Genome-wide association analysis of cystatin-C kidney function in continental Africa

BACKGROUND: Chronic kidney disease is becoming more prevalent in Africa, and its genetic determinants are poorly understood. Creatinine-based estimated glomerular filtration rate (eGFR) is commonly used to estimate kidney function, modelling the excretion of the endogenous biomarker (creatinine). However, eGFR based on creatinine has been shown to inadequately detect individuals with low kidney function in Sub-Saharan Africa, with eGFR based on cystatin-C (eGFRcys) exhibiting significantly superior performance. Therefore, we opted to conduct a GWAS for eGFRcys. METHODS: Using the Uganda Genomic Resource, we performed a genome-wide association study (GWAS) of eGFRcys in 5877 Ugandans and evaluated replication in independent studies. Subsequently, putative causal variants were screened through Bayesian fine-mapping. Functional annotation of the GWAS loci was performed using Functional Mapping and Annotation (FUMA). FINDINGS: Three independent lead single nucleotide polymorphisms (SNPs) (P-value 99%. The rs911119 SNP maps to the cystatin C gene and has been previously associated with eGFRcys among Europeans. With gene-set enrichment analyses of the olfactory receptor family 51 overlapping genes, we identified an association with the G-alpha-S signalling events. INTERPRETATION: Our study found two previously unreported associated SNPs for eGFRcys in continental Africans (rs59288815 and rs4277141) and validated a previously well-established SNP (rs911119) for eGFRcys. The identified gene-set enrichment for the G-protein signalling pathways relates to the capacity of the kidney to readily adapt to an ever-changing environment. Additional GWASs are required to represent the diverse regions in Africa. FUNDING: Wellcome (220740/Z/20/Z)

Virtual Patients and Sensitivity Analysis of the Guyton Model of Blood Pressure Regulation: Towards Individualized Models of Whole-Body Physiology

Mathematical models that integrate multi-scale physiological data can offer insight into physiological and pathophysiological function, and may eventually assist in individualized predictive medicine. We present a methodology for performing systematic analyses of multi-parameter interactions in such complex, multi-scale models. Human physiology models are often based on or inspired by Arthur Guyton's whole-body circulatory regulation model. Despite the significance of this model, it has not been the subject of a systematic and comprehensive sensitivity study. Therefore, we use this model as a case study for our methodology. Our analysis of the Guyton model reveals how the multitude of model parameters combine to affect the model dynamics, and how interesting combinations of parameters may be identified. It also includes a “virtual population” from which “virtual individuals” can be chosen, on the basis of exhibiting conditions similar to those of a real-world patient. This lays the groundwork for using the Guyton model for in silico exploration of pathophysiological states and treatment strategies. The results presented here illustrate several potential uses for the entire dataset of sensitivity results and the “virtual individuals” that we have generated, which are included in the supplementary material. More generally, the presented methodology is applicable to modern, more complex multi-scale physiological models

Constitutional Law

This has been a year of highly important constitutional decisions affecting Georgia. The federal courts have dealt with the County Unit System and a municipal movie censorship statute. The Georgia Supreme Court has had occasion to pass upon the recent Re-registration Law, in Franklin v. Harper, and upon racial exclusion from juries in Crumb v. State. A score of other interesting and important matters have been decided

Constitutional Law

Georgia appellate courts did not in the year under discussion have the occasion to pass on as many interesting and complex constitutional situations as in-the prior year. To a large extent the constitutional questions in the period related to matters of criminal law and procedure, and it was in this field, perhaps, more than any other that the principal decisions lay

Becoming animate in education: immanent materiality and outdoor learning for sustainability

Outdoor environmental education has long postulated a link between experiences outdoors in ‘natural’ environments and environmental concern. This paper suggests a straightforward relationship is problematic due to its implicit assumption of a nature/culture divide. Critical outdoor education has sought to overcome this dualism by describing a relational understanding of the world emphasizing ecological systems and highlighting humanity’s ‘connection’ to the environment. This relational approach aims to tackle the ‘crisis of perception’, argued to be the root cause of anthropogenic planetary degradation. We draw from the philosophical work of Deleuze and Guattari to suggest that relational ontologies, as currently conceived, may reinforce a static conception of the world by emphasizing ‘points of being’ (subject and object). Deleuze and Guattari proffer immanent materiality, where points of being are dispelled by movement and ‘becoming’. We then describe ‘animism’ as a mode of living where the world is understood to be immanent and constantly becoming. The consequences of animism are explored with regards to conceptions of ‘nature’, ‘place’ and ‘outdoor’ learning for sustainability. Creative practices to tackle the ‘crisis of perception’ are suggested as approaches that circumvent static conceptions of the world implied by points in relations and prevailing conceptions of nature as ‘other’