Although air pollution is well known to be harmful to the lung and airways, it can also damage most other organ systems of the body. It is estimated that about 500,000 lung cancer deaths and 1.6 million COPD deaths can be attributed to air pollution, but air pollution may also account for 19% of all cardiovascular deaths and 21% of all stroke deaths. Air pollution has been linked to other malignancies, such as bladder cancer and childhood leukemia. Lung development in childhood is stymied with exposure to air pollutants, and poor lung development in children predicts lung impairment in adults. Air pollution is associated with reduced cognitive function and increased risk of dementia. Particulate matter in the air (particulate matter with an aerodynamic diameter < 2.5 μm) is associated with delayed psychomotor development and lower child intelligence. Studies link air pollution with diabetes mellitus prevalence, morbidity, and mortality. Pollution affects the immune system and is associated with allergic rhinitis, allergic sensitization, and autoimmunity. It is also associated with osteoporosis and bone fractures, conjunctivitis, dry eye disease, blepharitis, inflammatory bowel disease, increased intravascular coagulation, and decreased glomerular filtration rate. Atopic and urticarial skin disease, acne, and skin aging are linked to air pollution. Air pollution is controllable and, therefore, many of these adverse health effects can be prevented.

Air pollution poses a great environmental risk to health. Outdoor fine particulate matter (particulate matter with an aerodynamic diameter < 2.5 μm) exposure is the fifth leading risk factor for death in the world, accounting for 4.2 million deaths and > 103 million disability-adjusted life years lost according to the Global Burden of Disease Report. The World Health Organization attributes 3.8 million additional deaths to indoor air pollution. Air pollution can harm acutely, usually manifested by respiratory or cardiac symptoms, as well as chronically, potentially affecting every organ in the body. It can cause, complicate, or exacerbate many adverse health conditions. Tissue damage may result directly from pollutant toxicity because fine and ultrafine particles can gain access to organs, or indirectly through systemic inflammatory processes. Susceptibility is partly under genetic and epigenetic regulation. Although air pollution affects people of all regions, ages, and social groups, it is likely to cause greater illness in those with heavy exposure and greater susceptibility. Persons are more vulnerable to air pollution if they have other illnesses or less social support. Harmful effects occur on a continuum of dosage and even at levels below air quality standards previously considered to be safe.

Exposure to household air pollution (HAP) from solid fuel combustion affects almost half of the world population. Adverse respiratory outcomes such as respiratory infections, impaired lung growth and chronic obstructive pulmonary disease have been linked to HAP exposure. Solid fuel smoke is a heterogeneous mixture of various gases and particulates. Cell culture and animal studies with controlled exposure conditions and genetic homogeneity provide important insights into HAP mechanisms. Impaired bacterial phagocytosis in exposed human alveolar macrophages possibly mediates several HAP-related health effects. Lung pathological findings in HAP-exposed individuals demonstrate greater small airways fibrosis and less emphysema compared with cigarette smokers. Field studies using questionnaires, air pollution monitoring and/or biomarkers are needed to better establish human risks. Some, but not all, studies suggest that improving cookstove efficiency or venting emissions may be associated with reduced respiratory symptoms, lung function decline in women and severe pneumonia in children. Current studies focus on fuel switching, stove technology replacements or upgrades and air filter devices. Several governments have initiated major programmes to accelerate the upgrade from solid fuels to clean fuels, particularly liquid petroleum gas, which provides research opportunities for the respiratory health community.

Background

Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.

Methods

We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.

Results

The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.

Conclusions

In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.