70 research outputs found
Custom and Common Law
No full text[N]or the laws of any Christian kingdom, are so rooted in antiquity. Hence there is no gainsaying nor legitimate doubt but that the customs of the English are not only good but the best.
For Sir John Fortescue, Chief Justice of the King’s Bench between 1442 and 1460, nominal Lord Chancellor to Henry VI following the deposition of the Lancastrian king in 1461, and author of De laudibus legum Angliae (from which the above quotation is taken), the laws and customs of England were coextensive and indivisible. Fortescue identified three separate forms of human or municipal law: these were ‘either law of nature, customs, or statutes’, and when customs and the law of nature ‘have been reduced to writing’ and received royal approval, then they ‘are changed into a constitution or something of the nature of statutes’. Of these three (supposedly indisputable) sources of English law, custom was arguably the least susceptible to irrefutable definition, and it is therefore something of a paradox that Fortescue was an exemplar of late medieval judicial authority expressing the opinion that custom was the singular, defining and unique feature of the common law.
It is the purpose of this chapter to examine and analyse the juridical notion of custom in relation to the institutional foundations of common law. I concentrate primarily on juristic ideas of custom attendant on the theories espoused by Fortescue in De laudibus (written c. 1470) and developed in the first half of the sixteenth century, notably by the barrister and jurist Christopher St German, author of Dialogus de fundamentis legum Anglie et de conscientia, more commonly known as Doctor and Student, published in English in 1530. In passing, I consider the gradual change in juridical meaning of consuetudo, from that intended by Chief Justiciar of England Ranulf de Glanvill and cleric, justice and jurist Henry de Bracton, to its meaning as recorded in the decisions of judges, handed down in the courts of common law. The judiciary adopted for themselves a didactic and rabbinical role, in accordance with the description of them by Fortescue as sacerdotes (priests): ‘For a priest is by etymology said to be one who gives or teaches holy things.’ Like Fortescue, they were trained in the arcane practices of the English legal system at the Inns of Court and practised their calling as serjeants-at-law in the law courts at Westminster prior to their elevation to the ranks of the judiciary
Genome Wide Association Studies of Variant-by-Thiazide Interaction on Lipids Identifies a Novel Low-Density Lipoprotein Cholesterol Locus
No full textAlthough thiazide diuretics are common therapies for the treatment of high blood pressure, they are also associated with elevated blood lipid concentrations after initiation. Total cholesterol concentrations have been shown to increase by 4%, low-density lipoprotein cholesterol (LDL-C) concentrations by 10%, and triglyceride (TG) concentrations by 5% to 15%; high density lipoprotein cholesterol concentrations remain unaffected. Pharmacogenomics could potentially help identify mechanistic pathways underlying this observation. However, few well-powered studies examining variant-by-thiazide interactions on blood lipid concentrations have been conducted. The purpose of this study was to identify genetic variants that modify the effect of thiazide diuretics on LDL-C, total cholesterol, and TG using data from the UK Biobank (UKBB), a publicly available, longitudinal study of UK adults
Author Correction: Metabolomic epidemiology offers insights into disease aetiology
No full textCorrection to "Metabolomic epidemiology offers insights into disease aetiology
Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk
No full textBackground: A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective: Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods: We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results: In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, beta = -25.9 mU mL(-1) per minor allele; FVIIa-AT, beta = -26.6 pM per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, beta = 7.8 mU mL(-1) per minor allele; FVIIa-AT, beta = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio HR], 1.12; 95% confidence interval CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among EuropeanAmerican CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions: The results support the importance of the F7 and PROCR loci in variation in circulating FVIIa and FVIIa-AT. The findings suggest FVIIa is a risk factor for ischemic stroke in older adults, whereas higher FVIIa-AT may reflect mortality risk
Ancestry-specific associations identified in genome-wide combined-phenotype study of red blood cell traits emphasize benefits of diversity in genomics
No full textBackground: Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population. Results: We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic population contained at least one significant association signal (p < 5E-9), with lead SNPs at nine loci significantly associated with three or more RBC traits. A majority of the lead SNPs were common (MAF > 5%) across all ancestral populations. Nineteen additional independent association signals were identified at seven known loci (HFE, KIT, HBS1L/MYB, CITED2/FILNC1, ABO, HBA1/2, and PLIN4/5). For example, the HBA1/2 locus contained 14 conditionally independent association signals, 11 of which were previously unreported and are specific to African and Amerindian ancestries. One variant in this region was common in all ancestries, but exhibited a narrower LD block in African Americans than European Americans or Hispanics/Latinos. GTEx eQTL analysis of all independent lead SNPs yielded 31 significant associations in relevant tissues, over half of which were not at the gene immediately proximal to the lead SNP. Conclusion: This work identified seven loci containing multiple independent association signals for RBC traits using a combined-phenotype approach, which may improve discovery in genetically correlated traits. Highly complex genetic architecture at the HBA1/2 locus was only revealed by the inclusion of African Americans and Hispanics/Latinos, underscoring the continued importance of expanding large GWAS to include ancestrally diverse populations. © 2020 The Author(s)
Importance of Genetic Studies of Cardiometabolic Disease in Diverse Populations
No full textGenome-wide association studies have revolutionized our understanding of the genetic underpinnings of cardiometabolic disease. Yet, the inadequate representation of individuals of diverse ancestral backgrounds in these studies may undercut their ultimate potential for both public health and precision medicine. The goal of this review is to describe the imperativeness of studying the populations who are most affected by cardiometabolic disease, to the aim of better understanding the genetic underpinnings of the disease. We support this premise by describing the current variation in the global burden of cardiometabolic disease and emphasize the importance of building a globally and ancestrally representative genetics evidence base for the identification of population-specific variants, fine-mapping, and polygenic risk score estimation. We discuss the important ethical, legal, and social implications of increasing ancestral diversity in genetic studies of cardiometabolic disease and the challenges that arise from the (1) lack of diversity in current reference populations and available analytic samples and the (2) unequal generation of health-associated genomic data and their prediction accuracies. Despite these challenges, we conclude that additional, unprecedented opportunities lie ahead for public health genomics and the realization of precision medicine, provided that the gap in diversity can be systematically addressed. Achieving this goal will require concerted efforts by social, academic, professional and regulatory stakeholders and communities, and these efforts must be based on principles of equity and social justice
Soluble Urokinase Plasminogen Activator Receptor: Genetic Variation and Cardiovascular Disease Risk in Black Adults
No full textBACKGROUND: suPAR (Soluble urokinase plasminogen activator receptor) has emerged as an important biomarker of coagulation, inflammation, and cardiovascular disease (CVD) risk. The contribution of suPAR to CVD risk and its genetic influence in Black populations have not been evaluated. METHODS: We measured suPAR in 3492 Black adults from the prospective, community-based JHS (Jackson Heart Study). Cross-sectional associations of suPAR with lifestyle and CVD risk factors were assessed, whole-genome sequence data were used to evaluate genetic associations of suPAR, and relationships of suPAR with incident CVD outcomes and overall mortality were estimated over follow-up. RESULTS: In Cox models adjusted for traditional CVD risk factors, estimated glomerular filtration rate, and CRP (C-reactive protein), each 1-SD higher suPAR was associated with a 21% to 31% increased risk of incident coronary heart disease, heart failure, stroke, and mortality. In the genome-wide association study, 2 missense (rs399145 encoding p.Thr86Ala, rs4760 encoding p.Phe272Leu) and 2 noncoding regulatory variants (rs73935023 within an enhancer element and rs4251805 within the promoter) of PLAUR on chromosome 19 were each independently associated with suPAR and together explained 14% of suPAR phenotypic variation. The allele frequencies of each of the four suPAR-associated genetic variants differ considerably across African and European populations. We further show that PLAUR rs73935023 can alter transcriptional activity in vitro. We did not find any association between genetically determined suPAR and CVD in JHS or a larger electronic medical record-based analyses of Blacks or Whites. CONCLUSIONS: Our results demonstrate the importance of ancestry-differentiated genetic variation on suPAR levels and indicate suPAR is a CVD biomarker in Black adults
Effect of sickle cell trait and apol1 genotype on the association of soluble upar with kidney function measures in black americans
No full textSoluble urokinase plasminogen activator receptor (suPAR) is the circulating form of urokinase plasminogen activator receptor, a glycosyl-phosphatidylinositol–anchored membrane protein expressed in various cell types including kidney podocytes and endothelial cells. suPAR has been associated with a decline in eGFR and the risk of incident CKD or proteinuria in a variety of clinical settings. In the United States, the higher risk of CKD in Black people compared with White people may be at least partially attributable to two genetic susceptibility factors, APOL1 and sickle cell trait, which occur respectively in approximately 13% and 8% of Black people. Hayeketal recently showed that suPAR levels modify the association between APOL1 genotype and eGFR decline in the African American Study of Kidney Disease and Hypertension and a cohort registry of Black people who underwent cardiac catherization
A large-scale transcriptome-wide association study (TWAS) of 10 blood cell phenotypes reveals complexities of TWAS fine-mapping
No full textHematological measures are important intermediate clinical phenotypes for many acute and chronic diseases and are highly heritable. Although genome-wide association studies (GWAS) have identified thousands of loci containing trait-associated variants, the causal genes underlying these associations are often uncertain. To better understand the underlying genetic regulatory mechanisms, we performed a transcriptome-wide association study (TWAS) to systematically investigate the association between genetically predicted gene expression and hematological measures in 54,542 Europeans from the Genetic Epidemiology Research on Aging cohort. We found 239 significant gene-trait associations with hematological measures; we replicated 71 associations at p < 0.05 in a TWAS meta-analysis consisting of up to 35,900 Europeans from the Women's Health Initiative, Atherosclerosis Risk in Communities Study, and BioMe Biobank. Additionally, we attempted to refine this list of candidate genes by performing conditional analyses, adjusting for individual variants previously associated with hematological measures, and performed further fine-mapping of TWAS loci. To facilitate interpretation of our findings, we designed an R Shiny application to interactively visualize our TWAS results by integrating them with additional genetic data sources (GWAS, TWAS from multiple reference panels, conditional analyses, known GWAS variants, etc.). Our results and application highlight frequently overlooked TWAS challenges and illustrate the complexity of TWAS fine-mapping
Supplementary Material for: Relationships between Cognitive Performance, Neuroimaging and Vascular Disease: The DHS-MIND Study
No full textBackground: Type 2 diabetes mellitus increases the risk of cognitive decline and dementia, and elevated burdens of vascular disease are hypothesized to contribute to this risk. These relationships were examined in the Diabetes Heart Study-MIND using a battery of cognitive tests, neuroimaging measures and subclinical cardiovascular disease (CVD) burden assessed by coronary artery calcified (CAC) plaque. We hypothesized that CAC would attenuate the association between neuroimaging measures and cognition performance. Methods: Associations were examined using marginal models in this family-based cohort of 572 European Americans from 263 families. All models were adjusted for age, gender, education, type 2 diabetes and hypertension, with some neuroimaging measures additionally adjusted for intracranial volume. Results: Higher total brain volume was associated with better performance on the Digit Symbol Substitution Task and Semantic Fluency (both p ≤ 7.0 × 10-4). Higher gray matter volume was associated with better performance on the Modified Mini-Mental State Examination and Semantic Fluency (both p ≤ 9.0 × 10-4). Adjusting for CAC caused minimal changes to the results. Conclusions: Relationships exist between neuroimaging measures and cognitive performance in a type 2 diabetes-enriched European American cohort. Associations were minimally attenuated after adjusting for subclinical CVD. Additional work is needed to understand how subclinical CVD burden interacts with other factors and impacts relationships between neuroimaging and cognitive testing measures
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