Limited Effect of Y Chromosome Variation on Coronary Artery Disease and Mortality in UK Biobank

The effect of genetic variation in the male-specific region of the Y chromosome (MSY) on coronary artery disease and cardiovascular risk factors has been disputed. In this study, we systematically assessed the association of MSY genetic variation on these traits using a kin-cohort analysis of family disease history in the largest sample to date. METHODS: We tested 90 MSY haplogroups against coronary artery disease, hypertension, blood pressure, classical lipid levels, and all-cause mortality in up to 152 186 unrelated, genomically British individuals from UK Biobank. Unlike previous studies, we did not adjust for heritable lifestyle factors (to avoid collider bias) and instead adjusted for geographic variables and socioeconomic deprivation, given the link between MSY haplogroups and geography. For family history traits, subject MSY haplogroups were tested against father and mother disease as validation and negative control, respectively. RESULTS: Our models find little evidence for an effect of any MSY haplogroup on cardiovascular risk in participants. Parental models confirm these findings. CONCLUSIONS: Kin-cohort analysis of the Y chromosome uniquely allows for discoveries in subjects to be validated using family history data. Despite our large sample size, improved models, and parental validation, there is little evidence to suggest cardiovascular risk in UK Biobank is influenced by genetic variation in MSY

Human lifespan: recent trends and genetic determinants

Human lifespan is determined by a complex interplay of genetics, environment, lifestyle and chance. In the UK, life expectancy has increased by roughly three years every decade, but despite longer lives, individuals also spend more years living with chronic disease. With populations greying and periods of morbidity becoming more prolonged, the burden of ageing and age-related disease is set to become a major healthcare challenge. Understanding the factors underlying trends in human lifespan could guide policy interventions to mitigate the burden of disease, while an understanding of the genetics of lifespan could provide insight into the ageing process. The latter could in turn reveal potential therapeutic targets to delay age-related disease and inform which individuals to target based on their genetic risk. In this thesis, I explore human lifespan from these two perspectives. First, I examined trends in mortality and morbidity in two million Scots using hospital admission and death records and found recent improvements in lifespan could be largely explained by improvements in the incidence and survival after hospitalisation of cancers and heart disease. However, I also found recent deteriorations in infectious disease, especially for individuals from lower socioeconomic classes, suggesting a need for a renewed public health focus in this area. Next, I performed a genome-wide association study (GWAS) to find genetic determinants of lifespan using DNA from 27 European cohorts and the lifespans of their parents (one million total). I identified 12 genomic regions affecting survival and found genetic variants across the genome, when aggregated into polygenic scores, could distinguish up to five years of survival between score deciles. Combining the lifespan GWAS with two other GWAS of lifespan-related traits, I identified 78 genes—some of which delay ageing in model organisms— which putatively influence both human lifespan and healthy years of life and which are enriched for haem metabolism. These findings present the most promising targets for therapeutic interventions to date, which may help delay the onset of age-related disease and extend the healthy years of life for all

Organic micropollutant removal in full-scale rapid sand filters used for drinking water treatment in The Netherlands and Belgium

Biological treatment processes have the potential to remove organic micropollutants (OMPs) during water treatment. The OMP removal capacity of conventional drinking water treatment processes such as rapid sand filters (RSFs), however, has not been studied in detail. We investigated OMP removal and transformation product (TP) formation in seven full-scale RSFs all treating surface water, using high-resolution mass spectrometry based quantitative suspect and non-target screening (NTS). Additionally, we studied the microbial communities with 16S rRNA gene amplicon sequencing (NGS) in both influent and effluent waters as well as the filter medium, and integrated these data to comprehensively assess the processes that affect OMP removal. In the RSF influent, 9 to 30 of the 127 target OMPs were detected. The removal efficiencies ranged from 0 to 93%. A data-driven workflow was established to monitor TPs, based on the combination of NTS feature intensity profiles between influent and effluent samples and the prediction of biotic TPs. The workflow identified 10 TPs, including molecular structure. Microbial community composition analysis showed similar community composition in the influent and effluent of most RSFs, but different from the filter medium, implying that specific microorganisms proliferate in the RSFs. Some of these are able to perform typical processes in water treatment such as nitrification and iron oxidation. However, there was no clear relationship between OMP removal efficiency and microbial community composition. The innovative combination of quantitative analyses, NTS and NGS allowed to characterize real scale biological water treatments, emphasizing the potential of bio-stimulation applications in drinking water treatment. © 2020 The Author

Prospectus, May 17, 1989

https://spark.parkland.edu/prospectus_1989/1012/thumbnail.jp

Cystatin C is associated with adverse COVID-19 outcomes in diverse populations

COVID-19 has highly variable clinical courses. The search for prognostic host factors for COVID-19 outcome is a priority. We performed logistic regression for ICU admission against a polygenic score (PGS) for Cystatin C (CyC) production in patients with COVID-19. We analyzed the predictive value of longitudinal plasma CyC levels in an independent cohort of patients hospitalized with COVID-19. In four cohorts spanning European and African ancestry populations, we identified a significant association between CyC-production PGS and odds of critical illness (n cases=2,319), with the strongest association captured in the UKB cohort (OR 2.13, 95% CI 1.58-2.87, p=7.12e-7). Plasma proteomics from an independent cohort of hospitalized COVID-19 patients ( n cases = 131) demonstrated that CyC production was associated with COVID-specific mortality (p=0.0007). Our findings suggest that CyC may be useful for stratification of patients and it has functional role in the host response to COVID-19.Peer reviewe

Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan.

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes

Development and Internal Validation of a Multivariable Prediction Model for Adrenocortical-Carcinoma-Specific Mortality

Adrenocortical carcinoma (ACC) has an incidence of about 1.0 per million per year. In general, survival of patients with ACC is limited. Predicting survival outcome at time of diagnosis is a clinical challenge. The aim of this study was to develop and internally validate a clinical prediction model for ACC-specific mortality. Data for this retrospective cohort study were obtained from the nine centers of the Dutch Adrenal Network (DAN). Patients who presented with ACC between 1 January 2004 and 31 October 2013 were included. We used multivariable Cox proportional hazards regression to compute the coefficients for the prediction model. Backward stepwise elimination was performed to derive a more parsimonious model. The performance of the initial prediction model was quantified by measures of model fit, discriminative ability, and calibration. We undertook an internal validation step to counteract the possible overfitting of our model. A total of 160 patients were included in the cohort. The median survival time was 35 months, and interquartile range (IQR) 50.7 months. The multivariable modeling yielded a prediction model that included age, modified European Network for the Study of Adrenal Tumors (mENSAT) stage, and radical resection. The c-statistic was 0.77 (95% Confidence Interval: 0.72, 0.81), indicating good predictive performance. We developed a clinical prediction model for ACC-specific mortality. ACC mortality can be estimated using a relatively simple clinical prediction model with good discriminative ability and calibration

Opportunities and implications related to future mobile communications

This chapter discusses the research, managerial, and policymaking-related future opportunities and implications that stem from the discussions presented in the preceding chapters. With a focus on overarching themes that concern everyone, the paper presents research questions to direct future research, advises managers in themes that may become of increasing interest in future 5G and 6G, and summarizes key concerns for policymaking that should be considered to reach a global 6G and beyond world

Genome-Wide Association Study of Non-Alcoholic Fatty Liver Disease using Electronic Health Records

Genome‐wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case‐control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co‐existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta‐analysis using available summary association statistics. Six risk loci were identified (P < 5*10(−8)) (apolipoprotein E [APOE], patatin‐like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co‐existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta‐analysis. Rs429358 (P = 2.17*10(−11)) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78‐0.90] and homozygotes 0.64 [0.50‐0.79]). Conclusion: This GWAS replicates six known NAFLD‐susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches

Association Between Statin Use and Prevalence of Exercise-Related Injuries: A Cross-Sectional Survey of Amateur Runners in the Netherlands.

BACKGROUND: HMG-CoA reductase inhibitors (statins) are the first-choice therapy for primary prevention of cardiovascular disease. Some maintain that statins cause adverse musculoskeletal outcomes in highly active individuals, but few studies have examined the effects of statins on exercise-related injuries. OBJECTIVE: We sought to compare the prevalence of exercise-related injuries between runners who do or do not use statins. METHODS: Amateur runners (n = 4460) completed an extensive online questionnaire on their exercise patterns and health status. Participants replied to questions on the prevalence of exercise-related injuries in the previous year. Injuries were divided into general injuries, tendon- and ligament-related injuries, and muscle-related injuries. Participants were also queried about statin use: the type of statin, statin dose, and duration of treatment. Runners were divided into statin users, non-statin users with hypercholesterolemia, and controls for analysis. RESULTS: The crude odds ratios (ORs) for injuries, tendon- or ligament-related injuries, and muscle-related injuries in statin users compared with controls were 1.14 (95% confidence interval [CI] 0.79-1.66), 1.10 (95% CI 0.71-1.72), and 1.15 (95% CI 0.69-1.91), respectively. After adjustment for age, sex, body mass index (BMI), and metabolic equivalent of task (MET) h/week of exercise, the ORs were 1.11 (95% CI 0.76-1.62), 1.06 (95% CI 0.68-1.66), and 0.98 (95% CI 0.58-1.64), respectively. Similar effect measures were found when comparing non-statin users with hypercholesterolemia and controls. CONCLUSION: We did not find an association between statin use and the prevalence of exercise-related injuries or tendon-, ligament-, and muscle-related injuries. Runners receiving statins should continue normal physical activity without concern for increased risk of injuries