ObjectivesPrevious studies have suggested that fibrates and glitazones may have a role in brain tumour prevention. We examined if there is support for these observations using primary care records ...from the UK Clinical Practice Research Datalink (CPRD).DesignWe conducted two nested case–control studies using primary and secondary brain tumours identified within CPRD between 2000 and 2016. We selected cases and controls among the population of individuals who had been treated with any anti-diabetic or anti-hyperlipidaemic medication to reduce confounding by indication.SettingAdults older than 18 years registered with a general practitioner in the UK contributing data to CPRD.ResultsWe identified 7496 individuals with any brain tumour (4471 primary; 3025 secondary) in total. After restricting cases and controls to those prescribed any anti-diabetic or anti-hyperlipidaemic medication, there were 1950 cases and 7791 controls in the fibrate and 480 cases with 1920 controls in the glitazone analyses. Longer use of glitazones compared with all other anti-diabetic medications was associated with a reduced risk of primary (adjusted OR (aOR) 0.89 per year, 95% CI 0.80 to 0.98), secondary (aOR 0.87 per year, 95% CI 0.77 to 0.99) or combined brain tumours (aOR 0.88 per year, 95% CI 0.81 to 0.95). There was little evidence that fibrate exposure was associated with risk of either primary or secondary brain tumours.ConclusionsLonger exposure to glitazones was associated with reduced primary and secondary brain tumour risk. Further basic science and population-based research should explore this finding in greater detail, in terms of replication and mechanistic studies.
Genome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to ...be systematically explored. We integrated multi-tissue expression quantitative trait loci (eQTLs) and glioma GWAS data using a combined Mendelian randomisation (MR) and colocalisation approach. We investigated how genetically predicted gene expression affects risk across tissue type (brain, estimated effective n = 1194 and whole blood, n = 31,684) and glioma subtype (all glioma (7400 cases, 8257 controls) glioblastoma (GBM, 3112 cases) and non-GBM gliomas (2411 cases)). We also leveraged tissue-specific eQTLs collected from 13 brain tissues (n = 114 to 209). The MR and colocalisation results suggested that genetically predicted increased gene expression of 12 genes were associated with glioma, GBM and/or non-GBM risk, three of which are novel glioma susceptibility genes (RETREG2/FAM134A, FAM178B and MVB12B/FAM125B). The effect of gene expression appears to be relatively consistent across glioma subtype diagnoses. Examining how risk differed across 13 brain tissues highlighted five candidate tissues (cerebellum, cortex, and the putamen, nucleus accumbens and caudate basal ganglia) and four previously implicated genes (JAK1, STMN3, PICK1 and EGFR). These analyses identified robust causal evidence for 12 genes and glioma risk, three of which are novel. The correlation of MR estimates in brain and blood are consistently low which suggested that tissue specificity needs to be carefully considered for glioma. Our results have implicated genes yet to be associated with glioma susceptibility and provided insight into putatively causal pathways for glioma risk.
Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these ...relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear.
We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10−8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value (“q-value”) <0.05 was used as a threshold to define “strong evidence” to support associations and 0.05 ≤ q-value < 0.20 to define “suggestive evidence”. A colocalisation posterior probability (PPH4) >70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis.
We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk.
Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated.
Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).
Glioma is the most common type of brain tumour (BT) and results in significant years of life lost. The risk profile of glioma is largely unknown, and there has been little innovation in treatments ...and therapies available for glioma. These points were expanded upon in Chapter 1. This thesis conceptualised a pipeline which combined population-level and multi-omic data with causal inference analyses and traditional and pharmaco-epidemiological techniques. Methods and relevant datasets were described in Chapters 2 & 3. Analyses in Chapter 4 utilised a combined Mendelian randomisation (MR) and colocalisation framework to provide causal evidence for germline genetic variants associated with gene expression levels that affect glioma risk. Chapter 5 leveraged the same framework with germline genetic variants associated with protein abundance levels. Results were combined with results from the previous Chapter and, with supporting evidence from the literature, inform on putative chemopreventive targets for glioma. The pharmaco-epidemiological analyses in Chapter 6 provided evidence that exposure to glitazones, a family of anti-type 2 diabetic medications, reduced risk of primary and secondary BT, highlighting these drugs as potential agents for re-purposing. Chapter 7 concluded that, altogether, analyses presented in this thesis may be combined to form a drug target identification, prioritisation and re-repurposing pipeline to improve patient outcomes in the clinic.
As we look towards the future of optical communications, there are ever more missions requiring low size, weight, and power (SWaP), low cost, and very agile space terminals. Increased numbers of ...end-users look to minimize the costs associated with non-recurring engineering, and spacecraft operators that prefer not to deviate from their primary mission during communications operations. We present an optical terminal architecture which is specifically designed to have ready access to a greater-than-hemispherical field of regard (±175° in azimuth and ±120° in elevation, at up to 10°/sec slew rate), is modular to facilitate future technology upgrades and technology transfer to industry, can be scaled for use in LEO, GEO and deep-space applications, and leverages experience from a variety of successful space terminals that precede this design. In the past two years, this agile, modular, and scalable optical terminal architecture concept has been realized as a 10-cm aperture space terminal design. The terminal design was divided into subassemblies and further developed by industry partners, yielding an Engineering Development Unit (EDU) that has been assembled and tested. The optical and pointing performance of the EDU have been measured and are reported. Flight units of this 10-cm aperture space terminal are being developed for two upcoming missions, one for a LEO-based application and another for a lunar-based application, both presently scheduled for launch in 2021.
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