Santiyagu M. Savarimuthu

Arg389Gly-[beta]1-adrenergic receptors determine improvement in left ventricular systolic function in nonischemic cardiomyopathy patients with heart failure after chronic treatment with carvedilol

Objective Administration of the &bgr;-adrenergic receptor blocker carvedilol to patients with chronic heart failure leads to clinically significant benefits, including improvement in left ventricular systolic function in some, but not all, patients. We sought to determine the basis of the variable effect obtained with carvedilol in patients with heart failure. Carvedilol blocks both &bgr;1-adrenergic and &bgr;2-adrenergic receptors, and both receptors exist as polymorphisms. We aimed to determine whether these polymorphisms contribute to variability in response to carvedilol in patients with chronic heart failure. Methods We retrospectively and prospectively investigated 135 patients with nonischemic cardiomyopathy and chronic stable heart failure (New York Heart Association class II, III) treated with carvedilol. Baseline echocardiography was obtained before introduction of carvedilol and repeated after stabilization of a maximally tolerated dose of carvedilol (50–100 mg/day) for at least 1 year. Polymerase chain reaction and restriction fragment length polymorphism analysis were used to genotype &bgr;1-adrenergic and &bgr;2-adrenergic receptor polymorphisms. Results When grouped according to receptor polymorphisms patients were well matched for severity of heart failure, comorbidity and treatment. No significant difference was observed in baseline left ventricular ejection fraction (LVEF) between groups (P>0.05). After 1.5 years of treatment with carvedilol patients with Arg389Arg-&bgr;1-adrenergic receptors had a significantly greater improvement in LVEF compared with Gly389 carriers (Arg389Arg 18.8%; Arg389Gly 9.4%; Gly389Gly 6.0%; P<0.001) whereas there were no differences attributable to other &bgr;1-adrenergic and &bgr;2-adrenergic receptor polymorphisms (P>0.05). Conclusion In patients with nonischemic dilated cardiomyopathy, carvedilol leads to a significantly greater improvement in LVEF in patients with the Arg389Arg-&bgr;1 adrenergic receptor phenotype.

Conservation of the cardiostimulant effects of (−)-norepinephrine across Ser49Gly and Gly389Arg beta1-adrenergic receptor polymorphisms in human right atrium in vitro ☆

OBJECTIVE The goal of this study was to determine whether the cardiostimulant effects of the endogenous beta(1)-adrenergic receptor (AR) agonist, (-)-norepinephrine are modified by polymorphic (Serine49Glycine [Ser49Gly], Glycine389Arginine [Gly389Arg]) variants of beta(1)-ARs in the nonfailing adult human heart. BACKGROUND Human heart beta(1)-ARs perform a crucial role in mediating the cardiostimulant effects of (-)-norepinephrine. An understanding of the significance of Ser49Gly and Gly389Arg polymorphisms in the human heart is beginning to emerge, but not as yet in adult patients who have coronary artery disease (CAD). METHODS The potency and maximal effects of (-)-norepinephrine at beta(1)-ARs (in the presence of beta(2)-AR blockade with 50 nM ICI 118,551 [erythro-DL-1(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol]) for changes in contractile force and shortening of contractile cycle duration were determined in human right atrium in vitro from 87 patients undergoing coronary artery bypass grafting who were taking beta-blockers before surgery. A smaller sample of patients (n = 20) not taking beta-blockers was also investigated. Genotyping for two beta(1)-AR polymorphisms (Ser49Gly and Gly389Arg) was determined from a sample of blood taken at the time of surgery. RESULTS (-)-Norepinephrine caused concentration-dependent increases in contractile force and reductions in time to reach peak force and time to reach 50% relaxation. There were no differences in the potency or maximal effects of (-)-norepinephrine in the right atrium from patients with different Ser49Gly and Gly389Arg polymorphisms. CONCLUSIONS The cardiostimulant effects of (-)-norepinephrine at beta(1)-ARs were conserved across Ser49Gly and Gly389Arg polymorphisms in the right atrium of nonfailing hearts from patients with CAD managed with or without beta-blockers.

Gene-environmental interaction in asthma

Purpose of review Asthma is likely to result from the effects of environmental stimuli in genetically susceptible individuals. This review summarizes recent studies of gene–environmental interaction in the pathogenesis of asthma, focusing on study designs. Recent findings Studies using genetic epidemiology, in-vitro and ex-vivo models and in-vivo model organisms demonstrate that gene–environmental interaction in involved in the development of asthma. Genetic association studies show a reduced risk of asthma and atopy with early life exposure to farming environments and house dust endotoxin, and increased risk with environmental tobacco smoke. These associations are modified by CD14 genotype. In people with a specific genotype, high environmental exposure may have the opposite effect of low exposure, possibly explaining some of the inconsistencies in previous studies. In-vitro and ex-vivo cell culture experiments show gene–environmental interactions with Toll-like receptor agonists, viruses and tobacco smoke. Interactions between innate immunity genes and exposure to endotoxin and air pollution have been observed in in-vivo mouse models. Summary The expanding evidence for gene–environmental interaction in asthma indicates the importance of measuring environmental factors in genetic studies of asthma. Understanding gene–environmental interaction would facilitate risk prognostication, improve preventive strategies and develop targeted interventions in people with asthma.

ADAM28: a potential oncogene involved in asbestos-related lung adenocarcinomas.

Asbestos‐related lung cancer accounts for 4–12% of all lung cancers worldwide. Since putative mechanisms of carcinogenesis differ between asbestos and tobacco induced lung cancers, tumors induced by the two agents may be genetically distinct. To identify gene expression biomarkers associated with asbestos‐related lung tumorigenicity we performed gene expression array analysis on tumors of 36 patients with primary lung adenocarcinoma, comparing 12 patients with lung asbestos body counts above levels associated with urban dwelling (ARLC‐AC: asbestos‐related lung cancer‐adenocarcinoma) with 24 patients with no asbestos bodies (NARLC‐AC: non‐asbestos related lung cancer‐adenocarcinoma). Genes differentially expressed between ARLC‐AC and NARLC‐AC were identified on fold change and P value, and then prioritized using gene ontology. Candidates included ZNRF3, ADAM28, PPP1CA, IRF6, RAB3D, and PRDX1. Expression of these six genes was technically and biologically replicated by qRT‐PCR in the training set and biologically validated in three independent test sets. ADAM28, encoding a disintegrin and metalloproteinase domain protein that interacts with integrins, was consistently upregulated in ARLC across all four datasets. Further studies are being designed to investigate the possible role of this gene in asbestos lung tumorigenicity, its potential utility as a marker of asbestos related lung cancer for purposes of causal attribution, and its potential as a treatment target for lung cancers arising in asbestos exposed persons.