6 research outputs found

    Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

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    Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

    AB: ATP P 2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord

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    ATP has been proposed to mediate synaptic transmission in the spinal cord dorsal horn, particularly in the pathway carrying nociceptive information. Using transverse spinal cord slices from postnatal rats, we show that EPSCs mediated by P 2X receptors, and presumably activated by synaptically released ATP, are evoked in a subpopulation of spinal cord lamina II neurons, a region known to receive strong input from nociceptive primary afferents. The P 2X receptors on acutely dissociated dorsal horn neurons are nondesensitizing, insensitive to �� methylene ATP, and show strong but variable sensitivity to the antagonists suramin and pyridoxal-phosphate-6-azophenyl-2�,4�-disulfonic acid (PPADS). These characteristics are consistent with a heterogeneous population of P 2X receptors, the composition of which includes P 2X2, P 2X4, and P 2X6 receptor subtypes. Our results suggest that ATP-activated P 2X receptors in lamina II of the rat spinal cord may play a role in transmitting or modulating nociceptive information. Key words: ATP; purinergic receptors; synaptic transmission; spinal cord; rat; patch-clamp technique; slice preparation Holton and Holton (1954) first proposed ATP as a possible neurotransmitter in the dorsal horn over 40 years ago. Since then, its role as a fast neurotransmitter in the peripheral nervous system has been demonstrated (Burnstock et al., 1972; Evans et al., 1992; Silinsky and Gerzanich, 1993; Galligan and Bertrand, 1994). In the CNS only one study, performed on neurons in the medial habenula, has demonstrated that ATP can act as a fast neurotransmitter (Edwards et al., 1992). Within the spinal cord dorsal horn, despite strong evidence implicating ATP as a putativ

    COVID-19 Pandemic Preparedness in a UK Tertiary and Quaternary Children's Hospital:Tales of the Unexpected

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    We describe the adaptive coping strategies required in the management of a heterogeneous group of SARS-CoV-2 paediatric patients. The diverse range of presentations, presenting in distinct phenotypic waves, exemplified the importance of preparedness for the unknown. Lessons learned will be essential in planning for a likely second wave of SARS-CoV-2
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