A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

Genome-wide associations for birth weight and correlations with adult disease

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW ($\textit{P}$  < 5 × 10$^{-8}$). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure ($\textit{R}$ $_{g}$ = -0.22, $\textit{P}$  = 5.5 × 10$^{-13}$), T2D ($\textit{R}$ $_{g}$ = -0.27, $\textit{P}$  = 1.1 × 10$^{-6}$) and coronary artery disease ($\textit{R}$ $_{g}$ = -0.30, $\textit{P}$  = 6.5 × 10$^{-9}$). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions ($\textit{P}$ = 1.9 × 10$^{-4}$). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.For a full list of the funders pelase visit the publisher's website and look at the supplemetary material provided. Some of the funders are: British Heart Foundation, Cancer Research UK, Medical Research Council, National Institutes of Health, Royal Society and Wellcome Trust

Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy

Treatment of HIV-1-infected individuals with a combination of anti-retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels below the limit of detection of available assays. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells and from semen. A reservoir of latently infected cells established early in infection may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy. However, whether virus replication persists in such patients is unknown. HIV-1 cDNA episomes are labile products of virus infection and indicative of recent infection events. Using episome-specific PCR, we demonstrate here ongoing virus replication in a large percentage of infected individuals on highly active anti-retroviral therapy, despite sustained undetectable levels of plasma viral RNA. The presence of a reservoir of \u27covert\u27 virus replication in patients on highly active anti-retroviral therapy has important implications for the clinical management of HIV-1-infected individuals and for the development of virus eradication strategies

MRE11 as a Predictive Biomarker of Outcome After Radiation Therapy in Bladder Cancer

Funding Information: Disclosures: S.B., L.B., A.C., E.H., R.H., N.J., A.E.K., V.S., and C.W. report grant funding from Cancer Research UK during the conduct of the study. A.C. is a Senior Editor of IJROBP and reports nonfinancial support from ASCO and ESTRO; personal fees and nonfinancial support from Bayer PLC; grants from Prostate Cancer UK, Medical Research Council UK, and National Institute for Health Research UK; grants, personal fees, and nonfinancial support from Elekta AB; and personal fees from ASTRO, outside the submitted work. E.H. reports grants from Merck Sharp & Dohm, grants and nonfinancial support from AstraZeneca, grants from Janssen-Cilag, grants and nonfinancial support from Bayer, grants from Aventis Pharma Limited (Sanofi), and grants from Accuray Inc., outside the submitted work. R.H. reports grants and personal fees from MSD and Roche; personal fees from Bristol Myers Squibb and Janssen; and grants from Elekta, outside the submitted work. G.I. reports personal fees from Bayer Pharmaceuticals, outside the submitted work.This work was funded by CRUK Biomarkers and Imaging Discovery and Development grant (C15140/A13492). The BC2001 trial was supported by grants (C547/A2606, C547/A6845, C9764/A9904, and C1491/A9895) from Cancer Research UK. The work was also supported by CRUK grant C2094/A11365, CRUK grant C5529/A16895, CRUK grant C5255/A15935, an MRC studentship MR/K501256/1, CRUK funding to the Cancer Research Manchester Centre (C147/A18083, C147/A25254), the NIHR Manchester, NIHR Oxford (Molecular Diagnostics Theme/Multimodal Pathology Theme), and Royal Marsden/Institute of Cancer Research Biomedical Research Centres. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Disclosures: S.B., L.B., A.C., E.H., R.H., N.J., A.E.K., V.S., and C.W. report grant funding from Cancer Research UK during the conduct of the study. A.C. is a Senior Editor of IJROBP and reports nonfinancial support from ASCO and ESTRO; personal fees and nonfinancial support from Bayer PLC; grants from Prostate Cancer UK, Medical Research Council UK, and National Institute for Health Research UK; grants, personal fees, and nonfinancial support from Elekta AB; and personal fees from ASTRO, outside the submitted work. E.H. reports grants from Merck Sharp & Dohm, grants and nonfinancial support from AstraZeneca, grants from Janssen-Cilag, grants and nonfinancial support from Bayer, grants from Aventis Pharma Limited (Sanofi), and grants from Accuray Inc., outside the submitted work. R.H. reports grants and personal fees from MSD and Roche; personal fees from Bristol Myers Squibb and Janssen; and grants from Elekta, outside the submitted work. G.I. reports personal fees from Bayer Pharmaceuticals, outside the submitted work. This work was funded by CRUK Biomarkers and Imaging Discovery and Development grant ( C15140/A13492). The BC2001 trial was supported by grants (C547/A2606, C547/A6845, C9764/A9904, and C1491/A9895) from Cancer Research UK. The work was also supported by CRUK grant C2094/A11365, CRUK grant C5529/A16895, CRUK grant C5255/A15935, an MRC studentship MR/K501256/1, CRUK funding to the Cancer Research Manchester Centre ( C147/A18083, C147/A25254), the NIHR Manchester, NIHR Oxford (Molecular Diagnostics Theme/Multimodal Pathology Theme), and Royal Marsden/ Institute of Cancer Research Biomedical Research Centres. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Publisher Copyright: © 2019 The AuthorsPeer reviewe

Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians

10.1038/ng.834Nature Genetics436531-538NGEN

RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation

Chikungunya virus (CHIKV) is an arthritogenic alphavirus causing epidemics of acute and chronic arthritic disease. Herein we describe a comprehensive RNA-Seq analysis of feet and lymph nodes at peak viraemia (day 2 post infection), acute arthritis (day 7) and chronic disease (day 30) in the CHIKV adult wild-type mouse model. Genes previously shown to be up-regulated in CHIKV patients were also up-regulated in the mouse model. CHIKV sequence information was also obtained with up to ≈8% of the reads mapping to the viral genome; however, no adaptive viral genome changes were apparent. Although day 2, 7 and 30 represent distinct stages of infection and disease, there was a pronounced overlap in up-regulated host genes and pathways. Type I interferon response genes (IRGs) represented up to ≈50% of up-regulated genes, even after loss of type I interferon induction on days 7 and 30. Bioinformatic analyses suggested a number of interferon response factors were primarily responsible for maintaining type I IRG induction. A group of genes prominent in the RNA-Seq analysis and hitherto unexplored in viral arthropathies were granzymes A, B and K. Granzyme Aand to a lesser extent granzyme K, but not granzyme B, mice showed a pronounced reduction in foot swelling and arthritis, with analysis of granzyme Amice showing no reductions in viral loads but reduced NK and T cell infiltrates post CHIKV infection. Treatment with Serpinb6b, a granzyme A inhibitor, also reduced arthritic inflammation in wild-type mice. In non-human primates circulating granzyme A levels were elevated after CHIKV infection, with the increase correlating with viral load. Elevated granzyme A levels were also seen in a small cohort of human CHIKV patients. Taken together these results suggest granzyme A is an important driver of arthritic inflammation and a potential target for therapy. Trial Registration: ClinicalTrials.gov NCT0028129