Respiratory diseases occur as a result of interactions between genotype and environment. Environmental influences include allergens, irritants, smoking, environmental tobacco smoke (ETS), diet, nutrients, drugs, infections and injuries. When a single gene has a very high impact on the development of a disease, this disease is called a “monogenic disease” (figure 1). Examples of such diseases are cystic fibrosis (CF) and α1-antitrypsin deficiency, which are inherited in a classical “Mendelian” fashion, with recessive or dominant forms of the gene in question being passed from generation to generation. Other diseases are triggered mainly by major environmental exposures; examples include carbon monoxide poisoning, acute lung injury and acute respiratory distress syndrome (due to severe pneumonia or major trauma). However, in the most common lung diseases, such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis and sarcoidosis, both the genotype and the environment play major roles in disease susceptibility: these diseases are called “complex diseases”.

Humans have 23 pairs of chromosomes (one pair of sex chromosomes and 22 pairs of autosomes). This provides every human with two versions of each gene: one on the maternally inherited chromosome and one on the paternally inherited chromosome. The human genome includes 3.3 billion base (nucleotide) pairs (the “building blocks” of DNA) and more than 25 000 genes, which code for proteins that build cells and tissues, and enzymes that catalyse biochemical reactions within cells. The DNA sequence is more than 99% identical between different individuals; but this still leaves scope for more than 10 million potential differences or variations between the genomes of two humans. Variations in gene structure that occur frequently in a population (1% or more of people) are called polymorphisms, whereas genetic variations that occur infrequently (less than 1%) are called mutations. There are several forms of polymorphism, of which single-nucleotide polymorphisms (SNPs) are by far the most common. SNPs constitute a single base-pair change in the DNA sequence at a particular point, relative to the common or “wild type” sequence. SNPs in parts of genes that code for proteins can lead to a change in the amino acid sequence of the protein, affecting its structure and/or function.

There are several methods to study the genetic factors that contribute to the development of an individual’s specific characteristics (referred to as phenotypes; for example, height or lung function) or complex diseases, such as asthma and COPD. Linkage studies are performed in families: these are based on the tendency of genetic loci (the site on a chromosome at which one or several genes for a particular disease or trait are located) or alleles that are physically close to one another on a chromosome to be inherited together (this is known as genetic linkage). Once a genetic locus for the phenotype or disease of interest has been identified through linkage analysis, positional cloning is performed to further delineate the susceptibility gene(s). For many years, genetic linkage combined with positional cloning has offered a rational way of discovering gene mutations that cause monogenic diseases, such as CF. These searches have led to the discovery of rare mutations (present in less than 1% of the population) that alter the amino acid sequence of a protein and increase the risk of disease enormously (very high effect size) (figure 2).

In contrast, association studies begin with the polymorphism or mutation rather than with the disease. They are typically based on a case–control design ( i.e . “cases” – people with the disease – are compared with healthy control subjects) in which SNPs are tested for association with a specific phenotype or disease. In single-candidate gene association studies, only one or a few SNPs near or in the gene under study are investigated for association with the disease of interest, based on an a priori hypothesis concerning the possible function and role of the particular gene. In genome-wide association studies, hundreds of thousands of SNPs across the entire human genome are genotyped and tested for association with the phenotype or disease of interest in hundreds or thousands of individuals. Without an a priori hypothesis, genome-wide association studies identify common genetic variants (which are present in more than 5% of the population) that confer a small risk of disease (small effect size, typically with odds ratios of 1.1 to 2.0).

This chapter on genetic susceptibility to respiratory diseases is neither exhaustive nor complete, but is intended as an introduction to the exponentially growing field of genetics and genomics in respiratory medicine and science.

See the entire Genetic Susceptibility Chapter