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The burden of chronic obstructive pulmonary disease (COPD) is increasing and it is expected to become the third leading cause of death worldwide by 2030. Components of both nature and nurture are important in the development and progression ofCOPD, with themain risk factor in most of the developed world being tobacco smoke exposure (1). Yet about 25% of COPD occurs in people who have never smoked (2), with other environmental (occupational exposures and early-life infections) and genetic (personal and familial history of asthma) factors likely being important in this group.
Genetic factors are important contributors to disease risk and progression, and a large number of candidate gene studies have indicated that several genes are associated with COPD. However, these studies were not able to unequivocally point to causal genes or variants for COPD (3-5). The fact that COPD is a heterogeneous disorder comprising different phenotypes with components of airway obstruction, emphysema, bronchiectasis, and comorbidities, in addition to its occurrence in both smokers and never-smokers, complicates genetic research.
In recent years much effort has been put into unraveling the genetics of COPD (defined using lung function measurements). The first hypothesis-free genome-wide association studies (GWAS) have revealed HHIP, CHRNA3/5, and FAM13A loci to be associated with COPD defined as airway obstruction (FEV1/FVC , 70%) (6-8) and BICD110 (9) loci to be associated with the emphysema phenotype that is not captured by lung function alone, but using radiographic measures. Recent studies confirmed these findings and indicated that these genes in fact play a role in both COPD phenotypes (10), suggesting potential underlying shared genetics.
These studies have in common that the explained variance in COPD due to the identified genes is very low, only up to a few percent. This "missing heritability" in COPD has been ascribed to rare variants and to gene-by-environment interactions. Geneby- environment interactions underlying COPD can be either due to genetic susceptibility to cigarette smoking and other environmental exposures (e.g., passive smoke exposure and air pollution) or due to epigenetic modifications. Such epigenetic modifications do not change the DNA sequence, but refer to alterations in the accessibility of the DNA. By changing the accessibility...