Cardiology & Cardiovascular Disease

Coffee, CYP1A2 genotype, and risk of myocardial infarction.

Cornelis, MC et al., 2006. J. Amer. Med. Assn. 295(10):1135-1141.

Abstract

Context The association between coffee intake and risk of myocardial infarction (MI) remains controversial. Coffee is a major source of caffeine, which is metabolized by the polymorphic cytochrome P450 1A2 (CYP1A2) enzyme. Individuals who are homozygous for the CYP1A2*1A allele are "rapid" caffeine metabolizers, whereas carriers of the variant CYP1A2*1F are "slow" caffeine metabolizers. Objective To determine whether CYP1A2 genotype modifies the association between coffee consumption and risk of acute nonfatal MI. Design, Setting, and Participants Cases (n = 2014) with a first acute nonfatal MI and population-based controls (n = 2014) living in Costa Rica between 1994 and 2004, matched for age, sex, and area of residence, were genotyped by restriction fragment-length polymorphism polymerase chain reaction. A food frequency questionnaire was used to assess the intake of caffeinated coffee. Main Outcome Measure Relative risk of nonfatal MI associated with coffee intake, calculated using unconditional logistic regression. Results Fifty-five percent of cases (n = 1114) and 54% of controls (n = 1082) were carriers of the slow *1F allele. For carriers of the slow *1F allele, the multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of nonfatal MI associated with consuming less than 1, 1, 2 to 3, and 4 or more cups of coffee per day were 1.00 (reference), 0.99 (0.69-1.44), 1.36 (1.01-1.83), and 1.64 (1.14-2.34), respectively. Corresponding ORs (95% CIs) for individuals with the rapid *1A/*1A genotype were 1.00, 0.75 (0.51-1.12), 0.78 (0.56-1.09), and 0.99 (0.66-1.48) (P = .04 for gene x coffee interaction). For individuals younger than the median age of 59 years, the ORs (95% CIs) associated with consuming less than 1, 1, 2 to 3, or 4 or more cups of coffee per day were 1.00, 1.24 (0.71-2.18), 1.67 (1.08-2.60), and 2.33 (1.39-3.89), respectively, among carriers of the *1F allele. The corresponding ORs (95% CIs) for those with the *1A/*1A genotype were 1.00, 0.48 (0.26-0.87), 0.57 (0.35-0.95), and 0.83 (0.46-1.51). Conclusion Intake of coffee was associated with an increased risk of nonfatal MI only among individuals with slow caffeine metabolism, suggesting that caffeine plays a role in this association.

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Comment

Coffee - a very practical example that faculty and students both can easily relate to in discussing possible interactions between genetic polymorphisms, dietary/environmental factors and disease risks.  it makes epidemiology a less abstract topic.  In addition, the data presented clearly demonstrate the relationship between genotype and diet (coffee consumption) and a patient's risk for myocardial infraction.

Review: Mitochondrial medicine--cardiomyopathy caused by defective oxidative phosphorylation.

Fosslien, E, 2003. Ann Clin Lab Sci. 33(4):371-395.

Abstract

During experimental hypertensive cardiac hypertrophy, the heart energy metabolism reverts from the normal adult type that obtains the majority of its requirement for adenosine triphosphate (ATP) from metabolism of fatty acids and oxidative phosphorylation (OXPHOS), to the fetal form, which metabolizes glucose and lactate. Mitochondrial synthesis and function require an estimated 1000 polypeptides, 37 of which are encoded by mitochondrial (mt) DNA, the rest by nuclear (n) DNA. Inherited or acquired aberrations of either mtDNA or nDNA mitochondrial genes cause mitochondrial dysfunction. Tissue expression of OXPHOS enzyme defects is often heterogeneous. As a result, cardiomyopathy and cardiac failure are frequent but unpredictable complications of mitochondrial encephalopathy, neuropathy, and myopathy. Several nuclear genes that encode mitochondrial proteins have been sequenced and specific defects associated with nuclear genes that affect mitochondrial structure and function have been linked to hypertrophic and dilated cardiomyopathies and to cardiac conduction defects. Thyroid hormone and exercise stimulate expression of a nuclear respiratory factor (NRF) that induces the nuclear gene TFAM, which encodes the mitochondrial transcription factor A that controls mitochondrial replication and transcription. TFAM-null mouse embryos lack mitochondria and fail to develop a heart. Mitochondrial dysfunction enhances the generation of radical oxygen species (ROS), which damage mtDNA, nDNA, proteins, and lipid membranes. Mice lacking the mitochondrial antioxidant enzyme manganese-superoxide dismutase (SOD) develop dilated cardiomyopathy. Palliative mitochondrial therapy with L-acetyl-carnitine and coenzyme Q10 improves cardiac function in patients with cardiomyopathy. Cure is only achievable by mitochondrial gene therapy. Experimental direct gene therapy uses vectors or targeting signal sequences to insert genes into mtDNA; indirect gene therapy employs viral or non-viral vectors to introduce genes into nDNA. Clinical repair of damaged somatic and germline genes that encode mitochondrial proteins may soon be within reach.

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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.

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Comment

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.

Genetic variation at the scavenger receptor class B type I gene locus determines plasma lipoprotein concentrations and particle size and interacts with type 2 diabetes: the framingham study.

Osgood, D et al., 2003. J. Clin. Endocrinol. Metab. 88(6):2869-2879.

The scavenger receptor class B type I (SR-BI) is a key component in the reverse cholesterol transport pathway. We have previously reported three common polymorphisms associated with plasma lipids and body mass index. We hypothesized that diabetic status may interact with these polymorphisms in determining plasma lipid concentrations and particle size. We evaluated this hypothesis in 2463 nondiabetic (49% men) and 187 diabetic (64% men) participants in the Framingham Study. SR-BI and APOE genotypes, anthropometric, clinical, biochemical, and lifestyle variables were determined. After multivariate adjustment, we found a consistent association between the exon 8 polymorphism and high-density lipoprotein cholesterol concentration and particle size. Interaction effects were not significant for exon 8 and intron 5 polymorphisms. However, we found statistically significant interactions between SR-BI exon 1 genotypes and type 2 diabetes, indicating that diabetic subjects with the less common allele (allele A) have lower lipid concentrations. For low-density lipoprotein cholesterol, the adjusted means (+/-SE) were 3.31 +/- 0.03 and 3.29 +/- 0.04 mmol/liter for G/G and G/A or A/A in nondiabetics, respectively, compared with 3.19 +/- 0.10 and 2.75 +/- 0.01 mmol/liter for G/G and G/A or A/A in diabetics (P = 0.03 for interaction). Similar results were obtained for HDL(2)-C. In conclusion, SR-BI gene variation modulates the lipid profile, particularly in type 2 diabetes, contributing to the metabolic abnormalities in these subjects

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Mining our ABCs: Pharmacogenomic approach for evaluating transporter function in cancer drug resistance.

Ross, DD & Doyle, LA, 2004. Cancer Cell 6(@):105-107

Review's Abstract

The association of transporter proteins and cancer drug resistance has been known for approximately 25 years, with recent discoveries pointing to an ever-increasing number of ATP binding cassette (ABC) transporter proteins involved with the response of cancer cells to pharmacotherapy. As reported in this issue of Cancer Cell, Szakacs et al. couple quantitative, real-time PCR assays for all 48 human ABC transporters with chemosensitivity information mined from the NCI-60 cancer cell line database. Predictions of transporter involvement in drug effect were validated in selected cases, and furthermore produced novel leads relating ABC transporter expression and chemoresistance or chemosensitivity.

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Connexins, Conduction, and Atrial Fibrillation

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

introductory paragraphs:

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.

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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., 2006. 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.

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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.

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

Comment

A nicely outline approach illustrating how various clinical data can be used to guide the development of genomic approaches that aid in the diagnosis of patients with LQTS and in their stratification for individualized pharmacological therapies.