Complex traits

Nicotine addiction and smoking

The locus encompassing the CHRNA3 and CHRNA5 (nicotinic acetylcholine receptor) gene cluster on chromosome 15q24–25 has been associated with nicotine dependence, as measured by the number of cigarettes smoked per day. This gene cluster has also been associated with smoking-related diseases such as peripheral arterial disease, lung cancer, COPD and emphysema. Whether the nicotinic acetylcholine receptor gene cluster confers an increased risk of developing smoking-related diseases such as COPD, emphysema and lung cancer, in addition to its major impact on smoking behaviour, is a matter of debate and intense investigation (figure 3).

Lung function

Asthma and COPD are classed as obstructive airway diseases. The ratio of a person’s forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) (i.e. the FEV1/FVC ratio) is an indicator of airflow obstruction; a reduced FEV 1 /FVC ratio is the primary criterion for defining airway obstruction. The first genome-wide association study of pulmonary function, performed in the Framingham Heart Study in the USA, identified SNPs near the HHIP gene on chromosome 4q31 that were associated with the FEV 1 /FVC ratio. Two large genome-wide association studies confirmed the HHIP locus and identified multiple novel loci associated with the FEV1/FVC ratio (table 4). Thanks to collaboration between two large scientific research consortia, CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) and SpiroMeta, 16 additional genetic loci have been shown to be associated with lung function, including RARB (retinoic acid receptor B). Since several identified genes (e.g. RARB and HHIP) play crucial roles in lung development by regulating branching morphogenesis (the development of the bronchial ‘tree’) during fetal life, the results of these genome-wide association studies suggest that genetic variations associated with lung development and growth might be important genetic determinants of lung function in childhood and adulthood, both in healthy subjects and in patients with airway disease (asthma and COPD).

See the entire Genetic Susceptibility Chapter