Case-control association studies for the genetics of complex respiratory diseases.

Abstract

In this issue of the Red Journal, Maliarik and colleagues present a case-control association study that examines the relationship between several polymorphic markers within the natural resistance‐associated macrophage protein (NRAMP1) gene and sarcoidosis. Sarcoidosis is a chronic granulomatous disorder of unknown cause, which is likely a “complex” disease (1). The principal distinction between simple monogenic diseases and complex genetic diseases is that the latter do not exhibit classical Mendelian patterns of inheritance and are likely influenced by multiple genetic and environmental factors (2). Many other respiratory illnesses, such as asthma and chronic obstructive pulmonary disease, are also complex diseases (3, 4). Understanding the genetic basis of complex human diseases has been increasingly emphasized as a means of achieving insight into disease pathogenesis, with the ultimate goal of improving preventive strategies, diagnostic tools, and therapies. Genetic approaches to complex disorders thus offer great potential to improve our understanding of their pathophysiology, but they also offer significant challenges. Genetic association studies have been applied in a variety of complex respiratory diseases, and the application of this study design could greatly increase with continued progress in the Human Genome Project and the Single Nucleotide Polymorphism (SNP) Consortium (5). In this Perspective, we will discuss the application of genetic association studies to complex respiratory disorders, review several potential problems with the case-control approach, and provide a strategy for evaluating case-control genetic association studies. Genetics of Complex Diseases Two types of statistical methods have been widely employed to attempt to identify genetic determinants of complex diseases—linkage analysis and association studies. Linkage analysis methods attempt to identify a region of the genome that is transmitted within families along with the disease phenotype of interest. Linkage analysis has been extremely useful in the identification of genes responsible for diseases with simple Mendelian inheritance, such as cystic fibrosis (6). The application of linkage analysis to complex disorders without obvious Mendelian inheritance has been much less successful because complex diseases are most likely influenced by genetic heterogeneity (multiple genetic causes leading to the same disease), environmental phenocopies (purely environmental forms of the disease), incomplete penetrance (subjects inheriting a disease gene but not developing the disease), genotype-by-environment interactions (nonadditivity of genetic and environmental influences on disease development), and multilocus effects (more than one gene influences disease development) (7). Despite these difficulties, multiple regions of the genome have been recurrently identified by linkage analysis as likely to contain asthma susceptibility genes. For sarcoidosis, linked regions have not yet been identified. Two general approaches have been used to investigate the molecular genetics of complex diseases: candidate gene approaches and whole genome screens followed by positional cloning attempts. Candidate gene approaches can utilize either linkage analysis of highly polymorphic, short tandem repeat marker loci in the candidate region, or association of (usually bi-allelic) coding or noncoding polymorphisms within candidate genes.