Field Of Human Genetics Research Articles

Personalized Medicine: Understanding Probabilities and Managing Expectations

Personalized medicine promises to represent a transformation in clinical care that will be ushered in by the unprecedented growth and development in the field of human genetics. Further examination of the scientific foundations of this new hope reveals a great number of challenges that lie ahead. While basic science research feverishly races to produce solutions, we continue to wait for the translation of deliverables. Products that have and will come to market may leave our clinical communities and systems exposed and unprepared. At each step, from basic science research to infrastructure development, a great deal of creativity and investment are required before the arsenal of more personalized tools can be assimilated into our current models of health care. This commentary seeks to share perspectives on the current status of personalized medicine from the vantage point of several potential investors, and integrate them into a common set of goals and understanding. We conclude that the stylized model of personalized medicine is more akin to a marketing tool than a literal prediction of the future.

Editorial: [Somatic Genome Variations: First Steps towards a Deeper Understanding of an Underappreciated Source of Biodiversity and Disease (Guest Editors: Y.B. Yurov and I.Y. Iourov)

Editorial: [Somatic Genome Variations: First Steps towards a Deeper Understanding of an Underappreciated Source of Biodiversity and Disease (Guest Editors: Y.B. Yurov and I.Y. Iourov)

The past, present, and future of direct-to-consumer genetic tests

Technological advances in the field of human genetics have resulted in a wave of discoveries of common DNA sequence variants that are associated with a risk of common complex diseases, such as heart attack, that account for a substantial proportion of morbidity, mortality, and health care costs in most contemporary populations. The overall predictive power of these sequence variants can be considerable, due to the high incidence of these diseases and the sheer number of associations that have been discovered. Health care providers have been slow to utilize this knowledge for preventative medicine. However, several companies have taken on a translational role by offering genetic tests based on these discoveries direct to consumers. In this paper, we review the current state and future prospects of such genetic tests, as scientists involved both in the discovery of disease associations and the development of genetic tests.

Pharmacogenetics guided anticoagulation

Advances in the field of human genetics has made it possible to develop prevention strategies for rare genetic disorders and to tailor pharmacotherapeutic approaches to anticoagulation and certain cancers. However, it is still not clear how genetic variations influence the risk and outcome of common diseases. Data from genome-wide association studies is just beginning to answer these questions. In contrast, pharmacogenetic knowledge is frequently not yet translated into clinical practice, even though in some cases, particularly regarding drugs used in treatment of thrombotic diseases (e.g., coumarines, platelet aggregation inhibitors), it is already known that testing for genetic variants prior to pharmacotherapy may help to prevent severe adverse drug reactions or avoid therapeutic failure. In this review, we address the potential impact that genetic alterations in the genes for vitamin K epoxide reductase and some cytochrome P450 variants may have on therapeutic strategies in anticoagulation.

Two kindred with x-linked recessive tuberculous mycobacterial disease: towards a genetic theory of infectious diseases

The observation that only a small fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. Although many studies have provided proof-of-principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. It is commonly thought that rare patients with multiple infections display Mendelian primary immunodeficiencies, whereas common infections in otherwise healthy patients reflect polygenic predisposition. However, patients cannot be ascribed to such discrete binary categories (rare v. common, multi-infected v. otherwise healthy), and we have previously documented various Mendelian traits predisposing to a single type of infection. For human genetics to establish a new paradigm, the genetic architecture of infectious diseases should be deciphered. Our laboratory tests the hypothesis that life-threatening diseases of childhood, typically in the course of primary infection, each result from a collection of highly diverse but immunologically related single-gene variations; whereas the corresponding infections in adults, typically caused by secondary infection or reactivation of latent infection, reflect a more complex predisposition. The genetic theory of infectious diseases has important clinical implications, paving the way to novel treatment, aimed at restoring the patients’ immunity to specific pathogens. The immunological implications are equally important, as studies of experiments of nature define the function of host defence genes in natura, i.e., in the setting of a natural ecosystem governed by natural selection. We will illustrate our endeavors in the field of human genetics of infectious diseases by relating the clinical investigation of patients from two unrelated kindreds with X-linked recessive susceptibility to tuberculous mycobacterial diseases.

Nurses transforming health care using genetics and genomics

Nurses are well positioned to incorporate genetic and genomic information across all aspects of the United States (U.S.) health care system. Nurses, the most trusted health professionals [1], make unique contributions to the field of human genetics and genomics and complement the work of other health care providers to improve the health of the public. Health care benefits greatly from the unprecedented and ongoing work elucidating the genetic/genomic basis of health, illness, disease risk, and treatment response. The progress in genetics and genomics is applicable to the entire spectrum of health care and all health professionals and as such to the entire nursing profession (2.9 million) [2] in the United States regardless of role, clinical specialty, or academic preparation. The majority of disease risk, health conditions and the therapies used to treat those conditions have a genetic and/or genomic element influenced by environmental, lifestyle, and other factors therefore impacting the entire nursing profession [3]. Nurses have intimate knowledge of the patient’s, family’s, and community’s perspectives; an understanding of biologic underpinnings; experience with genetic/genomic technologies and information; skills in communication and building coalitions; and most importantly, the public’s trust. Across the lifespan, nursing focuses on health promotion and disease prevention, which is an integral component of genetic/genomic health care practices. Awareness of nurses’ strengths and skills, together with the recognition that prevention is the hallmark of genetic/genomic health care, will inform public policymaking groups as they address issues that affect heath care practice in the area of genetics/genomics. Policy making process will be informed with new insights will be gained with inclusion of nurses and professional nursing organizations. These policies can facilitate the ability of U.S. health care systems to use genetic/genomic knowledge to promote health and manage disease.

Two kindred with x-linked recessive tuberculous mycobacterial disease: towards a genetic theory of infectious diseases

The observation that only a small fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. Although many studies have provided proof-of-principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. It is commonly thought that rare patients with multiple infections display Mendelian primary immunodeficiencies, whereas common infections in otherwise healthy patients reflect polygenic predisposition. However, patients cannot be ascribed to such discrete binary categories (rare v. common, multi-infected v. otherwise healthy), and we have previously documented various Mendelian traits predisposing to a single type of infection. For human genetics to establish a new paradigm, the genetic architecture of infectious diseases should be deciphered. Our laboratory tests the hypothesis that life-threatening diseases of childhood, typically in the course of primary infection, each result from a collection of highly diverse but immuno-logically related single-gene variations; whereas the corresponding infections in adults, typically caused by secondary infection or reactivation of latent infection, reflect a more complex predisposition.The genetictheory of infectiousdiseases hasimportant clinical implications, paving the way to novel treatment, aimed at restoring the patients’ immunity to specific pathogens. The immunological implications are equally important, as studies of experiments of nature define the function of host defence genes in natura, i.e., in the setting of a natural ecosystem governed by natural selection. We will illustrate our endeavors in the field of human genetics of infectious diseases by relating the clinical investigation of patients from two unrelated kindreds with X-linked recessive susceptibility to tuberculous mycobacterial diseases. The observation that only a small fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. Although many studies have provided proof-of-principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. It is commonly thought that rare patients with multiple infections display Mendelian primary immunodeficiencies, whereas common infections in otherwise healthy patients reflect polygenic predisposition. However, patients cannot be ascribed to such discrete binary categories (rare v. common, multi-infected v. otherwise healthy), and we have previously documented various Mendelian traits predisposing to a single type of infection. For human genetics to establish a new paradigm, the genetic architecture of infectious diseases should be deciphered. Our laboratory tests the hypothesis that life-threatening diseases of childhood, typically in the course of primary infection, each result from a collection of highly diverse but immuno-logically related single-gene variations; whereas the corresponding infections in adults, typically caused by secondary infection or reactivation of latent infection, reflect a more complex predisposition.The genetictheory of infectiousdiseases hasimportant clinical implications, paving the way to novel treatment, aimed at restoring the patients’ immunity to specific pathogens. The immunological implications are equally important, as studies of experiments of nature define the function of host defence genes in natura, i.e., in the setting of a natural ecosystem governed by natural selection. We will illustrate our endeavors in the field of human genetics of infectious diseases by relating the clinical investigation of patients from two unrelated kindreds with X-linked recessive susceptibility to tuberculous mycobacterial diseases.

Update to Soria et al.'s “F7 Gene and Clotting Factor VII Levels” (2005): Genetic Determinants of Quantitative Traits in Thrombotic Disease

The last 10 years have produced revolutionary advances in the field of human genetics, allowing a transition from the classical analysis of monogenic disorders to a new emphasis on the genetic basis of common disorders, such as thromboembolic disease. Thromboembolic disease is one of the most important causes of morbidity and mortality in industrialized nations and of great public health importance because of its high social and economic cost. Thus identification and characterization of specific loci and genes and the associated phenotypes involved in thrombotic risk will contribute to a greater understanding of the pathogenesis of this disease and will ultimately lead to the development of better diagnostic, prevention, and treatment strategies.

Towards individualized medicine: insights gained from genomic studies.

Advances in the field of human genetics have made it possible to develop specific management and prevention strategies for rare genetic disorders, and tailor pharmacotherapeutic approaches to anticoagulation and certain cancers. The role that genetic variation plays in influencing the risk and outcome of the most common diseases are still unclear. Data from genome-wide association studies is just beginning to answer these questions. We review the role of genome-wide association studies in the quest towards individualized medicine, and examine the promises and challenges that lie ahead.

Update to Soria et al.'s "F7 Gene and Clotting Factor VII Levels" (2005): Genetic Determinants of Quantitative Traits in Thrombotic Disease

Update to Soria et al.'s "F7 Gene and Clotting Factor VII Levels" (2005):Genetic Determinants of Quantitative Traits in Thrombotic Disease Itziar Arbesú and José Manuel Soria Keywords Thrombosis, Intermediate Phenotypes, Complex Disease, Quantitative Risk Factors, Quantitative Trait Loci, Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project, Factor VII Variability, F7 Gene, Bayesian Quantitative Trait Nucleotide (BQTN) Method The last 10 years have produced revolutionary advances in the field of human genetics, allowing a transition from the classical analysis of monogenic disorders to a new emphasis on the genetic basis of common disorders, such as thromboembolic disease. Thromboembolic disease is one of the most important causes of morbidity and mortality in industrialized nations and of great public health importance because of its high social and economic cost. Thus identification and characterization of specific loci and genes and the associated phenotypes involved in thrombotic risk will contribute to a greater understanding of the pathogenesis of this disease and will ultimately lead to the development of better diagnostic, prevention, and treatment strategies. Genetic Base of Thrombosis Disease Thrombosis is a complex disease that results from the interaction of genetic and environmental factors. The additive effect of genes is responsible for 61% of the variability in the susceptibility to thrombotic disease (Souto et al. 2000b), documenting the importance of genetic factors that influence this condition. Thus, in this genomic era, the search for genes involved in complex diseases, such as thrombophilia, is gaining momentum, as is the debate over gene-finding strategies (Rosendaal 2003; Souto 2003). To date, the vast majority of analyses of genetic factors in thrombotic risk have been based on population case-control studies to test for association between genetic variants in specific genes and risk of disease. Although such studies provide important indirect evidence of genetic effects, they have a number of statistical weaknesses. These problems illustrate how difficult it is to genetically dissect complex diseases, such as thrombosis, mainly because of the heterogeneity of the disease outcomes, in which multiple physiologic and metabolic pathways are [End Page 869] involved. A good way to better analyze these complex diseases is to look at measurable quantitative variation in phenotypes closely related to disease risk, known as intermediate phenotypes. These intermediate phenotypes have more power to localize and identify disease-related susceptibility genes than the examination of the highly complex disease outcome itself (Blangero et al. 2000). In this context, although the hunt for genes that influence thrombotic risk is still in its infancy, there are several examples of progress (Table 1). Click for larger view View full resolution Table 1. Results from the GAIT Genome Scan for Thrombosis-Related Phenotypes Quantitative Risk Factors for Thrombosis and Intermediate Phenotypes The physiological cascade that underlies the normal formation of thrombin and the pathological endpoint of thrombosis is complex; many components involved in the coagulation and fibrinolytic pathways are known. The risk of thrombosis is influenced not only by abnormalities in these systems but also by quantitative variation within what is considered the normal physiological range of these parameters. In addition, it is likely that pathways and proteins outside the coagulation system are also involved in the pathogenesis of venous thrombosis. Loci harboring genes that contribute to the patterns of variation in such phenotypes have been named quantitative trait loci (QTLs). Intermediate risk factors can be used jointly with disease status to search the genome for QTLs that pleiotropically affect both risk factor and disease (Blangero et al. 2003; Soria et al. 2000, 2002). [End Page 870] In this context, we designed the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project, the main objective of which is to identify the genetic factors that determine the variation of quantitative phenotypes and their relationship with venous thrombosis. From this study, based on extended pedigrees, we demonstrated significant genetic correlations between thrombosis and activated protein C resistance, homocysteine, tissue plasminogen activator, von Willebrand factor, and clotting factors VII, VIII, IX, XI, and XII, suggesting pleiotropic influences on these quantitative measures and risk of thrombosis (Souto et al. 2000a). On the other hand, case-control association studies, such as the Leiden Thrombophilia Study (LETS), have been useful for identifying several complex phenotypes that increase the risk of venous...

Recent advances in the genetics of autoimmune disease.

Extraordinary technical advances in the field of human genetics over the past few years have catalyzed an explosion of new information about the genetics of human autoimmunity. In particular, the ability to scan the entire genome for common polymorphisms that associate with disease has led to the identification of numerous new risk genes involved in autoimmune phenotypes. Several themes are emerging. Autoimmune disorders have a complex genetic basis; multiple genes contribute to disease risk, each with generally modest effects independently. In addition, it is now clear that common genes underlie multiple autoimmune disorders. There is also heterogeneity among subphenotypes within a disease and across major racial groups. The current crop of genetic associations are only the start of a complete catalog of genetic factors for autoimmunity, and it remains unclear to what extent common variation versus multiple rare variants contribute to disease susceptibility. The current review focuses on recent discoveries within functionally related groups of genes that provide clues to novel pathways of pathogenesis for human autoimmunity.

The single-nucleotide primer extension (SNuPE) method for the multiplex detection of various DNA sequences: from detection of point mutations to microbial ecology

Methods based on SNuPE (single-nucleotide primer extension) have become invaluable tools for the rapid and highly specific detection of point mutations and single-nucleotide polymorphisms in the field of human genetics. In the primer extension reaction, a DNA polymerase is used to label a specific primer hybridized to the target sequence by incorporating a single labelled ddNTP (dideoxynucleotide). This labelling provides not only information about the complementary nucleotide of interest in the opposite strand but also a semiquantitative analysis of the sequence targeted by the primer. Since several subdisciplines of microbiology increasingly require cultivation-independent molecular screening tools for elucidating differences between either strains or community structures based on sequence variations of marker genes, SNuPE offers a promising alternative to the existing tool box. The present review describes the method in detail and reports the state-of-the-art applications of this technique both in the field of nucleic acid detections in human genetics and in microbiology.

Cuba’s National Medical Genetics Program

Since first emerging in the late 1970s, the field of human genetics has advanced with extraordinary speed. In just thirteen years (1990 to 2003), the human genome project deciphered the code of life. Today, by detecting genetic predisposition to certain diseases, we can anticipate their appearance even before the onset of symptoms, and progress is being made toward creating so-called "personalized drugs" designed to fit an individual's genetic profile. Yet, these developments are far beyond the reach of the vast majority of people. Few countries have transformed the giant steps in human genetics into national policies, programs and services accessible to the general population.

Neural networks for genetic epidemiology: past, present, and future

During the past two decades, the field of human genetics has experienced an information explosion. The completion of the human genome project and the development of high throughput SNP technologies have created a wealth of data; however, the analysis and interpretation of these data have created a research bottleneck. While technology facilitates the measurement of hundreds or thousands of genes, statistical and computational methodologies are lacking for the analysis of these data. New statistical methods and variable selection strategies must be explored for identifying disease susceptibility genes for common, complex diseases. Neural networks (NN) are a class of pattern recognition methods that have been successfully implemented for data mining and prediction in a variety of fields. The application of NN for statistical genetics studies is an active area of research. Neural networks have been applied in both linkage and association analysis for the identification of disease susceptibility genes.In the current review, we consider how NN have been used for both linkage and association analyses in genetic epidemiology. We discuss both the successes of these initial NN applications, and the questions that arose during the previous studies. Finally, we introduce evolutionary computing strategies, Genetic Programming Neural Networks (GPNN) and Grammatical Evolution Neural Networks (GENN), for using NN in association studies of complex human diseases that address some of the caveats illuminated by previous work.

Immunology in natura: clinical, epidemiological and evolutionary genetics of infectious diseases

The field of human genetics of infectious diseases defines the genes and alleles rendering individuals (clinical genetics) and populations (epidemiological genetics) vulnerable to infection, and studies those selected by previous infections (evolutionary genetics). These disciplines--clinical, epidemiological and evolutionary genetics-delineate the redundant and nonredundant functions of host defense genes for past and present survival in natura--in natural ecosystems governed by natural selection. These disciplines, in other words, assess the ecologically relevant and evolutionarily selected roles of human genes and alleles in protective immunity to diverse and evolving microorganisms. The genetic dissection of human immunity to infection in natura provides unique immunological insight, making it an indispensable complement to experimental immunology in vitro and in vivo in plants and animals.

141st ENMC International Workshop Inaugural Meeting of the EURO-Laminopathies Project Nuclear Envelope-linked Rare Human Diseases: From Molecular Pathophysiology towards Clinical Applications 10–12 March 2006, Naarden, The Netherlands

EURO-Laminopathies is a European Commissionfunded research project, including 13 scientific group leaders in the fields of human genetics, clinical research, structural biology, molecular cell biology, and pharmaceutical industry, and one administrative manager from eight countries (Austria, France, Germany, Italy Israel, Spain, Switzerland and the United Kingdom). The consortium held its kick-off meeting as an International ENMC Workshop in Naarden on the weekend of March 10–12, 2006. The EURO-Laminopathies project aims at understanding the molecular mechanisms of laminopathies, which are rare human diseases linked tomutations in genes encoding nuclear envelope proteins, such as A-type lamins (LMNA), proteins involved in the post-translational processing of A-type lamins (ZMPSTE24), and lamin-binding proteins (EMD, LBR, LAP2). Laminopathies are clinically manifested after birth, can affect different tissues andprogressively develop during childhood or adolescence, often leading to early death. Efficient therapies have been hampered by the lack

Race and Genetics: Attempts to Define the Relationship

Many researchers working in the field of human genetics in the United States have been caught between two seemingly competing messages with regard to racial categories and genetic difference. As the human genome was mapped in 2000, Francis Collins, the head of the publicly funded project, together with his privately funded rival, announced that humans were 99.9 percent the same at the level of their genome. That same year, the National Institutes of Health (NIH) began a research program on pharmacogenetics that would exploit the .01 percent of human genetic difference, increasingly understood in racial terms, to advance the field of pharmacy. First, this article addresses Collins’ summary of what he called the ‘vigorous debate’ on the relationship between race and genetics in the open-access special issue of Nature Genetics entitled ‘Genetics for the Human Race’ in 2004. Second, it examines the most vexed (if not always openly stated) issue at stake in the debate: that many geneticists today work with the assumption that human biology differs by race as it is conceived through American census categories. It then presents interviews with researchers in two collaborating US laboratories who collect and organize DNA by American notions of ‘race/ethnicity’ and assume that US race categories of classification largely traduce human biogenetic difference. It concludes that race is a practical and conceptual tool whose utility and function is often taken for granted rather than rigorously assessed and that ‘rational medicine’ cannot precede a rational approach to addressing the nature of racial disparities, difference and inequality in health and society more broadly.

Maimon M. Cohen, PhD

Maimon M. Cohen, PhD

A Compendium of Inherited Disorders and the Eye

During the past two decades, our understanding of the molecular genetics of inherited eye diseases, their classification, and management has undergone a huge expansion as the field of human genetics has benefited from technological advances and increased interest by physicians and scientists in all fields. As a result, the amount of clinical and basic-science information on inherited systemic and eye diseases has become so large that general ophthalmologists, ophthalmic subspecialists, and physicians in other fields have found it difficult to keep up. This volume will act as a guide because it catalogues all the latest information about genetic diseases that involve the eye and presents it in a practical and accessible format. After an introductory chapter that reviews basic clinical and molecular-genetic principles, individual diseases and groups of diseases are listed alphabetically in order to make it as easy as possible to search for an entry. The material in each entry is a synthesis of numerous articles and reviews on the topic, accompanied by at least one high-quality illustration, at least one webpage of a patient support group or other organization related to the disease, and references that provide the original description of the disease, an excellent review, or useful illustrations. There is also a companion website containing electronic copies of all the illustrations to make it easy to use them in lectures. Health-care professionals who need immediate access to clinical and basic-science information on inherited systemic and eye diseases will find this volume indispensable.

Incorporating Single-Locus Tests into Haplotype Cladistic Analysis in Case-Control Studies

In case-control studies, genetic associations for complex diseases may be probed either with single-locus tests or with haplotype-based tests. Although there are different views on the relative merits and preferences of the two test strategies, haplotype-based analyses are generally believed to be more powerful to detect genes with modest effects. However, a main drawback of haplotype-based association tests is the large number of distinct haplotypes, which increases the degrees of freedom for corresponding test statistics and thus reduces the statistical power. To decrease the degrees of freedom and enhance the efficiency and power of haplotype analysis, we propose an improved haplotype clustering method that is based on the haplotype cladistic analysis developed by Durrant et al. In our method, we attempt to combine the strengths of single-locus analysis and haplotype-based analysis into one single test framework. Novel in our method is that we develop a more informative haplotype similarity measurement by using p-values obtained from single-locus association tests to construct a measure of weight, which to some extent incorporates the information of disease outcomes. The weights are then used in computation of similarity measures to construct distance metrics between haplotype pairs in haplotype cladistic analysis. To assess our proposed new method, we performed simulation analyses to compare the relative performances of (1) conventional haplotype-based analysis using original haplotype, (2) single-locus allele-based analysis, (3) original haplotype cladistic analysis (CLADHC) by Durrant et al., and (4) our weighted haplotype cladistic analysis method, under different scenarios. Our weighted cladistic analysis method shows an increased statistical power and robustness, compared with the methods of haplotype cladistic analysis, single-locus test, and the traditional haplotype-based analyses. The real data analyses also show that our proposed method has practical significance in the human genetics field.