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- Dadaev, T, et al.
(författare)
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Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2256-
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
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- Momozawa, Y, et al.
(författare)
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IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2427-
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Tidskriftsartikel (refereegranskat)abstract
- GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
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- Westhoff, Ellen, et al.
(författare)
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Body Mass Index, Diet-Related Factors, and Bladder Cancer Prognosis: A Systematic Review and Meta-Analysis.
- 2018
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Ingår i: Bladder cancer (Amsterdam, Netherlands). - 2352-3727. ; 4:1, s. 91-112
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Tidskriftsartikel (refereegranskat)abstract
- Urologists are frequently confronted with questions of urinary bladder cancer (UBC) patients about what they can do to improve their prognosis. Unfortunately, it is largely unknown which lifestyle factors can influence prognosis.To systematically review the available evidence on the association between body mass index (BMI), diet, dietary supplements, and physical activity and UBC prognosis.We searched PubMed and Embase up to May 2017. We included thirty-one articles reporting on observational and randomized controlled trials investigating BMI, diet and dietary supplements in relation to recurrence, progression, cancer-specific or all-cause mortality in UBC patients.In non-muscle invasive bladder cancer (NMIBC) patients, both overweight (3 studies, pooled hazard ratio (HR) 1.29, 95% CI 1.05-1.58, I2=0%) as well as obesity (3 studies, pooled HR 1.82, 95% CI 1.12-2.95, I2=79%) were associated with increased risk of recurrence when compared to normal weight. No association of BMI with risk of progression was found. Results for BMI and prognosis in muscle-invasive or in all stages series were inconsistent. Observational studies on diet and randomized controlled trials with dietary supplements showed inconsistent results. No studies on physical activity and UBC prognosis have been published to date.Evidence for an association of lifestyle factors with UBC prognosis is limited, with some evidence for an association of BMI with risk of recurrence in NMIBC. Well-designed, prospective studies are needed to develop evidence-based guidelines on this topic.
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