iGWAS: Integrative Genome‐Wide Association Studies of Genetic and Genomic Data for Disease Susceptibility Using Mediation Analysis

Genome‐wide association studies (GWAS) have been a standard practice in identifying single nucleotide polymorphisms (SNPs) for disease susceptibility. We propose a new approach, termed integrative GWAS (iGWAS) that exploits the information of gene expressions to investigate the mechanisms of the association of SNPs with a disease phenotype, and to incorporate the family‐based design for genetic association studies. Specifically, the relations among SNPs, gene expression, and disease are modeled within the mediation analysis framework, which allows us to disentangle the genetic effect on a disease phenotype into two parts: an effect mediated through a gene expression (mediation effect, ME) and an effect through other biological mechanisms or environment‐mediated mechanisms (alternative effect, AE). We develop omnibus tests for the ME and AE that are robust to underlying true disease models. Numerical studies show that the iGWAS approach is able to facilitate discovering genetic association mechanisms, and outperforms the SNP‐only method for testing genetic associations. We conduct a family‐based iGWAS of childhood asthma that integrates genetic and genomic data. The iGWAS approach identifies six novel susceptibility genes (MANEA, MRPL53, LYCAT, ST8SIA4, NDFIP1, and PTCH1) using the omnibus test with false discovery rate less than 1%, whereas no gene using SNP‐only analyses survives with the same cut‐off. The iGWAS analyses further characterize that genetic effects of these genes are mostly mediated through their gene expressions. In summary, the iGWAS approach provides a new analytic framework to investigate the mechanism of genetic etiology, and identifies novel susceptibility genes of childhood asthma that were biologically meaningful.     

High-dose inhaled albuterol in severe chronic airflow limitation

Higher doses of inhaled albuterol have been shown to cause slightly more bronchodilatation than standard doses from a metered-dose inhaler in patients with severe chronic airflow limitation. Higher doses, however, carry an increased risk of side effects, and the optimum dose balancing benefit and adverse effects have yet to be established. We have therefore looked at objective and subjective evidence of beneficial and adverse effects after 4 doses of albuterol in 30 patients with chronic bronchitis, severe airflow limitation, and less than 200 ml increase in FEV1 after 200 micrograms inhaled albuterol. Subjects were given placebo, 400 micrograms, 1 mg, 2 mg, and 4 mg albuterol by dry powder inhaler in random order on separate days in a double-blind study, and FEV1, relaxed VC, PEFR, 12-min walk distance, finger tremor, oxygen saturation, heart rate, and arrhythmias were measured at intervals over 6 h. With increasing doses of albuterol, there was a significant dose-related increase in FEV1, VC, and PEFR, the maximal mean changes being 196 ml, 480 ml, and 50 L/min, respectively. The duration of effect was longer with the higher doses. There was a dose-related increase in heart rate, tremor amplitude, and supraventricular ectopic beats and a dose-related fall in oxygen saturation. There was no drug-related effect on the frequency of ventricular ectopic beats either at rest or during the walk tests. The largest increases in walk distance occurred after the 1 and 2 mg doses and the least after the 4 mg dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory actions of loperamide on absorptive processes in rat small intestine.

Mucosal loperamide caused a dose dependent reduction in the absorption of actively transported hexoses and amino acids, together with the associated rise in short circuit current. Na+ and fluid movement were also inhibited. Serosal application of the drug was without effect on these processes. The passive movement of fructose across the gut was not affected by loperamide which is therefore unlikely to act by reducing tissue permeability. In low Na+ conditions the inhibitory actions of loperamide on glycine absorption were reduced. Loperamide reduced basal Na+ transport although it did not affect the stimulation of Na+ absorption caused by mannose. Loperamide had no effect on the total ATPase activity nor on the Na+, K+-ATPase activity of mucosal homogenates. The effects of loperamide were not mimicked by morphine nor were they antagonised by naloxone and hence do not seem to involve an opiate receptor. It is concluded that loperamide exerts its inhibitory effects by an interaction with the Na+ sites of the nutrient carriers.     

The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin

The relative importance of antithrombin and anti-factor Xa activities of heparin fractions required to achieve optimal antithrombotic effects is unknown. To study this, we measured the effects of standard heparin, an octasaccharide heparin fraction (anti-factor Xa activity only), and dermatan sulfate (antithrombin activity only) on the prevention of thrombosis and related this to their anticoagulant effects in vivo in rabbits. Thrombosis was measured as the incorporation of 125I- fibrinogen into tissue thromboplastin-induced thrombi using a Wessler- type model. Ex vivo changes in thrombin clotting time (TCT) were used as an index of antithrombin activity, and a chromogenic anti-factor Xa assay was used to measure anti-factor Xa activity. In addition, the ability of the three sulfated polysaccharides to simultaneously inhibit the generation of thrombin activity and to enhance the inactivation of the factor Xa added to initiate thrombin generation in plasma was determined. Standard heparin, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 90%, prolonged the TCT by two seconds, and resulted in an anti-factor Xa level of 0.32 U/mL. The octasaccharide heparin fraction, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 41%, had no effect on the TCT, and resulted in an anti-factor Xa level of 0.28 U/mL. Higher doses of the octasaccharide resulted in a further increase in the anti-factor Xa levels but had no further effect on thrombus formation. Dermatan sulfate, in a dose of 500 micrograms/kg, inhibited thrombus formation by 95%, but had no affect on the TCT. These results indicate that the antithrombotic effect achieved by inhibiting factor Xa is limited and that better antithrombotic effects are achieved by heparin or heparin- like substances capable of influencing the inactivation and/or the generation of thrombin.     

Methicillin-resistant Staphylococcus aureus in hospitals and the community: stealth dynamics and control catastrophes

Methicillin-resistant Staphylococcus aureus (MRSA) represents a serious threat to the health of hospitalized patients. Attempts to reduce the spread of MRSA have largely depended on hospital hygiene and patient isolation. These measures have met with mixed success: although some countries have almost eliminated MRSA or remained largely free of the organism, others have seen substantial increases despite rigorous control policies. We use a mathematical model to show how these increases can be explained by considering both hospital and community reservoirs of MRSA colonization. We show how the timing of the intervention, the level of resource provision, and chance combine to determine whether control measures succeed or fail. We find that even control measures able to repeatedly prevent sustained outbreaks in the short-term can result in long-term control failure resulting from gradual increases in the community reservoir. If resources do not scale with MRSA prevalence, isolation policies can fail "catastrophically."