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Physiology

Genetic causes of human heart failure.

Morita, H et al., 2005. J. Clin. Invest. 115(3):518-26.

Abstracts:

Factors that render patients with cardiovascular disease at high risk for heart failure remain incompletely defined. Recent insights into molecular genetic causes of myocardial diseases have highlighted the importance of single-gene defects in the pathogenesis of heart failure. Through analyses of the mechanisms by which a mutation selectively perturbs one component of cardiac physiology and triggers cell and molecular responses, studies of human gene mutations provide a window into the complex processes of cardiac remodeling and heart failure. Knowledge gleaned from these studies shows promise for defining novel therapeutic targets for genetic and acquired causes of heart failure.

Journal Link | PMID

Comments:

A good overview of muscle cell physiology and the known genetic factors that cause loss of function.  This is very well illustrated for both faculty development on this topic and the preparation of class materials.

Connexins, Conduction, and Atrial Fibrillation.

Saffitz, JE, 2006. N. Eng. J. Med. 354(25):2712-2714.

Intro. paragraph:

Atrial fibrillation has always been the little sister to its ventricular counterpart — but during the past decade, it has captured our attention, mainly because it is so common. Atrial fibrillation affects nearly 2.5 million Americans, and this number could double over the next 50 years as the population ages. Although not the killer that ventricular fibrillation is, atrial fibrillation is by no means benign. Roughly 15 percent of strokes in the United States have been attributed to this arrhythmia.

The pathogenesis of atrial fibrillation is complex, even as compared with the other tachyarrhythmias. Atrial fibrillation arises from dynamic interactions among an unusually wide range of structural, electrophysiological, inflammatory, and genetic factors — and once it develops, it has the curious property of inducing further changes that promote its likelihood to recur and its resistance to antiarrhythmia therapies. Most patients with atrial fibrillation have associated cardiovascular diseases such as diabetes, hypertension, heart failure, valvular dysfunction, hyperthyroidism, and myocardial infarction. These patients usually have abnormal atria characterized by dilatation, fibrosis, and degenerative changes in atrial myocytes. These structural alterations create an anatomical substrate that slows impulse propagation and alters atrial refractoriness, which are properties that promote reentry.

Journal Link | PMID

Comment:

A brief review of the clinical topic and an illustrated introduction to the paper by Gollob et al. (below).

Somatic Mutations in the Connexin 40 Gene (GJA5) in Atrial Fibrillation.

Gollob, MH et al., N. Eng. J. Med. 354(25):2677-2688

Abstract:

Background - Atrial fibrillation is the most common type of cardiac arrhythmia and a leading cause of cardiovascular morbidity, particularly stroke. The cardiac gap-junction protein connexin 40 is expressed selectively in atrial myocytes and mediates the coordinated electrical activation of the atria. We hypothesized that idiopathic atrial fibrillation has a genetic basis and that tissue-specific mutations in GJA5, the gene encoding connexin 40, may predispose the atria to fibrillation. Methods - We sequenced GJA5 from genomic DNA isolated from resected cardiac tissue and peripheral lymphocytes from 15 patients with idiopathic atrial fibrillation. Identified GJA5 mutations were transfected into a gap-junction-deficient cell line to assess their functional effects on protein transport and intercellular electrical coupling. Results - Four novel heterozygous missense mutations were identified in 4 of the 15 patients. In three patients, the mutations were found in the cardiac-tissue specimens but not in the lymphocytes, indicating a somatic source of the genetic defects. In the fourth patient, the sequence variant was detected in both cardiac tissue and lymphocytes, suggesting a germ-line origin. Analysis of the expression of mutant proteins revealed impaired intracellular transport or reduced intercellular electrical coupling. Conclusions - Mutations in GJA5 may predispose patients to idiopathic atrial fibrillation by impairing gap-junction assembly or electrical coupling. Our data suggest that common diseases traditionally considered to be idiopathic may have a genetic basis, with mutations confined to the diseased tissue.

Journal Link | PMID

Comment:

A clinical research paper on atrial fibrillaton that illustrates how a genetics basis for this disease was documented.  In addition to a presentation of the molecular and cellular data, the patient population is well described as a basis for validating their hypothesis.

Pharmacogenomics in inflammatory bowel disease.

Egan, LJ et al., 2006. Clin. Gastroenterol. Hepatol. 4(1):21-28

Abstract

Inherited variations in the nucleotide sequence of genes influence how individual patients respond to drugs. Most commonly, clinically significant genetic variations consist of single nucleotide polymorphisms (SNPs) within genes that affect drug disposition or drug targets. Up to now, relatively few clinically important examples of inherited traits that affect drug responses have been studied in detail. However, one of the well-characterized examples is highly relevant to inflammatory bowel disease therapeutics, that of thiopurine methyltransferase pharmacogenetics. Individuals with 2 normal alleles of the gene encoding thiopurine methyltransferase metabolize and clear thiopurines such as azathioprine and 6-mercaptopurine rapidly. Individuals with 1 normal and 1 variant allele are intermediate, whereas those with 2 variant alleles clear thiopurines very slowly. Intermediate and slow metabolizers are predisposed to have high active thiopurine drug levels and develop bone marrow suppression. Genomic era technology permits determination of large numbers of SNPs in large numbers of individuals. This capability is allowing the field of pharmacogenomics to become one of the most productive interfaces in translational biomedical research at present. By using high-throughput SNP genotyping, combined with careful phenotypic characterization of disease, pharmacogenomic research carries the potential of identifying individual biomarkers that predict the relative likelihood of benefit or risk from a therapeutic intervention. If this promise can be realized, pharmacogenomics will deliver the opportunity for personalized medicine.

Journal Link | PMID

Comment

Genetic Testing in the Long QT Syndrome: Development and Validation of an Efficient Approach to Genotyping in Clinical Practice

Napolitano, C et al., 2005. JAMA 294(23):2975-2980

Abstract:

Context In long QT syndrome (LQTS), disease severity and response to therapy vary according to the genetic loci. There exists a critical need to devise strategies to expedite genetic analysis. Objective To perform genetic screening in patients with LQTS to determine the yield of genetic testing, as well as the type and the prevalence of mutations. Design, Patients, and Setting We investigated whether the detection of a set of frequently mutated codons in the KCNQ1, KCNH2, and SCN5A genes may translate in a novel strategy for rapid efficient genetic testing of 430 consecutive patients referred to our center between June 1996 and June 2004. The entire coding regions of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 were screened by denaturing high-performance liquid chromatography and DNA sequencing. The frequency and the type of mutations were defined to identify a set of recurring mutations. A separate cohort of 75 consecutive probands was used as a validation group to quantify prospectively the prevalence of the recurring mutations identified in the primary LQTS population. Main Outcome Measures Development of a novel approach to LQTS genotyping. Results We identified 235 different mutations, 138 of which were novel, in 310 (72%) of 430 probands (49% KCNQ1, 39% KCNH2, 10% SCN5A, 1.7% KCNE1, and 0.7% KCNE2). Fifty-eight percent of probands carried nonprivate mutations in 64 codons of KCNQ1, KCNH2, and SCN5A genes. A similar occurrence of mutations at these codons (52%) was confirmed in the prospective cohort of 75 probands and in previously published LQTS cohorts. Conclusions We have developed an approach to improve the efficiency of genetic screening for LQTS. This novel method may facilitate wider access to genotyping resulting in better risk stratification and treatment of LQTS patients.

Journal Link | PMID