Impact of Basic Research on Tomorrow's Medicine

Genetics of Asthma: A Review

DEFINING THE PHENOTYPE

To study the genetics of a disease, we must define the phenotype (observable features of the disease), and then classify individuals as affected or unaffected. A serious impediment to studying asthma genetics has been difficulty in defining the asthma phenotype.² Asthma is commonly defined as an inflammatory airway disease that is characterized by bronchial hyperresponsiveness (BHR) and variable airway obstruction.³ This definition incorporates the dominant clinical manifestations while

EVIDENCE FOR GENETIC CONTRIBUTION TO ATOPY AND ASTHMA

Evidence for a genetic contribution to atopy and asthma comes from family aggregation studies. Aggregation of disease in a family may be due to shared genetic or environmental factors; nevertheless, it is the first clue that a disease may be genetic. Relative risk (X) is the prevalence of the disease in first-order relatives of the affected individual compared to its prevalence in the general population. The higher the value of X, the greater is the genetic contribution to the disease. For

ASTHMA: A COMPLEX GENETIC DISEASE

Most genetic diseases discovered so far have been single-gene diseases, in which there is a simple relationship between a single gene abnormality and the disease phenotype (Fig 2). The relationship in single-gene diseases follows classic mendelian patterns of inheritance (ie, autosomal dominant, autosomal recessive, or sex-linked). Examples include cystic fibrosis and α₁-antitrypsin deficiency. However, many common diseases like asthma, hypertension, and diabetes are genetically “complex”

METHODS FOR IDENTIFYING DISEASE GENES

The approaches that can be used to identify disease genes include functional cloning, candidate gene approach, and positional cloning.

CONCLUSIONS

There has been tremendous effort worldwide to identify atopy and asthma genes. We are likely to see much more progress in the next few years. Progress in gene identification will come from both genome-wide searches and the candidate gene approach. Large population-based genome-wide searches are in progress worldwide,³⁶,¹⁰²,¹⁰⁵ while continuing research into the basic biology of asthma will point us to additional candidate genes. Identification of asthma genes will be just the beginning for

APPENDIX

Allele—one of the variant forms of a gene or marker found at a given locus.

Autosome—any chromosome other than the sex chromosome.

Candidate gene—one whose product has functional properties that make its involvement in disease causation likely.

Concordant—twin pair in which both members exhibit a certain trait.

Dominant—trait is manifested in the heterozygote.

Genetic heterogeneity—mutation in any one of several genes results in the identical phenotype.

Genotype—(1) the precise genetic makeup of the