The Human Genome and Asthma


Vol. 10 •Issue 10 • Page 46
The Human Genome and Asthma * The Human Genome and Asthma

By Lyle J. Palmer, PhD

Asthma is the most serious of the atopic diseases and has become epidemic, affecting more than 155 million individuals in the developed world. It’s the most common chronic childhood disease in developed nations,1 and it carries a very substantial direct and indirect economic cost worldwide.2

Asthma is a complex disease and probably has multiple environmental and genetic determinants.3 A positive family history of asthma and other atopic disorders is one of the strongest risk factors for asthma, increased airways responsiveness, lower respiratory symptoms and atopy.4-8 Twin studies have generally shown that concordance rates for asthma are significantly higher in identical twins than non-identical twins,9-11 indicating a significant heritable component.

The genetic causes of asthma have been increasingly emphasized over the last two decades as a means of better understanding disease pathogenesis, with the ultimate goal of improving preventive strategies, diagnostic tools and therapies.3,12 At the same time, the Human Genome Project has produced enormous quantities of biological information, and extensive catalogues of DNA sequence variants across the human genome have begun to be constructed.13

There are several ways in which asthma research and treatment will potentially benefit from the data and tools produced by the Human Genome Project. These include: gene mapping; candidate polymorphism association testing; pharmacogenetics; diagnostics and risk profiling; prediction of response to non-pharmacological environmental stimuli; and homogeneity testing and epidemiological study design.14

While only a few of these are currently areas of active research in asthma genetics, it’s likely that some or all will become relevant to investigations of the genetic susceptibility to allergic disease. Here we focus on two of these areas, gene discovery and pharamacogenetics.

FINDING GENES

The availability of a draft outline of the human genome will greatly assist the investigation of the complex inter-relationships between the genes comprising each individual’s version of the human genome and genetically programmed phenotypes such as asthma and allergy. “In silico” discovery of genes in large computer databases (so-called “data-mining” using bioinformatic tools) and the use of single nucleotide polymorphisms (SNPs) discovered as a by-product of the project for disease-marker association studies (See Sidebar) are two of the ways that the Human Genome Project will facilitate gene discovery in asthma.

There are clear benefits associated with early detection and clinical management in asthma. However, we currently have a limited ability to explain the causes of most asthma in children or adults. Most obvious avenues have been explored, yet our ability to predict asthma remains poor. The discovery of major susceptibility loci conferring susceptibility or protection to asthma will therefore offer new insights into the pathogenesis, risk definition and, ultimately, prevention of asthma. The characterization of the frequency of genes involved in determining asthma susceptibility in the general population will assist in further defining the exact biochemical mechanisms involved in the regulation of asthma and in setting the stage for public health interventions.

Finding genes is also the first step in quantifying gen etically adjusted environment-disease relationships in asthma (e.g., tobacco smoke exposure). The discovery of susceptibility loci for asthma will make possible future attempts to definitively quantify these relationships and thus to alter risk through early detection and intervention. This in turn will pave the way for future prospective and retrospective population studies.

Risk models refined and developed in large, population-based studies of disease-associated genes could in the future form either the basis for interventions before the onset of asthma (primary prevention) or the entry point for secondary intervention studies. Information derived from the Human Genome Project and from gene discovery programs in asthma may thus eventually directly modulate clinical response and management.

PHARMACOGENETICS

A number of pharmacological treatments have been developed for asthma. These treatments have a modest efficacy overall, due in part to widely variable individual responses to asthma drugs. A component of the complexity of the asthma phenotype is a highly variable response to pharmacological therapy among individual patients with asthma.15,16 Because of such variability, it’s clear that some of the substantial resources expended on asthma medication, estimated to exceed $3 billion per annum in the United States alone,2 would be better spent targeting those patients who would benefit the most. At present there are no proven methods of effectively predicting response and prospectively targeting asthma treatment.

An expanding area of interest in the application of SNPs to investigations of asthma pathophysiology is the stratification of populations by their genetically determined response to therapeutic drugs (“pharmacogenetics”). Ideally, we would be able to stratify a population into responders, nonresponders and those with adverse side effects.17 The ultimate goal of such stratification would be to improve the efficacy of drug-based interventions and to expedite targeted drug discovery and development. Pharmacogenetic initiatives are currently an area of very active research in asthma.15

Current research in asthma pharmacogenetics has highlighted associations between SNPs in the b-adrenergic receptors and modified response to regular inhaled beta-agonist treatments (e.g., albuterol).18-20 A variant within the 5-lipoxygenase gene has been suggested to predict the response to the anti-leukotriene ABT-761 in asthmatic subjects.21 Other work has found associations between a SNP in the histamine N-methyltransferase (HNMT) gene and asthma, and speculated that genetically determined differences in histamine metabolism may contribute to the response to therapy in asthma.22 Confirmation of these findings may mark the beginning of the clinical use of genotyping at an individual level as an adjunct to pharmacotherapy for asthma and many other disorders.

The sequencing of the human genome, pursued both by government and industry, is rapidly informing us as to genetic structure and diversity. The availability of a complete reference sequence for the human genome together with new advances in high-throughput genotyping, functional genomics, chemistry, proteomics and in bioinformatics and biostatistical genetics will likely accelerate the gene discovery process in complex human diseases such as asthma.

Dr. Palmer is a statistical geneticist whose background in cludes training in clinical epidemiology, genetics and biostatistics. He is on the faculty of Harvard Medical School, Boston, and also holds an adjunct appointment as a faculty member at the Medical School of Case Western Reserve University, Cleveland.

For a list of references, please call Sharlene Sephton at (610) 278-1400, ext. 1324, or visit Respiratory-care-sleep-medicine.advanceweb.com/mrreflist.html.

Genetic Polymorphism Discovery

An important component of the Human Genome Project that is currently the focus of intense research effort internationally is the discovery and utilization of genetic polymorphisms for genetic disease-marker association studies.

The simplest class of polymorphism derives from a single-base substitution of one nucleotide for another–a single nucleotide polymorphism (SNP; pronounced “snip”).1 SNPs are identifiable through a variety of techniques that exploit the known DNA sequence variant. SNPs may be found in coding or regulatory regions of a gene, and thus can directly affect gene function or expression.

The generation of SNP maps from high-throughput sequencing projects has continued to accelerate over the last decade2 with the hope that these data will facilitate the process of gene discovery in complex human disease. In addition to large government-sponsored projects in England, the United States and Japan, there are now several major industrial group efforts, a large academic-industry consortium effort, and a number of smaller academic programs devoted to large-scale SNP discovery. The result is the creation of SNP catalogues (e.g., see http://www.ncbi.nlm.nih.gov/SNP/) and improving technologies for SNP genotyping.

REFERENCES

1. Marth GT , Korf I, Yandell MD, Yeh RT, Gu Z, Zakeri H, et al. A general approach to single-nucleotide polymorphism discovery. Nat Genet. 1999; 23:452-56.

2. Palmer LJ, Cookson W. Using single nucleotide polymorphisms (SNPs) as a means to understanding the pathophysiology of asthma. Respiratory Research. 2001; 2:102-112.

–Lyle J. Palmer, PhD

About The Author