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Background Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering t...

This is the first of 2 review papers on genetics and genomics appearing as part of the series on “omics.” Genomics pertains to all components of an organism’s genes, whereas genetics involves analysis of a specific gene or genes in the context of heredity. The paper provides introductory comments, describes the basis of human genetic diversity, and addresses the phenotypic consequences of genetic variants. Rare variants with large effect sizes are responsible for single-gene disorders, whereas complex polygenic diseases are typically due to multiple genetic variants, each exerting a modest effect size. To illustrate the clinical implications of genetic variants with large effect sizes, 3 common forms of hereditary cardiomyopathies are discussed as prototypic examples of single-gene disorders, including their genetics, clinical manifestations, pathogenesis, and treatment. The genetic basis of complex traits is discussed in a separate paper.

Anderson-Fabry disease (AFD), a pleiotropic lysosomal storage disease, is a masquerader wearing multiple cloaks. It commonly mimics hypertrophic cardiomyopathy, expressing itself as left ventricular hypertrophy without outflow tract obstruction [(1–3)][1]. It often manifests with angiokeratoma

“If epidemiologists are compared with fishermen, causality is the big fish. It is elusive to find, difficult to catch, and claims to have measured it are often exaggerated.” Burgess et al. [(1)][1] were correct: establishing a cause-and-effect relationship is always challenging. In its purest

A paradigm shift toward biology occurred in the 1990s and was subsequently catalyzed by the sequencing of the human genome in 2000. The cost of deoxyribonucleic acid (DNA) sequencing has gone from millions to thousands of dollars with sequencing of one's entire genome costing only $1,000. Rapid DNA sequencing is being embraced for single gene disorders, particularly for sporadic cases and those from small families. Transmission of lethal genes such as associated with Huntington's disease can, through in vitro fertilization, avoid passing it on to one's offspring. DNA sequencing will meet the challenge of elucidating the genetic predisposition for common polygenic diseases, especially in determining the function of the novel common genetic risk variants and identifying the rare variants, which may also partially ascertain the source of the missing heritability. The challenge for DNA sequencing remains great, despite human genome sequences being 99.5% identical, the 3 million single nucleotide polymorphisms responsible for most of the unique features add up to 40 to 60 new mutations per person which, for 7 billion people, is 300 to 400 billion mutations. It is claimed that DNA sequencing has increased 10,000-fold while information storage and retrieval only 16-fold. The physician and health user will be challenged by the convergence of 2 major trends, whole genome sequencing, and the storage/retrieval and integration of the data.

This is the first of 2 review papers on genetics and genomics appearing as part of the series on "omics." Genomics pertains to all components of an organism's genes, whereas genetics involves analysis of a specific gene or genes in the context of heredity. The paper provides introductory comments, describes the basis of human genetic diversity, and addresses the phenotypic consequences of genetic variants. Rare variants with large effect sizes are responsible for single-gene disorders, whereas complex polygenic diseases are typically due to multiple genetic variants, each exerting a modest effect size. To illustrate the clinical implications of genetic variants with large effect sizes, 3 common forms of hereditary cardiomyopathies are discussed as prototypic examples of single-gene disorders, including their genetics, clinical manifestations, pathogenesis, and treatment. The genetic basis of complex traits is discussed in a separate paper.

The seminal discovery of the R403Q mutation in the beta-myosin heavy chain (MyHC) gene as a cause of hypertrophic cardiomyopathy (HCM) by Dr. Thierfelder’s group a decade ago (1) ushered in a new era in the molecular genetics of HCM. To date, over 120 mutations in 10 genes, all encoding sarcomeric proteins, have been identified in patients with HCM (2), leading to the notion that HCM is a disease of contractile sarcomeric proteins (3). Mutations in nonsarcomeric genes, mitochondrial genome and genes responsible for the triplet repeat syndromes also have been found in patients with HCM (2). Although no large-scale systematic search has yet been performed, the existing data suggest that mutations in the beta-MyHC, myosin binding protein-C (MyBP-C) and cardiac troponin T (cTnT) are the most common causes of HCM, collectively accounting for approximately 60% to 70% of all HCM cases (2). It has also become evident that the frequency of each particular causal mutation in the HCM population is relatively low (

OBJECTIVES Our objectives were to determine whether angiotensin-1 converting enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with the severity of coronary artery disease (CAD) and its progression/regression in response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. BACKGROUND Genetic factors are involved in susceptibility to CAD. Angiotensin-1 converting enzyme I/D polymorphism, which accounts for half of the variance of plasma and tissue levels of ACE, has been implicated in susceptibility to CAD and myocardial infarction (MI). METHODS Angiotensin-1 converting enzyme genotypes were determined by polymerase chain reaction (PCR). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. RESULTS Ninety-one subjects had DD, 198 ID and 75 II genotypes. The mean blood pressure, minimum lumen diameter (MLD), number of coronary lesions and total occlusions were not significantly different at baseline or follow-up among the genotypes. There was a significant genotype-by-treatment interaction for total cholesterol (p = 0.018), low-density lipoprotein cholesterol (LDL-C) (p = 0.005) and apolipoprotein (apo) B (p = 0.045). In response to fluvastatin therapy, subjects with DD, compared with those with ID and II genotypes, had a greater reduction in total cholesterol (19% vs. 15% vs. 13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%). Definite progression was less (14%) and regression was more common (24%) in DD as compared with those with ID (32% and 17%) and II (33% and 3%) genotypes (p = 0.023). Changes in the mean MLD and lesion-specific MLD also followed the same trend. CONCLUSIONS Angiotensin-1 converting enzyme I/D polymorphism is associated with the response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. Subjects with DD genotype had a greater reduction in LDL-C, a higher rate of regression and a lower rate of progression of CAD.

The genome continues to fascinate and humble its enthusiasts. Any major step in the ladder of scientific discoveries taken toward understanding the genome is soon overshadowed by newer discoveries. The large monotonous macromolecule that Friedrich Miescher, the discoverer of deoxyribonucleic acid (DNA), called the “nuclein,” has only 4 randomly repeating letters (1). This apparent simplicity misled scientists for about 75 years until the surprising discovery that the 4 randomly repeating nucleotides contained Johann Gregor Mendel's “elements of hereditary” (2). It was just as fascinating to discover that the “elements of hereditary” comprised

Objectives. We determined the influence of angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism on the extent of myocardial ischemia in patients with acute myocardial infarction. Background. The I/D polymorphism, which in part controls plasma and tissue expression of ACE, has been implicated in predisposition to myocardial infarction and ventricular remodeling. Methods. I/D genotyping, predischarge adenosine–thallium-201 perfusion tomography and radionuclide angiography were performed in 113 patients (72 men, 41 women) with a diagnosis of acute myocardial infarction. A subgroup of 96 patients also underwent coronary angiography. Results. Genotypes DD, ID and II were present in 27, 56 and 30 patients, respectively. There was no significant difference in the baseline characteristics of patients, total creatine kinase, peak MB fraction, Killip class, mean ejection fraction or the number of diseased vessels in patients with the DD, ID or II genotype. However, the size of the total and the reversible perfusion defects was greater in those with DD than in those with ID or II genotype (total defect size [mean ± SD] 33.7 ± 22.5%, 29.5 ± 19.2% and 22.2 ± 16.0%, respectively [p = 0.022]; reversible defect size 18.0 ± 16.0%, 12.1 ± 11.6% and 8.2 ± 7.8%, respectively [p = 0.006]). Occlusion of the infarct-related artery was also more common in patients with DD genotype (odds ratio 3.9, 95% confidence interval 1.4 to 11.0). Multivariate analysis showed that the I/D genotype was an independent predictor of perfusion defect size and patency of the infarct-related artery (p = 0.001). Conclusions. DD genotype was associated with a larger ischemic defect and occlusion of the infarct-related artery. Patients with DD genotype, having a larger ischemic defect, are expected to be at a greater risk for subsequent cardiovascular events. (J Am Coll Cardiol 1997;29:1468–73)

Since its initial description by two French pathologists more than a century ago [(1)][1], hypertrophic cardiomyopathy (HCM), a genetic model of cardiac hypertrophic response [(2)][2], has remained an intriguing disease that has fascinated clinicians and scientists alike. While it is easy to fathom

Genotype-phenotype correlation studies have shown that β myosin heavy chain (βMHC) mutations are determinants of frognosis in patients with hypertrophic cardiomyopathy (HCM). While Arg719Trp mutation is associated with a high incidence of sudden cardiac death (SCD) and an average life expectancy of 38 years, the Val606Met mutation is associated with a near normal life expectancy in the families studied here. However, it is unknown whether the prognostic significance of HCM mutations correlates with the degree of left ventricular hypertrophy (LVH) associated with each mutation. Accordingly, we determined the left ventricular mass index (LVMI) and the extent of LVH in 12 patients with the Arg719Trp mutation and five patients with the Val606Met mutation. Left ventricular mass was derived by the arealength method using 2-D echocardiograms and indexed for body surface area (BSA). Extent of LVH was determined using a semi-quantitative point score method that takes into account the extent of involvement of the septum, apex, and lateral wall of the left ventricle. The mean LVMI was 147.0 ± 36 g/m2 in patients with the Arg719Trp mutation and 111.7 ± 19 g/m2 in patients with the Val606 Met mutation (p = 0.020). Similarly the extent of hypertrophywas greater in patients with the Arg719Trp mutation than in those with the Val606Met mutation (5.92 ± 2.3 vs. 3.2 ± 1.5, respectively, p = 0.015). The mean septal thickness was also greater in patients with the Arg719Trp mutation than in those with the Val60 Met mutation, however, this was not statistically significant (2.03 ± 0.7 vs. 1.62 ± 0.26, p = 0.095). There was no difference in the mean BSA, age, or gender among the two groups of patients. In conclusion, HCM patients, due to a malignant mutation such as the Arg719Trp, have greater LVH than patients with a benign mutation such as the VaI606Met. These results indicate the grave prognosis of HCM mutations are associated with expression of greater hypertrophy. This provides an easily detectable clinical parameter to further stratify patients at risk of sudden death that are candidates for invasive interventions such as implantation of cardiac defibrillators.