Hyperuricemia Is Not an Independent Predictor of Erectile Dysfunction

Introduction: Erectile dysfunction (ED) is strongly associated with physiological and metabolic disturbances, and hyperuricemia has been proposed to predict the onset of ED.Aim: To investigate if hyperuricemia is an independent predictor for ED when all relevant confounding factors are taken into account.Methods: This is a cross-sectional study of men aged between 45 and 70 years. The population was well characterized for established cardiovascular risk factors, metabolic syndrome, as well as kidney function, depression, and socioeconomic factors. Analysis was limited to 254 men with complete data and also serum uric acid (SUA) measurements were available. This included 150 men with and 104 without ED. The presence and severity of ED was evaluated using International Index of Erectile Function-5 questionnaire. Risk of ED by SUA level was calculated using univariate and multivariable-adjusted logistic regression. Effect modification by participant characteristics were evaluated in subgroup analyses.Main outcome measures: The main outcome measures of this study are prevalence and severity of erectile dysfunction.Results: Patients with ED (59% of the study population) were older than men without ED (59 vs 54 years) and had lower serum testosterone (14.3, 95% CI 11.3-17.3 vs 15.1 nmol/l, 95% CI 12.1-18.8, respectively). Regarding all other variables, the groups were comparable. No significant difference was found for SUA by ED. SUA was not associated with ED risk in univariate or multivariable analysis (multivariable-adjusted OR 1.14, 95% CI 0.59-2.19, P = .7) for SUA level higher than median compared with median or lesser (OR 1.00, 95% CI 0.997-1.006, P = .7 for continuous variable). No subgroup analysis modified the association. After multivariable adjustment age, education level and depression were statistically significant predictors of ED.Conclusions: Elevated SUA was not found to be an independent risk factor for ED. Metabolic syndrome, glomerular filtration rate, or cardiovascular risk factors did not modify this result. ED cannot be predicted based on the level of SUA. A Tuokko, T Murtola, P Korhonen, et al. Hyperuricemia Is Not an Independent Predictor of Erectile Dysfunction.</p

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

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. © 2018 The Author(s).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. © 2018 The Author(s).Peer reviewe

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

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

Hyperuricemia Is Not an Independent Predictor of Erectile Dysfunction

Introduction: Erectile dysfunction (ED) is strongly associated with physiological and metabolic disturbances, and hyperuricemia has been proposed to predict the onset of ED. Aim: To investigate if hyperuricemia is an independent predictor for ED when all relevant confounding factors are taken into account. Methods: This is a cross-sectional study of men aged between 45 and 70 years. The population was well characterized for established cardiovascular risk factors, metabolic syndrome, as well as kidney function, depression, and socioeconomic factors. Analysis was limited to 254 men with complete data and also serum uric acid (SUA) measurements were available. This included 150 men with and 104 without ED. The presence and severity of ED was evaluated using International Index of Erectile Function-5 questionnaire. Risk of ED by SUA level was calculated using univariate and multivariable-adjusted logistic regression. Effect modification by participant characteristics were evaluated in subgroup analyses. Main Outcome measures: The main outcome measures of this study are prevalence and severity of erectile dysfunction. Results: Patients with ED (59% of the study population) were older than men without ED (59 vs 54 years) and had lower serum testosterone (14.3, 95% CI 11.3–17.3 vs 15.1 nmol/l, 95% CI 12.1–18.8, respectively). Regarding all other variables, the groups were comparable. No significant difference was found for SUA by ED. SUA was not associated with ED risk in univariate or multivariable analysis (multivariable-adjusted OR 1.14, 95% CI 0.59–2.19, P = .7) for SUA level higher than median compared with median or lesser (OR 1.00, 95% CI 0.997–1.006, P = .7 for continuous variable). No subgroup analysis modified the association. After multivariable adjustment age, education level and depression were statistically significant predictors of ED. Conclusions: Elevated SUA was not found to be an independent risk factor for ED. Metabolic syndrome, glomerular filtration rate, or cardiovascular risk factors did not modify this result. ED cannot be predicted based on the level of SUA. A Tuokko, T Murtola, P Korhonen, et al. Hyperuricemia Is Not an Independent Predictor of Erectile Dysfunction. Sex Med 2021;XX:XXX–XXX.publishedVersionPeer reviewe

Prostate cancer-specific survival among warfarin users in the Finnish Randomized Study of Screening for Prostate Cancer

Background: Venous thromboembolic events (VTE) are common in cancer patients and associated with higher mortality. In vivo thrombosis and anticoagulation might be involved in tumor growth and progression. We studied the association of warfarin and other anticoagulant use as antithrombotic medication and prostate cancer (PCa) death in men with the disease. Methods: The study included 6,537 men diagnosed with PCa during 1995-2009. Information on anticoagulant use was obtained from a national reimbursement registry. Cox regression with adjustment for age, PCa risk group, primary therapy and use of other medication was performed to compare risk of PCa death between warfarin users with 1) men using other types of anticoagulants and 2) non-users of anticoagulants. Medication use was analyzed as a time-dependent variable to minimize immortal time bias. Results: In total, 728 men died from PCa during a median follow-up of 9 years. Compared to anticoagulant nonusers, post-diagnostic use of warfarin was associated with an increased risk of PCa death (overall HR 1.47, 95% CI 1. 13-1.93). However, this was limited to low-dose, low-intensity use. Otherwise, the risk was similar to anticoagulant non-users. Additionally, we found no risk difference between warfarin and other types of anticoagulants. Pre-diagnostic use of warfarin was not associated with the risk of PCa death. Conclusions: We found no reduction in risk of PCa death associated with warfarin use. Conversely, the risk was increased in short-term use, which is probably explained by a higher risk of thrombotic events prompting warfarin use in patients with terminal PCa.Peer reviewe

Low density lipoprotein: structure, dynamics, and interactions of apoB-100 with lipids

Low-density lipoprotein (LDL) transports cholesterol in the bloodstream and plays an important role in the development of cardiovascular diseases, in particular atherosclerosis. Despite its importance to health, the structure of LDL is not known in detail. This is worrying since the lack of LDL’s structural information makes it more difficult to understand its function. In this work, we have combined experimental and theoretical data to construct LDL models comprised of the apoB-100 protein wrapped around a lipid droplet of about 20 nm in size. The models are considered by near-atomistic multi-microsecond simulations to unravel structural as well as dynamical properties of LDL, with particular attention paid to lipids and their interactions with the protein. We find that the distribution and the ordering of the lipids in the LDL particle are rather complex. The previously proposed 2- and 3-layer models turn out to be inadequate to describe the properties of the lipid droplet. At the surface of LDL, apoB-100 is found to interact favorably with cholesterol and its esters. The interactions of apoB-100 with core molecules, in particular cholesteryl esters, are rather frequent and arise from hydrophobic amino acids interacting with the ring of cholesteryl esters, and also in part from the rather loose packing of lipids at the surface of the lipoparticle. The loose packing may foster the function of transfer proteins, which transport lipids between lipoproteins. Finally, the comparison of the several apoB-100 models in our study suggests that the properties of lipids in LDL are rather insensitive to the conformation of apoB-100. Altogether, the findings pave the way for further studies of LDL to better understand the central steps in the emergence of atherosclerosis.

Warfarin use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer

<p><b>Objective:</b> Anticoagulants, especially vitamin K antagonists (VKAs) such as warfarin, have been hypothesized to have antitumor properties, and use of VKAs has been associated with a lower prostate cancer (PCa) risk. This study estimated PCa risk among users of warfarin and other anticoagulants.</p> <p><b>Materials and methods:</b> All anticoagulant use among 78,615 men during 1995–2009 was analyzed. Cox regression, adjusted for age, screening trial arm and use of other medications, with medication use as a time-dependent variable, was used to estimate PCa risk overall, and by tumor grade and stage.</p> <p><b>Results:</b> In total, 6537 men were diagnosed with PCa during 1995–2009 (1210 among warfarin users). Compared to non-users, warfarin use was associated with an increased risk of PCa [multivariable-adjusted hazard ratio (HR) = 1.11, 95% confidence interval (CI) 1.01–1.22]. This was limited to short-term, low-dose use, and was not observed in long-term use. A similar overall risk increase was observed for Gleason grade 7–10 PCa. Low-dose, short-term use of warfarin was associated with an increased risk of metastatic PCa. However, the increase in risk vanished with continued use. Compared to other anticoagulants, low-dose use of warfarin was associated with a slightly elevated overall PCa risk (HR = 1.19, 95% CI 1.00–1.43). The increase in risk disappeared in long-term, high-dose use.</p> <p><b>Conclusions:</b> This study, which included a larger number of PCa cases with warfarin exposure than previous studies, does not support previous notions of decreased risk of PCa among warfarin users. A similar risk of PCa was found among warfarin users and the general population, and no difference in risk was found between warfarin and other anticoagulants.</p