Complex diseases


Using the candidate gene approach (discussed earlier in this chapter), many genes have been associated with asthma or asthma-related traits such as allergy and high concentrations of immunoglobulin E (IgE) in serum (table 2). Not all of these suspected asthma susceptibility genes have been replicated in multiple independent studies. One group of (allergic) asthma susceptibility genes is involved in innate immunity responses, encompassing pattern-recognition receptors, immunoregulatory cytokines and molecules involved in antigen presentation. A second group of asthma susceptibility genes are key players in T-helper type 2 (Th2)-cell differentiation and Th2- cell effector function. Th2 cells are T-lymphocytes that drive the production of allergic immunoglobulins (IgE) and the chronic airway inflammation in (allergic) asthma.

Linkage studies in families have discovered several novel asthma susceptibility genes that are expressed in epithelial cells and/or smooth muscle cells in the airways (table 2). Although the functional role of these asthma susceptibility genes is not yet fully understood, they are thought to be involved in maintaining the integrity of the epithelial barrier, airway remodelling and bronchial hyperresponsiveness. These asthma susceptibility genes indicate the importance of altered communication between the epithelium and the underlying smooth muscle cells in the pathogenesis of asthma.

The first genome-wide association study of asthma showed that multiple markers at chromosomal location 17q21, encompassing genetic variants of ORMDL3 and GSDMB, were strongly associated with childhood asthma. The association of the ORMDL3/GSDMB locus with early-onset asthma is further increased in children exposed to environmental tobacco smoke, implicating an interaction between gene and environment. In infancy, passive smoking does indeed significantly increase the risk of developing asthma. A large-scale genome-wide association study of asthma performed by the European GABRIEL consortium revealed that some genes involved in communication of epithelial damage to the adaptive immune system are susceptibility genes for asthma (table 2). This genome-wide association study of asthma confirmed the role of antigen presentation and of the Th2-cytokine gene IL13 (interleukin 13) in the pathogenesis of asthma. Many of these asthma susceptibility genes have been confirmed by the American EVE consortium. Finally, several loci have been linked to increased serum total IgE levels in genome-wide association studies. These are IL13, IL4R, STAT6 (signal transducer and activator of transcription 6), FCER1A (high-affinity Fc receptor for IgE) and HLA-DRB1 (a human leukocyte antigen).

Gene/locus Chromosomal
Gene name Mechanism
Candidate gene association studies
TLR2 4q31.3 Toll-like receptor 2 Pathogen recognition/
innate immunity
CD14 5q31.3 Cluster of differentiation 14:
monocyte antigen
LPS signalling
IL10 1q32.1 Interleukin-10 Anti-inflammatory/
regulatory T-cells
TGFB 19q13.2 Transforming growth factor-β Anti-inflammatory/
airway remodelling
HLA-DR 6p21.32 Human leukocyte antigens Antigen presentation
HLA-DQ 6p21.32 Human leukocyte antigens Antigen presentation
HLA-DP 6p21.32 Human leukocyte antigens Antigen presentation
IL4 5q31.1 Interleukin-4 Th2 responses/IgE
IL13 5q31.1 Interleukin-13 Mucus production/IgE
IL4R 16p12.1 Interleukin-4 receptor Th2 responses/IgE
STAT6 12q13.3 Signal transducer and
activator of transcription 6
Transcription factor (Th2
Genome-wide association studies
ORMDL3 17q21 Orosomucoid like 3 Unknown
IL2R 10p15.1 Interleukin-2 receptor T-cell proliferation Th1
IL18R1 2q12.1 Interleukin-18 receptor 1 T-cell proliferation Th1
IL13 5q31.1 Interleukin-13 Mucus production/IgE
IL33 9p24.1 Interleukin-33 Innate immunity/danger
Linkage studies and positional cloning
ADAM33 20p13 A disintegrin and
Airway remodelling/
DPP10 2q14.1 Dipeptidyl peptidase 10  
GPRA   G-protein coupled receptor for
asthma susceptibility
Table 2 – Genetic susceptibility to asthma. This is a partial list of selected genes intended as an illustrative example of genetic susceptibility to asthma. LPS: lipolysaccharide; Th: T-helper type 2; IgE: immunoglobulin E. #: p refers to the short arm of the chromosome. q refers to the long arm of the chromosome. The location numbers after p and q reflect the relative distance to the centromeres of the chromosomes (numbering by convention).

Chronic obstructive pulmonary disease and emphysema

Since only about 20% of smokers develop COPD, genetic risk factors are thought to be involved in the pathogenesis of the disease. The best known genetic risk factor for emphysema is α1-antitrypsin deficiency, implicating an imbalance of protease (neutrophil elastase) and antiprotease (α1-antitrypsin) in the pathogenesis of the disease. Two meta-analyses of candidate gene studies in COPD concluded that only a few other COPD susceptibility genes have been firmly identified. These include TNFA (tumour necrosis factor-α), TGFB1 (transforming growth factor-β1), GSTP1 and GSTM1 (glutathione S-transferases P1 and M1), and SOD3 (superoxide dismutase 3).

Genome-wide association studies in COPD have identified three major susceptibility loci: the FAM13A locus on chromosome 4q22, the locus near HHIP on chromosome 4 and the CHRNA3/CHRNA5 locus on chromosome 15 (see the nicotine addiction and smoking section later in this chapter). Recently, several of the genetic determinants of lung function, encompassing genes involved in lung development and growth, such as HHIP (hedgehog-interacting protein), have been confirmed as genetic risk factors for COPD (see the lung function section later in this chapter).

Since there are some similarities between the disease phenotypes and pathophysiological pathways of asthma and COPD, several susceptibility genes are suspected to be common to both diseases, whereas other susceptibility genes will be specific to asthma or COPD. Both asthma and COPD are very heterogeneous diseases with multiple distinct phenotypes, suggesting that the degree of overlap between the genetic susceptibilities will depend on the asthma or COPD phenotypes examined. Using the candidate gene approach, several genes, such as TNFA , TGFB1 , MMP12 (matrix metalloproteinase 12)  and ADAM33, have been implicated as susceptibility genes for both asthma and COPD. Common pathogenetic pathways in airway inflammation and remodelling might explain this common genetic susceptibility. Some genes, such as IL13, have been specifically associated with allergy and allergic asthma, but not with COPD. In contrast, SERPINE (serine protease inhibitors) genes such as that for α1-antitrypsin have been specifically implicated in the pathogenesis of emphysema, an important phenotype of COPD.

Pulmonary fibrosis

Although the cause of pulmonary fibrosis is unknown (i.e. it is idiopathic), it is estimated that 0.5–2.0% of cases of idiopathic pulmonary fibrosis (IPF) are familial. Several mutations and polymorphisms in different genes have been shown to increase susceptibility to IPF: mutations in TERT (the telomerase reverse transcriptase gene), the catalytic subunit of the telomerase enzyme; mutations in TERC (the telomerase RNA component gene); and a promoter mutation in the MUC5B gene, which codes for the mucin B protein. A polymorphism in the SFTPA1 gene encoding pulmonary surfactant protein A1 influences susceptibility to IPF in nonsmokers, and a mutation in the SFTPA2 gene encoding pulmonary surfactant protein A2 can cause IPF.


Sarcoidosis is suspected to be caused by a combination of environmental exposure to a still-unknown agent (e.g. a microorganism or inorganic material) and genetic susceptibility. Class II molecules of the major histocompatibility complex (MHC), also called human leukocyte antigens (HLA), are cell surface proteins that present processed foreign antigens to T-lymphocytes. These T-lymphocytes are then stimulated to become effector cells of adaptive immune responses. There is a high degree of polymorphism in class II MHC genetic loci.

Variation in the HLA-DRB1 gene on chromosome 6p21.3, affecting antigen presentation to T-lymphocytes, is a major contributor to susceptibility to sarcoidosis (the locus is called susceptibility locus for sarcoidosis 1 (SS1)). The second susceptibility locus for sarcoidosis, SS2, is on chromosome 6p21.32 and is associated with variation in the BTNL2 (Butyrophilin-like protein 2) gene, which may regulate T-cell activation. The strongest association signal from a genome-wide association study for sarcoidosis mapped to the ANXA11 gene, belonging to the annexin family, on chromosome 10q22.3.

Genetic variation of another MHC class II molecule, HLA-DPB1 , has been shown to confer susceptibility to sarcoidosis and chronic beryllium disease, a hypersensitivity disorder of the lung caused by exposure to beryllium (used in diverse industries such as aerospace). Both sarcoidosis and chronic beryllium disease are characterised by chronic adaptive immune responses, leading to the formation of granulomas in the lung and lymph nodes.

Respiratory infections and pneumonia

Genetic factors can increase the risk of respiratory infections, including acute bronchitis and pneumonia. Most often, genetic polymorphisms underlie vulnerability to recurrent infections, but in rare cases monogenic defects are responsible (table 1). Repeated respiratory infections can be precipitated by structural defects of the lungs (e.g. bronchiectasis due to CF or PCD) or by genetic defects in the immune system. This defence system can be divided into the innate immune system, which recognises broadly conserved, generic structures of microbes via cell surface receptors (called pattern-recognition receptors), and the adaptive immune system, which recognises specific parts of microbial structures via very specific receptors on T-cells (which produce cytokines) and B-cells (which produce immunoglobulins (Ig)). These immunoglobulins, also called antibodies, are present in serum (e.g. IgM and IgG) and in sputum (IgA).

A disorder characterised by impaired immune responses towards infectious agents is called an ‘immunodeficiency’. This can be either inherited or acquired (e.g. acquired immune deficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV)). Numerous genetic defects can impair the host’s immune response to infection, leading to inherited immunodeficiencies. Genetic defects in innate immunity lead to several groups of immunodeficiencies. Firstly, chronic granulomatous diseases (table 1) are caused by immunodeficiencies due to impaired intracellular killing of microbes within phagocyte cells (neutrophils and macrophages). Secondly, defective recognition of microbes caused by genetic polymorphisms or mutations in pattern-recognition receptors can increase the risk of infection by particular micro-organisms. Deficiency of Toll-like receptor 3 (TLR3), which recognises double-stranded RNA, confers susceptibility to viral infections (e.g. herpesvirus), whereas deficiency of TLR5, which recognises flagellin, increases the risk of Legionella infections (e.g. pneumonia due to Legionella (Legionnaires’ disease)). Lastly, the common deficiency of mannose-binding lectin, which activates complement, increases the risk of infections with bacteria and fungi.

Genetic defects in adaptive immunity can affect the development and function of B-cells, leading to decreased levels of immunoglobulins (e.g. IgA deficiency), or of T-cells, impairing cellular immunity and predisposing to opportunistic infections. The most severe cases of inherited immunodeficiency are already apparent in infancy and are caused by impairment of both B- and T-cell immunity (e.g. X-linked severe combined immunodeficiency syndrome (SCID)).


One-third of the global population is latently infected with Mycobacterium tuberculosis. Exposure to M. tuberculosis can lead to asymptomatic ‘latent’ infection or to overt clinical tuberculosis. Why only 10% of individuals infected with M. tuberculosis develop active disease is not known, but variation in many genes has been associated with susceptibility to, or resistance against, M. tuberculosis (table 3). These genetic variants encompass a spectrum from causal susceptibility in rare cases, to very mild predisposition in the general population.

Lung cancer

Smoking is a major risk factor for lung cancer, and several studies have shown that a first-degree family history of lung cancer confers an approximately two-fold increased risk of lung cancer, implicating a familial aggregation of lung cancer. Genome-wide association studies have identified a region on chromosome 15 (15q25.1), containing the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, that is associated with nicotine addiction (i.e. number of cigarettes smoked per day) and lung cancer. Whether genetic variation in the nicotinic acetylcholine receptor increases the risk of lung cancer only indirectly via nicotine addiction or whether it also influences the lung epithelium directly in pulmonary carcinogenesis, is currently the subject of intense investigation (figure 3).

Gene/locus Location# Name of gene or locus Mechanism
Susceptibility to tuberculosis
CISH 3p21.2 Cytokine-inducible SH2-
containing protein
Adaptive immunity
CD209 19p13.2 DC-SIGN: membrane lectin
receptor of dendritic cells
Pathogen recognition/
cell adhesion
MCP1 17q12 Monocyte chemotactic protein 1
or CCL2
VDR 12q13.11 Vitamin D receptor Innate and adaptive
MTBS1 2q35 M. tuberculosis susceptibility
locus 1
MTBS2 8q12-q13 M. tuberculosis susceptibility
locus 2
MTBS3 20q13.31-q33 M. tuberculosis susceptibility
locus 3
Protection against tuberculosis
TIRAP 11q24.2 TIR domain-containing adaptive
TLR4 signalling
IFNG 12q15 Interferon-γ Th1 adaptive immunity
IFNGR1 6q23.3 Interferon-γ receptor 1 Th1 adaptive immunity
Table 3 – Genetic susceptibility to, or protection against, Mycobacterium tuberculosis. This is a partial list of selected genes and loci intended as an illustrative example of genetic susceptibility to tuberculosis. #: p refers to the short arm of the chromosome. q refers to the long arm of the chromosome. DC-SIGN: dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin; CCL2: chemokine ligand 2; TIR: Toll/IL1R; TLR4: Toll-like receptor 4; Th1: T-helper type 1.

Both in small cell lung cancer and in nonsmall cell lung cancer, numerous somatic mutations and chromosomal aberrations have been described within the tumour cells. However, a detailed description of these is beyond the scope of this chapter. We refer the interested reader to one of the excellent reviews that are available on the genomics of lung cancer (see Further reading).

Pulmonary embolism

Most pulmonary embolisms arise from blood clots in the deep veins (i.e. deep vein thrombosis) of the legs. Risk factors for deep vein thrombosis and acute pulmonary embolism include immobilisation, surgery, stroke, malignancy, obesity and pregnancy, but also genetic susceptibility. If the former risk factors are absent (i.e. unprovoked venous thromboembolism), or if there is a positive family history of deep vein thrombosis or pulmonary embolism, then an inherited thrombophilia, or hypercoagulable state, should be suspected.

The most common inherited hypercoagulable state is due to a mutation in the coagulation factor V gene (called the factor V Leiden mutation), which causes resistance to the anticoagulation factor, activated protein C. Heterozygosity (one copy of the mutated gene) for the factor V Leiden mutation is present in approximately 5% of a Caucasian population, and homozygosity (two copies of the mutated gene) in 1%. Homozygotes for the factor V Leiden mutation have a more than two-fold increased lifetime risk of developing deep vein thrombosis, with or without pulmonary embolism. Other inherited thrombophilias include a mutation in the prothrombin gene (coagulation factor II), antithrombin (ATIII) deficiency, protein C deficiency and protein S deficiency. Deficiencies of these anticoagulation factors increase the lifetime risk of venous thromboembolism seven- to eight-fold. Use of oral contraceptives (mainly third-generation oral contraceptives) is associated with an increased risk of venous thromboembolism, especially in heterozygote and homozygote carriers of the factor V Leiden mutation, implicating a gene–environment interaction.

See the entire Genetic Susceptibility Chapter