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

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

The effect of low light levels on postural stability in older adults with age‐related macular degeneration

Purpose: To investigate the effect of low light levels on postural stability in older adults with and without age-related macular degeneration (AMD). Methods: Participants included 28 older adults [14 with AMD (mean age ± S.D., 83.4 ± 6.7 years) and 14 controls with normal vision (74.6 ± 3.3 years)]. Postural stability was assessed with eyes open on both a firm and foam surface under four lighting conditions in a randomised order: photopic (~436 lux, vertically at the eye), sudden reduction to mesopic (~436 to ~1 lux), adapted mesopic (~1 lux) and adapted mesopic with a light emitting diode (LED) door frame lighting system (~1.3 lux), using the root mean square (RMS) of the centre of pressure measures derived from an electronic force plate in the anterior-posterior (AP) and medio-lateral (ML) directions. Visual function was assessed binocularly (visual acuity, contrast sensitivity and visual fields), physical function was assessed using standardised measures (sit-to-stand, grip strength and the timed walk test) and self-reported difficulties under low light levels were recorded using the Low Luminance Questionnaire. Data were analysed using linear mixed models. Results: For all participants, low light levels significantly increased postural sway on the foam surface in the AP (p = 0.01) but not ML (p = 0.80) direction, but had no effect on postural stability on the firm surface. On the foam surface, while AP-RMS sway was significantly greater in the sudden (p < 0.001) and adapted (p = 0.02) mesopic compared to the photopic condition, sway for the adapted mesopic with the LED lighting system was not significantly different to the photopic condition (p = 0.20). On the foam surface, AP-RMS (p = 0.02) and ML-RMS (p < 0.001) sway were significantly greater in the AMD compared to the control group. None of the measures of visual function was significantly associated with AP- or ML-RMS sway. Conclusions: On the foam surface, low light levels significantly reduced postural stability in older adults with and without AMD, and postural stability was significantly reduced for the AMD group compared to controls, regardless of light level. Importantly, the LED lighting system reduced sway under mesopic conditions, which was not significantly greater than that measured under photopic conditions in either group. These findings have important implications for enhancing the visual environment for older adults with and without AMD to improve postural stability and reduce the risk of falls in low lighting environments.</p

Epidemiology of mucopolysaccharidoses.

The aim of this study was to obtain data about the epidemiology of the different types of mucopolysaccharidoses in Japan and Switzerland and to compare with similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II, accounting for 55% of all MPS. MPS I, III, and IV accounted for 15, 16, and 10%, respectively. MPS VI and VII were more rare and accounted for 1.7 and 1.3%, respectively. A retrospective epidemiological data collection was performed in Switzerland between 1975 and 2008 (34years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12, 24, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3 and 2.4%, respectively. The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms of MPS is also reported to be higher in these countries. Birth prevalence of MPS II in Switzerland and other European countries is comparatively lower. The birth prevalence of MPS III and IV in Switzerland is higher than in Japan but comparable to that in most other European countries. Moreover, the birth prevalence of MPS VI and VII was very low in both, Switzerland and Japan. Overall, the frequency of MPS varies for each population due to differences in ethnic backgrounds and/or founder effects that affect the birth prevalence of each type of MPS, as seen for other rare genetic diseases. Methods for identification of MPS patients are not uniform across all countries, and consequently, if patients are not identified, recorded prevalence rates will be aberrantly low

Association of British Clinical Diabetologists and Renal Association guidelines on the detection and management of diabetes post solid organ transplantation

Post-transplant diabetes mellitus (PTDM) is common after solid organ transplantation (SOT) and associated with increased morbidity and mortality for allograft recipients. Despite the significant burden of disease, there is a paucity of literature with regards to detection, prevention and management. Evidence from the general population with diabetes may not be translatable to the unique context of SOT. In light of emerging clinical evidence and novel anti-diabetic agents, there is an urgent need for updated guidance and recommendations in this high-risk cohort. The Association of British Clinical Diabetologists (ABCD) and Renal Association (RA) Diabetic Kidney Disease Clinical Speciality Group have undertaken a systematic review and critical appraisal of the available evidence. Areas of focus are; 1) Epidemiology, 2) Pathogenesis, 3) Detection, 4) Management, 5) Modification of immunosuppression, 6) Prevention, and 7) PTDM in the non-renal setting. Evidence-graded recommendations are provided for the detection, management, and prevention of PTDM, with suggested areas for future research and potential audit standards. The guidelines are endorsed by Diabetes UK, the British Transplantation Society and the Royal College of Physicians of London. The full guidelines are available freely online for the diabetes, renal and transplantation community using the link below. The aim of this review article is to introduce an abridged version of this new clinical guideline. https://abcd.care/sites/abcd.care/files/site_uploads/Resources/Position-Papers/ABCD-RA%20PTDM%20v14.pdf

Multiple loci on 8q24 associated with prostate cancer susceptibility

Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility

Identification of seven new prostate cancer susceptibility loci through a genome-wide association study

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10−8 to P=2.7×10−33)