Genome Medicine

Roberts, Lee; Hassall, David; Winegar, Deborah; Haselden, John; Nicholls, Andrew; Griffin, Julian

doi: 10.1186/gm115pmid: 19968882

Ichida, Kimiyoshi

doi: 10.1186/gm118pmid: 20090896

Many factors, including genetic components and acquired factors such as obesity and alcohol consumption, influence serum uric acid (urate) concentrations. Since serum urate concentrations are determined by the balance between renal urate excretion and the volume of urate produced via purine metabolism, urate transporter genes as well as genes coding for enzymes involved in purine metabolism affect serum urate concentrations. URAT1 was the first transporter affecting serum urate concentrations to be identified. Using the characterization of this transporter as an indicator, several transporters have been shown to transport urate, allowing the construction of a synoptic renal urate transport model. Notable re-absorptive urate transporters are URAT1 at apical membranes and GLUT9 at basolateral membranes, while ABCG2, MRP4 (multidrug resistance protein 4) and NPT1 are secretive transporters at apical membranes. Recent genome-wide association studies have led to validation of the in vitro model constructed from each functional analysis of urate transporters, and identification of novel candidate genes related to urate metabolism and transport proteins, such as glucokinase regulatory protein (GKRP), PDZK1 and MCT9. However, the function and physiologic roles of several candidates, as well as the influence of acquired factors such as obesity, foods, or alcoholic beverages, remain unclear.

Murray, Andrew

doi: 10.1186/gm117pmid: 20090895

In most tissues of the body, cellular ATP production predominantly occurs via mitochondrial oxidative phosphorylation of reduced intermediates, which are in turn derived from substrates such as glucose and fatty acids. In order to maintain ATP homeostasis, and therefore cellular function, the mitochondria require a constant supply of fuels and oxygen. In many disease states, or in healthy individuals at altitude, tissue oxygen levels fall and the cell must meet this hypoxic challenge to maintain energetics and limit oxidative stress. In humans at altitude and patients with respiratory disease, loss of skeletal muscle mitochondrial density is a consistent finding. Recent studies that have used cultured cells and genetic mouse models have elucidated a number of elegant adaptations that allow cells with a diminished mitochondrial population to function effectively in hypoxia. This article reviews these findings alongside studies of hypoxic human skeletal muscle, putting them into the context of whole-body physiology and acclimatization to high-altitude hypoxia. A number of current controversies are highlighted, which may eventually be resolved by a systems physiology approach that considers the time-or tissue-dependent nature of some adaptive responses. Future studies using high-throughput metabolomic, transcriptomic, and proteomic technologies to investigate hypoxic skeletal muscle in humans and animal models could resolve many of these controversies, and a case is therefore made for the integration of resulting data into computational models that account for factors such as duration and extent of hypoxic exposure, subjects' backgrounds, and whether data have been acquired from active or sedentary individuals. An integrated and more quantitative understanding of the body's metabolic response to hypoxia and the conditions under which adaptive processes occur could reveal much about the ways that tissues function in the very many disease states where hypoxia is a critical factor.

Peters, Bas; Klungel, Olaf; Visseren, Frank; de Boer, Anthonius; Maitland-van der Zee, Anke-Hilse

doi: 10.1186/gm120pmid: 20090898

Although statins are generally well tolerated, the most common adverse drug reaction from statin therapy is myopathy. This article reviews the current pharmacogenomic knowledge of statin-induced myopathy. Furthermore, we will discuss the importance of recent pharmacogenetic advances for the treatment and management of statin-induced myopathy. Variation in the SLCO1B1 gene is associated with increased incidence of statin-induced myopathy, particularly with simvastatin and less so with other statins. If different pharmacokinetic enzymes and transporters are responsible for susceptibility to myopathy, this may explain differences in the occurrence of statin-induced myopathy in individual patients. Genotyping in patients suffering from statin-induced myopathy may help to personalize the choice of statin for the lowest chance of developing myopathy.

Sadee, Wolfgang

doi: 10.1186/gm116pmid: 20090894

Regulatory polymorphisms have emerged as a prevalent source of phenotypic variability, capable of driving rapid evolution. mRNA profiling combined with genome-wide genotyping of polymorphisms has revealed pervasive genetic influences on gene expression, acting both in cis and in trans. Measuring allelic ratios of RNA transcripts makes it possible to focus on cis-acting factors separately from trans-acting processes. Using large-scale allelic expression analysis, a recent study by Ge and colleagues demonstrates a high incidence of cis-acting regulatory variants, promising insights into the 'missing heritability' component of complex disorders. Here, I evaluate their results and discuss the limitations of the current approach and avenues for exploring disease risk, guiding successful therapy, early intervention, and prevention.

Nathan, David; Orkin, Stuart

doi: 10.1186/gm114pmid: 20017892

The lysosomal storage diseases, such as Gaucher's disease, mucopolysaccharidosis I, II and IV, Fabry's disease, and Pompe's disease, are rare inherited disorders whose symptoms result from enzyme deficiency causing lysosomal accumulation. Until effective gene-replacement therapy is developed, expensive, and at best incomplete, enzyme-replacement therapy is the only hope for sufferers of rare lysosomal storage diseases. Preventive strategies involving carrier detection should be a priority toward the successful management of these conditions.

Pitteri, Sharon; Hanash, Samir; Aragaki, Aaron; Amon, Lynn; Chen, Lin; Busald Buson, Tina; Paczesny, Sophie; Katayama, Hiroyuki; Wang, Hong; Johnson, Melissa; Zhang, Qing; McIntosh, Martin; Wang, Pei; Kooperberg, Charles; Rossouw, Jacques; Jackson, Rebecca; Manson, JoAnn; Hsia, Judith; Liu, Simin; Martin, Lisa; Prentice, Ross

Dowling, Nicole; Gwinn, Marta; Mawle, Alison

doi: 10.1186/gm119pmid: 20090897

Public health preparedness requires effective surveillance of and rapid response to infectious disease outbreaks. Inclusion of research activities within the outbreak setting provides important opportunities to maximize limited resources, to enhance gains in scientific knowledge, and ultimately to increase levels of preparedness. With rapid advances in laboratory technologies, banking and analysis of human genomic specimens can be conducted as part of public health investigations, enabling valuable research well into the future.