Conclusions and future prospects

The monogenic diseases CF and α1-antrypsin deficiency are inherited in a recessive Mendelian fashion (i.e. mutations in both alleles are required for the disease to be present). However, the term ‘monogenic’ is an oversimplification, since the causal gene interacts both with other genes and with environmental exposures in the course of the disease. Indeed, several modifier genes influence the severity of the disease in CF, implicating gene–gene interactions in its development. Active and passive smoking have deleterious effects in subjects with α1-antitrypsin deficiency, implicating important gene–environment interactions in the pathogenesis of panlobular emphysema.

The most common chronic respiratory diseases – asthma and COPD – are complex airway diseases that result from interaction between multiple environmental exposures and many genetic risk factors. Thanks to the development of novel, powerful tools for genetic studies, many genetic loci have been discovered that are associated with asthma, allergy, smoking behaviour, lung function and COPD. Despite the impressive advances in the genetics of asthma and COPD in the past decade, major challenges remain. Firstly, a large proportion of the genetic variance in disease risk remains unexplained. Most genetic variants identified so far by genome-wide association studies confer relatively small increments in risk, and explain only a small proportion of familial clustering. The remaining, ‘missing’ heritability can be attributed to additional genetic variation as yet unidentified, including structural variation (e.g. copy number variation of genes) and rare sequence variation. Secondly, the biological pathways and molecular mechanisms involved in the pathogenesis of chronic airway disease need to be elucidated in order to translate these new genetic insights into better strategies for prevention and treatment.

Gene Gene name Gene function
HHIP Hedgehog-interacting protein Lung development
GPR126 G-protein-coupled receptor 126 Unknown
ADAM19 A disintegrin and metalloproteinase 19 Cell migration and adhesion, cell-matrix
AGER Advanced glycation end products receptor Receptor for danger signals,
pro-inflammatory gene activation
FAM13A Family with sequence similarity 13, member A Signal transduction
GSTCD Glutathione S-transferase, C-terminal domain
HTR4 5-hydroxytryptamine receptor-4 Receptor for serotonin, modulates
release of neurotransmitters
PTCH1 Patched 1 Receptor for HHIP, lung development
MMP15 Matrix metalloproteinase 15 Breakdown of extracellular matrix
TGFB2 Transforming growth factor-β2 Embryonic development
HDAC4 Histone deacetylase 4 Transcriptional regulation, cell cycle
progression and development
RARB Retinoic acid receptor, beta Transcriptional regulation, limits cell
Table 4 – Genes associated with lung function.

Current and future applications of genetic testing in respiratory medicine encompass screening (e.g. newborn screening for CF), antenatal diagnosis, early diagnosis and prediction of disease risk (e.g. risk of recurrent venous thromboembolism according to underlying inherited thrombophilia). Pharmacogenetic and pharmacogenomic applications will improve our ability to use drugs more effectively and with less risk (e.g. optimising the dosing of the anticoagulant warfarin according to the genetic constitution of the patient). Finally, this genetic revolution will lead to the discovery of novel causal pathways, guiding mechanistic research in respiratory diseases and revealing new therapeutic targets.

See the entire Genetic Susceptibility Chapter