene lists included from Molecular Signatures Database, the Human Biological Pathway Unification Database, and the HUGO Gene Nomenclature Committee (https://pathcards.genecards.org, (http://software.broadinstitute.org/gsea/msigdb/index.jsp, https://www.genenames.org) searching the keyword “complement.” After removing the duplicated genes and genes directly encoding for C4 (C4A, C4B, C4BPA, C4BPB, C4_B), 108 genes remained as the candidate genes for further analysis (Table S1). As 90 of these genes were available to be tested for enrichment using MAGMA, these 90 genes were brought forward for analysis (listed in Table ).…”

“…To test for enrichment of genes related to complement function in IQ and SZ, we based our gene-set list on recent publications targeting complement-related immunity genes. 18,19 The Birnbaum paper 18 provided a gene-set related to complement in SZ by collating information from neuroimmunology and general immunology literature, as well as pathway annotation programs, cross-referenced with multiple gene expression databases (eg, GO, KEGG, IMPORT, IPA, and IMMU-NOME) to assemble 34 complement-related genes. 13,[24][25][26][27] The second publication 19 (Table S1).…”

“…Given these lines of evidence, this study aimed to systematically characterize, for the first time, the association between genetic variation within genes related to complement function and both SZ risk and cognition. To do this, we performed gene‐set analysis (GSA) of complement pathway genes, based on prior work in curating complement gene‐sets based on publically available data by References and . The resulting complement gene‐set was tested for enrichment using IQ GWAS summary data from Savage et al, and SZ GWAS summary data from the Psychiatric Genomics Consortium .…”

Effects of complement gene‐set polygenic risk score on brain volume and cortical measures in patients with psychotic disorders and healthy controls

“…Given the above evidence that variation within genes encoding for complement associated with SZ could affect memory and brain structure, we hypothesized that (1) A “complement” gene‐set PRS created using SZ GWAS summary statistics (Pardiñas et al, 2018) explained variation in behavioral measures of memory function in a sample of patients with psychotic disorders and healthy controls, using a gene‐set curated by previous studies (Birnbaum et al, 2018; Qian et al, 2019), excluding variants from C4 in our PRS calculation (see Table S1). Depending on whether this hypothesis was supported, we further sought to test whether (2) The same “complement” PRS based on SZ GWAS summary statistics (excluding C4) would explain variation in memory‐related brain structures (i.e., the hippocampus).…”